Download REVIEW ARTICLE Biology and Pathogenesis of Lentiviruses

J. gen. ViroL (1989), 70, 1617-1639 Printedin Great Britain
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Key words: lentiviruses/pathogenesis/AIDS
R E V I E W ARTICLE
Biology and Pathogenesis of Lentiviruses
By O P E N D R A
NARAYAN
1,2. AND J A N I C E E. C L E M E N T S 1'2'3
1Division of Comparative Medicine, 2Department of Neurology and 3Department of Molecular
Biology and Genetics, The Johns Hopkins University School of Medicine, 720 Rutland Avenue,
Baltimore, Maryland 21205, U.S.A.
Lentiviruses are a family of retroviruses linked by similarities in genetic composition,
molecular mechanisms of replication and in biological interactions with their hosts. They are
best known as agents of slow disease syndromes that begin insidiously after prolonged periods of
subclinical infection and progress slowly leading to the degeneration of multiple organ systems,
cachexia and death. The viruses are species-specific in host range and several have been
recognized as pathogens of domestic animals, non-human primates and humans. The prototypes
of the family are the agents causing maedi-visna in sheep and infectious anaemia in horses.
These diseases have been known for several decades and studies on the biology of the viruses
have provided a fund of information that predicted most of the properties of their human
counterpart which was identified only 6 years ago as the aetiological agent of AIDS.
Lentiviruses persist indefinitely in their hosts and replicate continuously at variable rates
during the course of the lifelong infection. Persistent replication of the viruses depends on their
ability to circumvent host defences. In this respect the agents have evolved a repertoire of
strategies that surpass those of any other known pathogen. Studies on immunization have shown
that the viruses are poor immunogens for the induction of protective antibodies but this varies
among the virus families. The 'Achilles heel' of these viruses lies in their absolute dependence on
blood and tissue fluids for host-to-host transmission.
The viruses are tropic for macrophages in vivo and replication is regulated by non-structural
viral genes and by factors produced by the activated host cells. Clinical disease is related to virus
replication in macrophages and two types of disease are produced: primary disease, caused
directly by the lentivirus and secondary disease, caused by opportunistic agents.
Primary disease is the major pathological manifestation of infection in domestic animals and
is associated with the activation of virus replication in selective populations of macrophages
which are tissue-specific. Host and viral factors determine which populations will be involved in
the support of virus replication. Primary disease also occurs in humans and is exemplified by the
unique lesions in the brain, lungs and lymph nodes of patients with AIDS and AIDS-related
complex. Development of primary lesions is associated with the enhanced production of
cytokines that are produced partly by the macrophage and partly by the lymphocytes,
responding to antigens presented by the immunologically activated, infected macrophages.
Secondary disease (AIDS) is caused by opportunistic agents which proliferate as a result of the
loss of function of activated helper T lymphocytes. In humans, macaques and cats, these ceils are
highly susceptible to lysis by the respective viruses and/or by virus-infected macrophages under
cell culture conditions. Loss of the lymphocytes in vivo leads to profound immunosuppression.
Helper T lymphocytes of ungulate animals are not as sensitive to the specific lentivirus infecting
the animal and this correlates with the lack of secondary diseases in these animals.
INTRODUCTION AND HISTORICAL PERSPECTIVE
The biology of lentiviruses can be best grasped by comparing them to viruses that cause acute
transient disease. The classical viral infection consists of three phases of interaction between
parasite and host: dissemination of the agent to specific target cells following infection of the
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O. N A R A Y A N A N D J. E. C L E M E N T S
host, productive virus replication in the target cells and thirdly, the period of virus elimination.
The decline in virus replication in the third stage is associated with the mobilization of nonspecific and immunologically specific host defence mechanisms. Disease results either from
direct pathophysiological effects of virus replication in tissue cells or from immunopathological
consequences associated with virus elimination. In most cases, the sequence of these events is
complete within days to weeks, as seen in influenza, poliomyelitis, measles and mumps.
Furthermore, the immune responses associated with recovery from these infections can be
induced by vaccines that protect against disease. Successful vaccine prophylaxis has been
accomplished by various procedures including the use of live viruses with stably attenuated
virulence (e.g. measles virus), inactivated viruses (e.g. poliovirus) or viral subunits (e.g. surface
antigen of hepatitis B virus).
The infection and diseases caused by the human immunodeficiency viruses (HIV) are the
antithesis of this general concept of pathogenesis of viral disease. The incubation period of
months to years that precedes the onset of clinical AIDS, the chronic progressive nature of the
disease leading to cachexia and death, the diversity of organ systems affected and the failure of
people to recover from the infection emphasize that there is a marked difference between the
mechanisms of pathogenesis of HIV and those of viruses that cause acute disease.
This concept is new with respect to human infections but had been established more than 3
decades ago in the field of infectious diseases of domestic animals. The idea that viruses, like
certain intracellular bacteria, can cause a slowly progressive disease with prolonged periods of
subclinical infection was put forward originally by Bjorn Sigurdsson during his studies on two
slow diseases in sheep in Iceland (Sigurdsson, 1954). The first was scrapie (rida in Icelandic), a
slowly progressive degenerative disease of the brain. This is the prototype of a group of human
diseases that includes Creutzfeldt-Jakob disease, Gerstmann-Str/~ussler disease and kuru, and
which are caused by unconventional infectious agents thought to be devoid of nucleic acid
(Prusiner, 1982). The second was maedi-visna (maedi, laboured breathing; visna, paralysis and
wasting, in Icelandic) a pneumo-encephalitic disease complex, the prototype lentiviral disease,
caused by a conventional enveloped virus. Experimental studies in sheep showed that both
scrapie and maedi-visna agents replicated persistently but at a remarkably slow rate in infected
hosts. Clinical disease developed with gradual onset after an incubation period of months to
years and then followed a chronic protracted course. Disease was manifested by cachexia and
chronic neurological disease. The aetiological agent of scrapie is still uncharacterized in terms of
its genetic content but the causal agent of maedi-visna was shown to be a replication-competent,
non-oncogenic retrovirus that is unique in structure, morphogenesis, genetic composition and
molecular mechanisms of replication (reviewed in Narayan & Clements, 1988). Experimental
inoculation of sheep with maedi-visna virus reproduced the persistent infection and slowly
progressive disease with incubation periods that extended for months to years. Some animals
remained persistently infected throughout life, never becoming ill. Primarily because of this
slow pathogenic process, the aetiological agent of maedi-visna was named lentivirus (lentus,
slow, in Latin).
Lentiviruses of sheep are relatively common pathogens in most parts of the world but
explosive epizootics of the type seen in Iceland are rare (Dawson, 1980). The usual picture is that
infection is widespread but attrition from disease is relatively low. Few animals become ill and
these are usually adults that had been infected 2 to 3 years previously. Many virus strains have
been obtained from diseased sheep in different countries; these are closely related genetically
and antigenically but have varying degrees of genetic heterogeneity. Some of these genetic
properties are associated with distinct characteristics in cell culture (Querat et al., 1984). The
arthritis-encephalitis virus of goats (caprine arthritis-encephalitis virus, CAEV) is one such
virus which has genetic and biological properties that differ from those of maedi-visna virus
(Narayan et al., 1980, 1984; Roberson et al., 1982; Pyper et al., 1984). CAEV has a low virulence
for tissue cultures of sheep origin, is tropic for synovial tissues and has a unique interaction with
the immune system resulting in the failure to induce neutralizing antibodies. Some strains of
virus that cause pneumonia and arthritis in sheep in the United States have the general
properties of CAEV. In contrast, visna virus causes lytic infection in cell cultures of goats and
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Table 1. Summary o f the biological properties o f lentiviruses
Lentiviruses are host species-specific, exogenous, non-oncogenicretroviruses.
The viral genomecontains severalsmallgenes that regulate expressionof structural genes during virus replication.
The env gene encodes a single highly glycosylatedglycoproteinthat forms the virus envelope. This structure
contains determinants that bind virionsto receptorson cells and also cause cell fusion. It also contains multiple
determinants that induce neutralizing antibodies. Mutations in certain regions of this gene result in
rearrangement of these determinants and result in development of neutralization-escape mutants.
Lentiviruses are tropic for cellsof the macrophagelineage in vivo. Virus gene expression is curtailed to a minimum
degree in precursor cells and is increased when the cells become differentiated and/or immunologically
activated.
The viruses replicate continuously in vivo and escape host defences by a variety of mechanisms including
sequestration of neutralization epitopes by carbohydrate molecules, resistance to inactivation by proteolytic
enzymes, antigenic variation, infection in macrophages and enhanced infection in macrophages by nonneutralizing antibodies.
Lentivirus disease is characterized by a variable and often prolongedincubation period and a chronicprogressive
course. Disease is primaryor secondary.Primarydisease correlates with amplified virus replication in selective
populations of macrophages in different tissues; secondary disease is associated with loss of helper T cell
function and inability to cope with opportunistic pathogens.
sheep. It induces neutralizing antibodies in infected sheep and undergoes antigenic variation in
these animals. The lentiviruses of small ruminant animals can thus be segregated into two types,
with some overlapping properties using Icelandic visna virus and CAEV as the prototypes
(Narayan & Clements, 1988).
The virus that causes equine infectious anaemia (EIA) has recently been shown to have the
biophysical properties of lentiviruses although the pathogenicity of the agent has been known
for several decades (Vallee & Carre, 1904). EIA is the most important infectious disease of
horses and occurs throughout the world. Difficulty in the cultivation of field strains of this virus
has limited the biological characterization of these agents but transmission studies with tissue
homogenates have suggested differences in virulence among virus strains (Konno & Yamamoto,
1970). The EIA virus (EIAV) is a retrovirus (Crawford et al., 1978; Cheevers & McGuire, 1985)
and recent studies have shown it to be similar to the lentiviruses of sheep and goats with respect
to molecular organization and in many aspects of its biological interaction with the horse
(Gonda et al., 1986). These properties (Table 1) have been used as taxonomic criteria for
classifying EIAV and certain other retroviruses as lentiviruses. These latter agents include
newly identified immunodeficiency viruses of cats (Pederson et al., 1987), cattle (Van Der
Maaten et al., 1972; Gonda et al., 1987) and primates (Barr6-Sinoussi et al., 1983; Clavel et al.,
1986; Desrosiers & Letvin, 1987). The primate lentiviruses comprise HIV types 1 and 2 (HIV-1,
HIV-2), the simian immunodeficiency viruses ~(SIV) of Asian macaques (SIVmae)(Daniel et al.,
1985; Benveniste et al., 1986) and those of African monkeys [the African green monkey (SIVagm)
(Ohta et al., 1988), the sooty mangabey monkey (SXVsm)(Fultz et al., 1986; Murphey-Corb et al.,
1986) and the mandril (SIVm,d) (Tsujimoto et al., 1988)].
The lentiviruses of humans and macaques cause severe immunodeficiency in their natural
hosts, a property not shared by the viruses that infect ungulates. Aside from this, however, many
of the newly defined molecular and biological properties of HIV have been mirrored by similar
previous reports on viruses that cause maedi-visna in sheep, arthritis-encephalitis in goats
(Narayan & Cork, 1985; Narayan & Clements, 1988) and infectious anaemia in horses
(Cheevers & McGuire, 1985). In this review, we highlight the general characteristics of the
lentiviruses and illustrate points of congruence between the animal and the human agents. The
mechanisms of disease production are poorly understood but, given that lentivirus-host
interactions follow common pathways (Narayan et al., 1988), lessons learnt from the earlier
studies on animal lentiviruses may be applicable to a better understanding of current studies on
the human pathogens.
GENETIC STRUCTURE AND REPLICATION
The lentiviral genome, larger than that of oncogenic retroviruses, is a positive-stranded
polyadenylated RNA of 9000 to 10000 bp (Clements & Narayan, 1981; Harris et al., 1981 ;
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O. NARAYAN AND J. E. CLEMENTS
R coding exon
[ 5' LTR ]
[
[
gag
I
pol
tat
env
nef
3' LTR
rev
U3
['-
....
R
U5
I
l Enhancer
/ TAT/A!ap~ T r a n s -actm
" g responsive sequences (TAR)
Negative regulatory element
Fig. 1. The lentivirus DNA genome. The genomic organization of the DNA from HIV-1 and visna
virus genomes (Wain-Hobson et al., 1985; Ratner et al., 1985; Sonigo et al., 1985). The rectangles
delineate ORFs (except for the 5' and 3' LTRs), showing the proteins that are encoded. The lower left
part shows the organization of the LTR which is composed (5' to 3') of the U3, R and U5 regions.
Important enhancer/promoter and regulatoryelements reside in the U3 region. The cap site is situated
at the 5' end of the R region; this is the 5' terminus of all viral RNAs. The TAR element is present in
HIV (Rosenet al., 1985)and EIAV (Dorn & Derse, 1988)and is responsiveto the protein product of the
tat gene, shown in the figure as a dotted block (N).
Molineaux & Clements, 1983 ; Yaniv et al., 1985). Lentiviruses contain three structural genes
organized, 5' to 3', gag, pol and env, typical of all retroviruses (Fig. 1). In addition, the
lentiviruses have unique small open reading frames (ORFs) located between pol and env and at
the 3' terminus (Pyper et al., 1986; Davis et al., 1987; Sonigo et al., 1985). In HIV, visna virus
and EIAV, these ORFs code for regulatory proteins (Rather et al., 1985; Sanchez-Pescador et
al., 1985; Wain-Hobson et al., 1985; Rushlow et al., 1986; Derse et al., 1987). At both the 5' and
3' ends of the R N A (R region) are sequences that contain the cap site, the polyadenylation signal
and the termination signal for viral RNA transcription (Hess et al., 1986). Sequences at the 3'
end of the viral RNA in the U3 region contain the enhancer-promoter elements for initiation of
RNA transcription. The nucleotide sequence immediately downstream of the U5 region is
complementary to mammalian lysine tRNA and serves as a primer binding site for the synthesis
of minus strand viral D N A (Sonigo et al., 1985; Hess et al., 1986). Purine-rich sequences located
immediately upstream of these U3 sequences serve as the initiation site for the synthesis of plus
strand DNA.
In general, retroviruses have a strong requirement for dividing cells (Weiss et al., 1982); these
cells presumably provide optimal conditions for the synthesis of viral D N A and integration of
the proviral DNA. In contrast, lentiviruses replicate efficiently in non-dividing, end-stage cells
both in the animal and in cell cultures (Thormar, 1963). Rather than depend on cell division, the
lentiviruses require activation and/or differentiation of the host cell for productive replication
(Narayan & Cork, 1985). These physiological changes are associated with D N A synthesis that
may not necessarily result in cell division. Since these viruses utilize cellular enzymes to
complete the synthesis of viral D N A and since integration in the host cell genome is similar to
that of the oncogenic retroviruses, the lentiviruses must either provide additional virus-encoded
replication functions or must activate the non-dividing cells to synthesize proteins and other
factors that are required for D N A replication and integration. The effectors of these additional
functions are probably encoded by the lentiviral RNAs in the small ORFs unique to these
viruses.
The second major difference in replication between lentiviruses and oncogenic retroviruses is
the cellular location of synthesis of viral DNA. Synthesis of proviral D N A of the oncogenic
retroviruses take place in the cytoplasm of the infected cell (Weiss et al., 1982). In contrast, visna
virus replicates its proviral D N A almost exclusively in the nucleus (Haase et al., 1982). This may
be a common property of the lentiviruses and is probably linked to their ability to replicate in
non-dividing cells. Since the nucleus is the location of cellular D N A synthesis, the enzymes and
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cofactors necessary for this would be expected to be located there even when the cell is not
dividing. Thus, by replicating in the nucleus, the lentivirus may circumvent the need for the
dividing cell or even exert some function to stimulate expression of cellular enzymes required for
the completion of synthesis and integration of the viral DNA.
The DNA replication schemes of oncogenic retroviruses and lentiviruses are similar to each
other but they differ with respect to the ratio of linear to circular DNA synthesized during
replication. During replication of oncogenic retroviruses, both types of DNA can be detected
but the circular form predominates. It has recently been shown that the linear DNA is the
precursor to integrated DNA (Fujiwara & Mizuuchi, 1988). In contrast only a small proportion
of lentiviral DNA becomes circularized and only a small number of copies become integrated in
each infected cell CYaniv et al., 1985; Chiu et al., 1985). However, many more copies (100 to 200)
per cell are found as free linear dsDNA molecules in the nucleus of the infected cell (Clements et
al., 1979; Harris et al., 1981). In other retroviral systems, the integrated viral DNA is the most
efficient template for viral RNA transcription (Panganiban & Temin, 1983). In the case of
lentivirnses, it is not currently known whether transcription of the linear non-integrated DNA
also contributes to the large amount of viral RNA found in the infected cell (Somasundaran &
Robinson, 1988).
T R A N S C R I P T I O N A N D T R A N S - A C T I V A T I O N OF G E N E E X P R E S S I O N
In a similar way to oncogenic retroviruses, the lentiviruses utilize the eukaryotic cell
machinery to transcribe viral DNA into genomic RNA and mRNA. This is accomplished by
cellular RNA polymerase II. The U3 region of the virus genomes contain elements commonly
found in polymerase II promoters and transcription of lentivirus mRNA begins in the 5' long
terminal repeat (LTR). The region of the DNA to be transcribed by polymerase II contains the
nucleotide sequence TATA which is located upstream (5') with the initiation site of
transcription and is the recognition signal (promoter) for RNA transcription. Polymerase II
presumably binds to the viral DNA near the TATA box in the U3 region and RNA
transcription is initiated at the cap site located at the U3-R junction. Transcription proceeds
through the R-U5 region of the viral genome to the poly(A) site in the R region of the 3' LTR.
The RNA termination signal is found beyond the poly(A) site.
Lentiviruses have a more complex pattern of transcription than other retroviruses; lentivirusinfected cells contain at least five species of mRNA (Rabson et al., 1985; Muesing et al., 1987;
Davis et al., 1987). The full-length genomic RNA serves as the mRNA for the gag- and polencoded polyproteins. A single splicing event removes the gag andpol genes leaving a portion of
the genome that serves as mRNA for the envelope protein and the product of at least one of the
small ORFs betweenpol and env. Smaller mRNAs produced by multiple splicing events contain
the coding regions for both positive (tat and rev) and negative (3' ORF or nef) regulatory
proteins. The positively acting genes have been identified in HIV, visna virus, EIAV and SIV
(Hess et al., 1985; Sodroski et al., 1985; 1986b; Arya et al., 1987; Dorn & Derse, 1988) whereas
the negative regulatory genes are postulated by analogy to HIV (Guy et al., 1987; Ahmad &
Venkatesan, 1988).
The positive acting regulatory genes [tat and rev (previously art/trs) (Hess et al., 1985;
Sodroski et al., 1985, Cullen, 1986; Feinberg et al., 1986; Guy et al., 1987; Arya et al., 1987;
Knight et al., 1987; Dorn & Derse, 1988)] are transcribed in lentivirus-infected cells and are
required for viral replication. These small regulatory proteins have basic amino acid
compositions that suggest they may interact with nucleic acid. The tat proteins regulate
expression of the viral genome via the viral LTR by both transcriptional and posttranscriptional mechanisms (Sodroski et al., 1985; Cullen, 1986). The trans-activation of viral
gene expression may be responsible for rapid mobilization of the transcriptional machinery of
the cell that is essential for transcription of viral R N A . This results in rapid accumulation of
viral RNA in the infected cell. In cell culture systems, the trans-activation of virus gene
expression is associated with the highly productive and cytolytic replication that is typical of
lentiviruses.
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O. NARAYAN
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J . E. C L E M E N T S
The rev gene is required for viral replication in HIV and is translated from a second ORF in
the mRNA which codes for tat (Feinberg et al., 1986; Knight et al., 1987). The rev protein of
HIV suppresses splicing, resulting in the accumulation of genomic RNA, and is also required for
the translation of viral structural genes (gag, pol and env). The n e f g e n e of HIV acts negatively to
regulate genes which are under the control of the viral LTR (Guy et al., 1987). It is not clear
whether all lentiviruses have this gene. Thus, the small mRNAs are important for the complex
gene expression exhibited by these viruses and may also play a role in the restricted expression
observed in vivo.
Lentivirus infections in vivo are characterized by both latent and productive virus replication
in monocyte-macrophage cells and T4 lymphocytes (Popovic et al., 1984; Gendelman et al.,
1985, 1986). Cellular factors play important roles in the activation of viral gene expression and in
the shift from latency to productive replication. For example, a small number of monocytes from
visna virus-infected animals have viral RNA detectable by in situ hybridization, but no viral
proteins (Gendelman et al., 1985, 1986). Mature macrophages in target organs of the infected
animal have much higher levels of viral RNA and many of these cells also have viral proteins
(Gendelman et al., 1986). An analogous situation is found in HIV/SIV-infected T lymphocytes
from infected hosts. These cells are latently infected and must be activated or stimulated to
produce virus (Popovic et al., 1984). Studies on gene expression of HIV in T cells have shown
that a cellular factor in activated T lymphocytes is important for the transcriptional activity of
the HIV LTR (Nabel & Baltimore, 1987). Similarly, the LTR of visna virus becomes activated
by a factor produced by macrophages that are differentiated/activated by treatment with the
phorbol ester 12-O-tetradecanoylphorbol 13-acetate (Clements et al., 1988b). Thus, the
activated state of the lentivirus' host cell, be it lymphocyte or macrophage, provides factors that
are important in the shift of the viral life cycle from latency to a productive state.
VIRAL
ANTIGENS
The viral core is composed of three proteins, p16, p27 and p14 cleaved from a polyprotein
encoded by the gag gene. This gene is highly conserved among lentiviruses of each host species,
but to a lesser degree among viruses from different host species. (Roberson et al., 1982; Pyper et
aL, 1984; Chiu et al., 1985; Gonda et al., 1985, 1986). The p27 is the major core protein of the
virion and elicits a strong antibody response during infection. The antibodies are group-specific
and recognize a wide spectrum of viruses from a particular host species. The antibodies do not
protect against infection. Rather, their presence in serum is used as an index for infection. The
p14 is a highly basic protein that contains a repeated motif of cysteines (Cys-Xz-Cys-X9-Cys),
characteristic of retrovirus nucleic acid-binding proteins.
The pol gene encodes the RNA-dependent DNA polymerase (reverse transcriptase, RT) and
the endonuclease/integrase of the virus (Sonigo et al., 1985 ; Vigne et al., 1982). A viral protease
has been identified in the nucleotide sequence at the 5' end of the pol ORF.
The env gene encodes a single large polypeptide varying from l15K to 160K among the
various lentiviruses (Sonigo et al., 1985; Vigne et al., 1982). This protein becomes highly
glycosylated during synthesis and forms the envelope of the virus. It is processed into its final
form during assembly of the virions. The env gene of all lentiviruses contains the amino acid
sequence Arg-X-Lys-Arg which is present in all retroviruses (Sonigo et al., 1985). This
sequence represents the site of cleavage of the envelope glycoprotein into a hydrophilic outer
membrane protein and hydrophobic transmembrane portion.
The envelope glycoproteins oflentiviruses contain many biologically important determinants.
These include the determinants of virus-cell receptor interaction and virus-induced cell fusion
(Harter & Choppin, 1967; Lifson et al., 1986a, b; Sodroski et al., 1986a; Crane et al., 1988) and
also the epitope(s) that induce neutralizing antibodies (Scott et al., 1979). The envelope is highly
glycosylated; carbohydrate moieties in the protein protect the viruses from proteases, reduce the
affinity of neutralizing antibodies for the virus and in some cases sequester neutralizing epitopes
from the immune system (Huso et al., 1988). Some infected animals produce antibodies to these
epitopes in a sequential order during a course of several months; early post-infectious sera from
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these animals thus contain a narrow spectrum of antibodies whereas late sera contain a broad
spectrum. Other animals produce antibodies to all of the epitopes soon after infection (Narayan
et al., 1987). The implication of these reactions in selection of antigenically variant viruses are
discussed in the later section entitled PATHOGENESIS.
The nucleotide sequences comprising the gag and pol genes are the most highly conserved of
the lentivirus genes (Gonda et al., 1985) whereas the env gene is highly heterogeneous. The
latter is caused in part by point mutations that occur either at random or at specific sites with
subsequent accumulations during the replication of the viral nucleic acid (Clements et al.,
1988 a). These mutations arise as a result of the high intrinsic mutation rates (approximately 1 in
104) of retroviruses since the RT lacks editing functions. Mutations are associated frequently
with the development of neutralization-escape variants. Under the selective pressure of
antibodies described above, variants of visna virus, EIAV, and more recently HIV, have been
obtained easily (Narayan et al., 1981 ; Kono et al., 1973; Kono, 1988; Reitz et al., 1988).
MORPHOLOGY AND MORPHOGENESIS
The viruses are enveloped particles 80 to 100 nm in diameter with dense cylindrical cores
(Thormar, 1976; Dubois-Dalcq et al., 1976; Gonda et al., 1985). Each virus replicates optimally
in cell cultures (macrophages, T4 lymphocytes and/or fibro-epithelial ceils derived from its
natural host). Inoculation of virus into host macrophage cultures is followed by endocytosis of
the particles. The cells do not fuse 'from without'. Progeny virus is produced within cytoplasmic
vacuoles by budding off the vacuolar membrane and accumulating within the vacuole (Narayan
et al., 1982; Gartner et al., 1986). The cells develop a minimal c.p.e, during the first week or two
after inoculation. Eventually they develop extensive multinucleated giant cell formation,
exceeding that seen during normal ageing of macrophage cultures.
The viral life cycle is different in cultures of lymphocytes and fibroblasts. Inoculation of these
cells at a high multiplicity ( > 10) results in fusion of the cells 'from without' and degeneration
within 24 h without the production of virus particles. Inoculation at a lower m.o.i, results in
productive replication. The virus enters the cell by fusion with the plasma membrane and the life
cycle is completed in approximately 20 h. Maturation of the particles occurs by budding from
the plasma membrane (Dubois-Dalcq et al., 1976; Popovic et al., 1984) (in contrast to the
intracellular maturation of virus particles in macrophages). Multinucleated giant cell formation
occurs at the peak of virus production. The lymphoid/fibroblastic cell culture systems are much
more permissive for virus replication than for macrophage cultures.
PERSISTENT I N F E C T I O N
Infection by lentiviruses is followed by the indefinite persistence of the agents in cells of the
macrophage lineage. (Klatzmann et al., 1984; Ho et al., 1987; Narayan & Zink, 1988).
Integration of proviral DNA into stem cells may be a mechanism for maintining the virus in
these cells. The infection is not affected by neutralizing antibodies produced by the host
(Narayan et al., 1977a; Crawford et al., 1978; Fauci, 1988). Not only do the neutralizing
antibodies fail to cure infection but antibodies induced by inactivated virions or viral subunits
may or may not protect against infection. This depends on the particular lentivirus species
(Narayan et al., 1984). In fact, goats immunized with inactivated virus developed more severe
lesions after challenge (McGuire et al., 1986) (see under PATI-IOGENESIS.)Similar failure to
obtain protective immunity has been obtained subsequently in challenge studies of macaques
immunized with inactivated SIVma e (Letvin et al., 1987) and chimpanzees immunized with
HIV-1 (Nara et al., 1987). A continuous presence of the viral genome in monocyte-macrophage
cells and possibly lymphocytes is the basis for the infectious carrier status of the host. These cells
are important for virus dissemination because they are present in inflammatory exudates and in
secretions such as milk and semen (Ho et al., 1984; Narayan & Clements, 1988; Narayan et al.,
1988).
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I N C U B A T I O N P E R I O D OF THE D I S E A S E
The phenomenon of an incubation period of the disease that may extend for several years is
one of the main features of lentivirus infections. It is important to note however that the
incubation period is variable and, although unpredictable, it may extend from weeks at one
extreme to the remaining life span of the host at the other. In the latter case, the infected host
may remain clinically normal but is a continuous source of infectivity. Virus can be obtained at
any time by cultivation (and activation) of monocytes from peripheral blood or by explantation
of biopsied tissues (Narayan et al., 1977a, b).
Infectious anaemia in horses (Konno & Yamamoto, 1970), encephalitis in kid goats (Cork et
al., 1974) and AIDS in children (Connor et al., 1987; Epstein et al., 1984; Joshi et al., 1985) are
notable exceptions to the generalization of long incubation periods in lentivirus diseases.
Although EIA is best known as a chronic relapsing disease, experimental inoculation may result
in fulminant disease and death of the horse within 1 month. In goat herds endemically infected
with CAEV, kids born from infected mothers frequently develop encephalitic disease within
1 month of birth. These animals progress to paralytic disease by 6 weeks of age after the initial
development of ataxia at 2 to 3 weeks of age. In humans the majority of children born with HIV
develop AIDS within 2 years of age. Pneumonia (lymphoid interstitial pneumonia, similar to
mild maedi in sheep) and overt neurological disease are major forms of disease expression.
However, earlier signs such as failure to thrive and failure to achieve infantile developmental
landmarks indicate short incubation periods of disease. Early disease expression in both
children and goats may be associated with intrauterine infection, in addition to the exposure to
virus perinatally and in milk.
The end of the incubation period (i.e. the onset of disease) is unpredictable in all host species.
In humans, loss of antigenaemia frequently precedes the onset of AIDS. The only known
example of disease that can be induced artificially from a subclinical state is EIA; carrier
animals injected with steroids or subjected to stressful conditions have been reported to develop
an acute onset of the disease (Cheevers & McGuire, 1985). Steroids may interfere with host
mechanisms that maintain virus replication at a minimal level and thus potentiate enhanced
production of virus.
C L I N I C A L DISEASE
Disease in lentivirus-infected hosts may be primary, caused by the lentivirus, or secondary,
caused by opportunistic pathogens that proliferate unchecked as a result of the loss of helper T
lymphocyte function. In nature, the diseases of ungulate animals (horses, cattle, sheep and goats)
are of the primary category. These animals become cachectic with severe pathological
involvement of different organ systems. However, diseases caused by other organisms do not
occur to any noticeable degree (Konno & Yamamoto, 1970; Cheevers & McGuire, 1985;
Narayan & Cork, 1985). In contrast, humans (Ho et al., 1987; McArthur, 1988), macaques
(Chalifoux et al., 1984) and domestic cats (Pederson et aL, 1987) develop both primary and
secondary disease. Primary disease is seen as lymphadenopathy, pneumonia and neurological
impairment and the secondary disease is characterized by lesions pathognomonic for the
particular opportunistic organisms (protozoan, mycotic, bacterial or viral agents) as seen in
AIDS.
Specific diseases
Equine infectious anaemia
This disease may express itself as an acute syndrome that ends fatally within 1 month of
inoculation, or a chronic relapsing disease that ends in cachexia and chronic anaemia or to the
occurrence of infected carriers of the virus that never develop the disease (Konno & Yamamoto,
1970). Generally, inoculated horses develop clinical disease and this is characterized by
anorexia, fever and anaemia within 1 month. Horses that survive this attack recover 3 to 5 days
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later and remain clinically normal for weeks to months. A relapse of the disease with the same
transient duration of illness usually occurs within the same year. These cyclical recrudescences
of disease may occur three or four times, after which cycling stops and chronic wasting disease
sets in. Alternatively, the animal may remain clinically normal. In these latter animals, stressful
events or administration of corticosteroids may trigger the onset of a new cycle of disease. Acute
disease is characterized by haemolytic anaemia and haemorrhages and by necrosis of
parenchymal cells in the liver and lymphocytes in the spleen and lymphatic tissues. Animals
with chronic disease have chronic anaemia but only minimal parenchymal necrosis in visceral
organs. These animals develop lymphadenopathy (hyperplasia in the lymph nodes, spleen, etc).
Immune complex disease, manifest as glomerulonephritis and autoimmune haemolytic
anaemia, becomes pronounced during the late disease. Interestingly, the horse also develops
encephalitis characterized by gliosis and cuffing of cerebral blood vessels with mononuclear
cells (O. Narayan, unpublished observations).
The disease complex (maedi-visna) in sheep
For reviews, see Dawson (1980) and Narayan & Cork (1985). The main disease expression in
lentivirus-infected sheep is dyspnoea and severe loss of flesh. The disease is disseminated worldwide except in Australia and New Zealand from which it has been kept out by the restricted
importation of sheep. This may be coincidental because this disease complex rarely occurs
among free-range animals. The disease had occurred in epidemic form in Iceland following the
introduction of latently infected sheep from Europe during the 1930s. The Icelandic epidemic
described by Sigurdsson reached its peak in the 1950s and the disease was eliminated from the
Island by the slaughter of affected animals and prohibition of further importation of sheep. The
neurological disease, visna, occurred mainly among the pristine Icelandic sheep during the
maedi epidemic of the 1950s and usually occurred as a complication of maedi. Visna occurs
rarely among non-Icelandic sheep. Arthritis and mastitis also occur in sheep but vary in
incidence.
In all cases clinical disease is due to active-chronic inflammation in the particular organ or
tissue. Lesions are characterized by the proliferation and infiltration of mononuclear cells
including lymphocytes and macrophages. Normal tissue architecture is disrupted and
degenerates in the face of invasion by inflammatory cell populations. These histological changes
may be observed in the lung, brain and spinal cord, lymph nodes and spleen, joints and areas of
the glandular tissue of the mammary glands. In addition, nodular accumulation of lymphoid
cells are seen frequently in all affected tissues including those of the brain and lung.
The disease complex (arthritis-encephalitis--mastitis) in goats
For review, see Narayan & Cork (1985). The main expression of disease in goats is synovitis
and this occurs mainly in adult dairy animals. The gradual onset of synovitis and its slow
progression to crippling arthritis is similar, in its slow progression, to maedi in sheep. A sporadic
slowly progressive neurological disease among adult animals has also been observed in certain
goat populations in Sweden and Germany which is analogous to visna in sheep. Mastitis is also
highly prevalent in dairy goats. Newborn goats in endemically infected herds develop the
rapidly progressive paralytic disease described above. Similar to sheep, clinical disease is
associated with severe active-chronic inflammation in the affected tissues.
The disease complex in cattle
See Van Der Maaten et al. (1972). The original isolate of bovine immunodeficiency virus
(BIV) was obtained from a cachectic cow that had lymphadenopathy and mild encephalitis. A
similar virus was obtained from other animals that had persistent lymphocytosis. The virus was
propagated in bovine tissue cultures and shown to have the structural, genomic and biological
properties typical of lentiviruses. Calves were inoculated with tissue culture-propagated virus
which persisted throughout a 6 month observation period but did not cause a further
deterioration of health.
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A I D S in cats
See Pederson et al. (1987). The recently isolated feline immunodeficiency virus (FIV) is
distinct from the oncogenic retrovirus feline leukaemia virus (FeLV). Infection with FIV has
been associated with lymphadenopathy characterized by hyperplasia in the lymph nodes,
enteropathy and wasting. Infection with opportunistic agents occurs frequently and these
diseases complicate the pathological effects of the lentivirus. Preliminary studies in cats
inoculated with virus (cultivated in primary cultures of feline T cells) have shown that cats
become persistently infected and develop lymphadenopathy. None has developed AIDS as yet
during the 1½ years of observation.
The disease complex in humans
For references, see Fauci et al. (1985), Fauci (1988), McArthur (1988), Johnson et al. (1988)
and Price et al. (1988). The earliest symptom of HIV-induced disease is an influenza-like
syndrome that develops about 2 weeks after infection and which lasts for 2 to 3 weeks.
Symptoms include fever, sore throat, myalgia, arthralgia and macula-papular rashes. Recovery
from these symptoms is followed weeks to months later by lymphadenopathy, characterized by
follicular hyperplasia in the lymph nodes and spleen. Progressive loss of helper T lymphocytes
and their function frequently accompanies lymphadenopathy. Weeks or months later, these
signs progress gradually to the onset of AIDS. This is seen as loss in weight, diarrhoea and
infection with opportunistic pathogens. These diseases are exacerbated by the loss of function of
helper T lymphocytes. Oral thrush, enteropathy, generalized disease caused by cytomegalovirus,
pneumonia associated with Pneumocystis carini, toxoplasmosis, etc., are all parts of the
syndrome; neurological disease is a frequent manifestation of the opportunistic infections.
However, primary lentivirus-induced neurological disease also occurs frequently. The lesions
are characterized by gliosis, diffuse but mild deterioration of myelin, and in some cases by
multinucleated giant cells that resemble macrophages containing lentivirus particles. In
children, as discussed above, the onset of disease is relatively acute; lymphoid interstitial
pneumonia and encephalopathy are the major and most severe forms of the disease. Lesions in
the CNS may vary from microcephaly and atrophy of the brain to loss of neurons with microglial
nodule formation and multinucleated giant cells containing viral particles. Opportunistic
infections in the brain of children are rare. The disease complex in adults and children is caused
by both HIV-1 and HIV-2.
The disease in macaques
SIVma e is closely related genetically to HIV-2 and replicates efficiently in human T cells
(Daniel et al., 1985; Chakrabarti et al., 1987). Whereas neither HIV-1 nor HIV-2 is pathogenic
for macaques, SIVma c is highly virulent and causes disease in macaques similar to HIV-induced
disease in humans. The first clinical indication of infection in macaques after experimental
inoculation with SIVmaooccurs weeks to months later and is seen as focal cutaneous rashes in the
inguinal areas (Ringler et al., 1986) and onset of lymphadenopathy (Chalifoux et aL, 1987).
Clinical deterioration sets in with diseases caused by opportunistic organisms that include
protozoa (e.g. toxoplasma), bacteria (e.g. cryptosporidia and salmonella) and viruses (e.g.
adeno-, papova- and cytomegaloviruses) (King, 1986). Wasting disease sets in and is
accompanied by involution of the lymphatic system. Enteropathy occurs frequently and loss of
body fluids becomes life-threatening. The macaques do not develop neurological signs of disease
but frequently develop encephalopathy with neural lesions similar to those seen in brains of
patients with AIDS dementia (Letvin et al., 1985). However, lesions in the white matter of the
brain and spinal cord have been recognized only in humans. Multinucleated cells with lentivirus
particles are also seen in other affected tissues such as the lung and gastrointestinal tract.
Infection in African monkeys
There is a high prevalence of persistent infection in sooty mangabeys, African green monkeys
and mandrils by the lentiviruses SIV .... SIVagm and SIVmnd, respectively. However, there are no
reports that these viruses cause disease in these animals (Ohta et al., 1988; Fultz et al., 1986).
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NATURAL
HISTORY
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OF THE LENTIVIRUSES
Spread of lentiviruses in nature involves a complex bio-ecological system in which host,
parasite and a range of social and environmental problems interact. The viruses are
disseminated exclusively by exchange of body fluids. Any factors that facilitate such exchange
on a large scale have potentiated epidemics and epizootics. Such outbreaks of disease are usually
associated with some aspect of human socio-economic intervention.
Equine infectious anaemia virus
For review, see Cheevers & McGuire (1985). Infection in horses, mules, donkeys and other
equidae is followed by a highly productive phase of replication of the virus resulting in plasma
viraemia. This high concentration of infectious virus in plasma is unique among the lentiviruses.
Virus is spread by blood-sucking flies that act as mechanical vectors in the transfer of virus with
blood-contaminated mouth parts. It is the only lentivirus known to be spread by an insect vector.
This occurs at a very high rate when agricultural, sporting and military (in previous times)
events necessitated dense crowding of these animals during the summer months. The disease is
distributed world-wide.
Visna-maedi, progressive pneumonia or zwoegerziekte
For reviews, see Dawson (1980) and Narayan & Cork (1985). Maedi-visna developed in
Icelandic flocks following the introduction of European Karakul rams found in retrospect to be
latently infected with a lentivirus. These rams had been obtained from flocks that had no
previous history of the type of disease that broke out among the Icelandic animals. The severe
outbreak of maedi-visna was thought to be related causally to three factors: firstly, for centuries
the Icelandic sheep had been bred in isolation from other breeds and had become more
susceptible to lentivirus disease than European sheep; secondly, nose-to-nose contact is common
among sheep during winter housing conditions and this potentiated the spread of virus in nasal
exudates; thirdly, coinciding with the development of maedi, the Icelandic sheep had developed
another respiratory disease, pulmonary adenomatosis. This disease is associated with the
production of profuse quantities of pulmonary exudates. Dispersal of these fluids under close
housing conditions enhanced further spread of the lentivirus. The maedi-visna complex was
eliminated from Iceland by the slaughter of all sheep in affected flocks on individual farms.
The maedi form of the disease occurs in most other countries. Disease prevalence is low
although sheep of certain breeds such as Border Leicester sheep in the U.S.A. and Texel sheep in
Holland seem more susceptible. The virus is transmitted primarily in milk and perhaps by
husbandry practices including overcrowding and by the loan of breeding rams to different
farms. Virus is present in macrophages in the mammary gland and these cells are present in both
colostrum and milk. Other infections that cause mastitis result in the extrusion of increased
numbers of macrophages into the milk and thereby increase the load of lentivirus infectivity of
the milk. Such enhanced infection has been observed in individual animals in which one half of
the udder was normal and had a low virus load whereas the other was mastitic and had a heavy
virus load (Kennedy-Stoskopf et al., 1985). In Holland, the authorities have succeeded to a great
extent in controlling the disease by eliminating all seropositive animals and their lambs
(Houwers, 1985).
Caprine arthritis-encephalitis virus
Arthritis-encephalitis of goats occurs primarily in industrialized countries. Approximately
8 0 ~ of dairy goats in the U.S.A., Canada and western Europe are infected with this virus in
contrast to 0 to 10 ~ in many other countries in Africa and South America (Crawford & Adams,
1981 ; Adams et al., 1984). This disparity has been ascribed to husbandry practices in the dairygoat industry in which milk from lactating animals is pooled and a portion of the pool is fed to
kid goats. This practice greatly accelerated the spread of virus within goat herds by the wide
dispersal of infected macrophages from a rare, possibly infected doe in the herd.
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O. NARAYAN AND J. E. CLEMENTS
Bovine immunodeficiency virus
This virus has only recently been identified and epidemiological data are scant. However in
the U.S.A., small-scale surveys of cattle herds in Iowa and Maryland suggest that the virus may
be spread within herds by hypodermic needles used repeatedly for mass immunizations or
parenteral injections (M. A. Gonda, personal communication).
Feline immunodeficiency virus
See Pederson et al., (1987). Limited serological surveys suggest that FIV causes infection
mainly in free-roaming cats and that the incidence is highest in males. Biting is speculated to be
the major mechanism for spread because of the propensity for fighting among tom cats.
Infectious virus is present in saliva. In addition, gingivitis is relatively common among these
cats and inflammatory cells in the lesions may contain virus.
The human immunodeficiency viruses, HIV-1 and HIV-2
A vast number of studies and reports have been devoted to the natural history of HIV. The
brief remarks on the subject in this review are intended only to provide a perspective on the
biology of the virus within the framework of lentiviruses in general. Two major types of viruses,
HIV-1 (Barr6-Sinoussi et al., 1983) and HIV-2 (Clavel et al., 1986) occur in nature. The two
viruses share sequence homology in their pol and gag genes but differ greatly in env and in the
number and organization of their regulatory genes (Clavel et al., 1986). This is similar to the
differences between maedi-visna viruses of sheep and CAEV (Pyper et al., 1984). There is
extensive genetic variability among strains of both HIV-I and HIV-2 (McClure & Weiss, 1987).
HIV-1 is distributed throughout the world whereas HIV-2 seems to be confined to West Africa.
The viruses are pathogenic only for humans. Inoculation of subhuman primates and other
species of animals with both viruses has shown that the disease agents infected and replicated
only in chimpanzees. However, 4 years after infection, these animals have not yet developed
clinical disease.
As is typical of mechanisms for the dissemination of lentiviruses, spread of HIV requires
exchange of blood, blood products and/or body secretions (Lifson & Curran, 1987). The extent of
virus spread correlates directly with the nature of the mechanism of exchange and can be
compartmentalized into specific groups of individuals, depending on risk factors. The major
means of spread is by sexual contact, primarily among homosexuals in western countries and
among homosexual and heterosexual groups in Africa, Haiti and Brazil. Prostitution is a major
factor in heterosexual transmission. Intercurrent mucosal infections in HIV-infected
individuals may result in infiltration of lentivirus-infected monocytes into areas of inflamed
epithelium. This may enchance the transmission of HIV among people with infections in the
peri-anal area or in the genitalia. In addition to sexual transmission, repeated use of single
hypodermic needles among many individuals (by intravenous drug users in the west and by
unqualified community therapists in underdeveloped countries) is a major mechanism of
spread. These mechanisms are reminiscent of the spread of maedi-visna virus among sheep and
BIV among cattle.
The role of milk and colostrum as vehicles of transmission of HIV have not yet been evaluated
thoroughly. HIV has been obtained from human milk and transmission by this route has been
inferred in individual cases (Thiry et al., 1985). It is noteworthy that pooled human milk is used
to feed undernourished infants in underdeveloped countries. Whether this practice holds a
potential for transmission of HIV as it is for the spread of CAEV to kid goats is yet to be
determined.
Simian immunodeficiency virus
Lentiviruses have been isolated from captive Asian macaques (SlVmae)in the U.S.A. from
African sooty mangabey monkeys (SIV~m) bred in captivity in the U.S.A., from African green
monkeys (SIVa~m) in Africa, the U.S.A. and Japan and from African mandrils (SIVmnd) in
Kenya (Desrosiers, 1988). All of the viruses replicate productively in cultures of human T
lymphocytes.
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SIVmac
The origin of this virus is obscure. It is closely related, genetically and antigenically, to HIV-2.
Limited serological surveys have shown no evidence that the virus occurs in nature in the Asian
habitat of these animals (Lowenstein et al., 1986; Ohta et al., 1986). The first description of
SIVmac was by investigators at the New England Primate Center in Massachusetts, who
identified the lentivirus during studies on experimentally transmitted lymphomas of rhesus
monkeys (Macaca mulatta) (Hunt et al., 1983). Serological studies on other animals in the Center
showed that only three of more than 800 rhesus macaques had antibodies to the virus (Daniel et
al., 1988). The original virus was apparently obtained from a macaque purchased in the early
1970s from another centre that had no history of AIDS-like syndromes in their colony. This is
reminiscent of the lentivirus-infected Karakul rams that introduced maedi-visna virus into
Icelandic sheep. A similar virus was obtained from serum of a stump-tail macaque (M. arctoides)
(M. B. Gardner, personal communication), that died during an outbreak of AIDS among these
macaques during the early 1970s at the Primate Center at Davis, California. Several animals
had died mysteriously from lymphoma, progressive multifocal leukoencephalopathy, tuberculosis, etc., diseases that are seen typically in human patients with AIDS. The association between
these outbreaks and the infection with SIV was obtained retrospectively because the virus was
cultivated only in the 1980s from the serum sample that had been stored frozen since 1972. A
third occurrence of SIVmac has been obtained from a pig-tail macaque (M. nemestrina) dying
from a lymphoma at the Primate Center in Seattle, Washington (Benveniste et al., 1986).
Preliminary studies on genetic homology and antigenic relatedness among these viruses suggest
that they are closely related (Desrosiers, 1988).
S/Vsm
Sooty mangabeys (Cercocebus atys) are monkeys of West African origin and are present in
several zoos in the U.S.A. A large colony of these animals has been maintained at the Yerkes
Primate Center in Atlanta, Georgia and more than 8 0 ~ of adults are seropositive. Animals
seroconvert after 1 year of age. The virus is thought to be disseminated by the oral-faecal route
and this route of infection has been confirmed experimentally (H. McClure, personal
communication). Naturally infected mangabey monkeys do not become ill and are virus carriers
for life. However, inoculation of the virus obtained from mangabey monkeys into macaques
results in acute disease and the onset of AIDS (Murphey-Corb et al., 1986). The relationship
between this virus and SIVmae has not been established as yet. The question whether mangabey
monkeys are infected in nature has not been determined.
SW~m
Several strains of lentiviruses, distinct biologically and genetically from HIV-1, HIV-2 and
SIVmae, have been obtained from African green monkeys (Cercopithecus aethiops) in the U.S.A.,
Japan and from the wild in Africa. The viruses are non-pathogenic for African green monkeys
but probably not for rhesus macaques.
S/~
A new lentivirus, distinct from any of the other SIV agents from primates has been obtained
from mandril monkeys (Papio sphinx) caught in the wild in Kenya. Biological characterization
of this virus is in progress. No sign of illness was seen in these naturally infected animals.
The natural occurrence of lentiviruses among monkeys in Africa provides intriguing
speculations that viruses from these animals may have been the source of the virus in humans.
Further studies on the natural history of these agents from non-human primates will add to the
understanding of the possible origin of the human pathogens.
PATHOGENESIS
The lentiviruses follow many common pathways that lead to disease. This includes the
mechanisms the viruses use to elude host defences, the direct effect of infection on cells of the
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o . N A R A Y A N A N D J. E. C L E M E N T S
immune system and the pathological effects of replication of opportunistic organisms that
proliferate as a consequence.
Mechanisms o f continuous replication
The nature of lentivirus disease with its long incubation period, its gradual onset and its
chronic progressive course requires the continuous replication of the virus. In order to
accomplish this, the agent must have mechanisms for escaping from host defences. The
lentiviruses have evolved a number of strategies that provide formidable survival advantages
[for review see Narayan & Clements (1988), also Narayan et al. (1988); Jolly et al. (1989)].
Contribution of proviral D N A
Lentiviruses utilize the DNA intermediate phase of replication common to all retroviruses.
Integration of CAEV proviral DNA has been documented in infected cell cultures (Chiu et al.,
1985). However, whether integration occurs in macrophages or lymphocytes in vivo is not
known. Latent viral genomes would not be detectable by the defence systems of the host.
Infection in macrophages
Cells of the macrophage lineage are major hosts for replication of lentiviruses in vivo. The first
report of this was shown by the demonstration by immunofluorescence of EIAV antigens in
Kupffer macrophages in the liver of horses with acute EIA (McGuire et al., 1971). The role of
macrophages in lentivirus infection was explored further in visna and CAE viral systems and
has been reviewed recently (Narayan & Zink, 1988; Zink et al., 1987). Not only are cells of the
macrophage lineage the hosts for the virus but virus gene expression is a function of maturation
differentiation of the cells. The virus is latent in precursor cells and its life cycle is completed
only in the mature cell (Narayan et al., 1983; Gendelman et al., 1986). In vivo, this occurs only in
macrophage populations in specific tissues (Kennedy et al., 1988). Infected macrophages in
these locations present lentivirus antigens among their class II major histocompatibility
complex (MHC) antigens to T lymphocytes (Kennedy et al., 1985) and probably cause infection
in helper T lymphocytes during this interaction. Tropism of the lentivirus for macrophages and
antigen-presenting cells has been observed also in tissues of humans and macaques infected with
HIV (Ho et al., 1986, 1987; Koenig et al., 1986; Salahuddin et al., 1986) and SIWma c (Letvin &
King, 1984) respectively. Viral gene expression in specific populations of cells of these lineages
correlates with histological lesions in the respective organs such as the lung (Salahuddin et al.,
1986), brain (Koenig et al., 1986) and skin (Ringler et al., 1986). Since macrophages constitute
the main non-specific cellular defence system of the host, lentivirus replication undoubtedly
subverts this arm of the defence system and results in failure of the host to eliminate the virus.
Infection in helper T lymphocytes
Most of the lentiviruses infect helper T lymphocytes and this most probably compromises the
ability of these ceils to perform specific immunological functions (Fauci, 1988). Although
lentivirus infection in helper T lymphocytes of humans, subhuman primates and cats has been
well established, the phenomenon has only recently been observed in lentivirus-infected sheep
(S. Kennedy-Stoskopf & O. Narayan, unpublished). However, unlike the primate and feline
viruses which cause lyric infection in cultured helper T cells, the viruses infecting sheep appear
to cause non-cytopathic infection. Loss of this part of the defence system allows continuous
replication of the virus.
Low induction o f neutralizing antibodies
In general, lentiviruses are poor inducers of neutralizing antibodies (Narayan et al., 1987;
Weiss et al., 1985; Robert-Guroff et aL, 1985). The efficiency at which they induce these
antibodies varies among the viruses. Some, such as visna virus, EIAV and HIV, induce
neutralizing antibodies whereas others such as CAEV are intrinsically poor inducers. Studies on
the poor neutralizing antigenicity of CAEV suggests that it may be due to the glycosylation
pattern of the viral envelope glycoprotein. Sialic acids on the surface of the virus decreased the
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1631
avidity of binding between virus and antibodies (Huso et al., 1988) and in some cases completely
obscured the neutralization determinant(s). Treatment of the virus with neuraminidase
improved the kinetics of both tests (P. E. Jolly et al., unpublished).
Non-neutralizing antibodies enhance infection in macrophages
Goats persistently infected with CAEV have antibodies to all lentivirus polypeptides.
Nevertheless, the antibodies do not neutralize viral infectivity in fibroblast cultures. However
when tested in macrophage cultures the antibody-treated virus was internalized more rapidly
than untreated virus particles (Jolly et al., 1989). The virus replication cycle was thus accelerated
by the rapid completion of the early phases of the infection. Fc receptors (FcR) on the surface of
the macrophages probably had a role in phagocytosis of antibody-coated virus because the
process did not occur when only F(ab')2 portions of Ig were used in the experiment. Therefore
the net result of the development of non-neutralizing antibodies is that infectious immune
complexes are produced and these are taken up by macrophage populations that remove such
complexes by FcR-mediated phagocytosis. Antibody-mediated enhancement of infection in
macrophages with HIV-1 has also been observed (Takeda et al., 1988).
Low af/~nity o f neutralizing antibodies
Neutralizing antibodies induced by the more immunogenic lentiviruses generally have a low
affinity for the viruses. The biological effect of this phenomenon has been investigated in the
visna virus system. Visna virus induces neutralizing antibodies during the first month or two
after infection. However, to achieve neutralization, antibodies required a prolonged incubation
of at least 30 rain with the virus. Furthermore, the antibodies required more than 20 min
incubation to bind virus particles, whereas the virus particles bound to cells within 2 min
(Kennedy-Stoskopf & Narayan, 1986). The role of sialic acids in delaying (or decreasing) the
firmness of binding between the antibodies and neutralization determinants was described
above. It is thus theoretically possible that the highly sialylated virus particles could spread
efficiently from cell to cell before they can be neutralized.
Antigenic variation
EIAV, visna virus and HIV undergo antigenic variation during infection in individual hosts
(Clements et al., 1988 a; Hahn et al., 1985, 1986). This phenomenon, by definition, occurs only in
infections in which the viruses induce neutralizing antibodies. As described in the section
entitled VIRALA~rrlG~NS, the lentiviruses mutate at a high rate and this provides a basis for
genetic heterogeneity among the viral agents in the host population as well as in the individual
host. Studies on EIAV have shown that the virus mutates at random and mutants are selected by
specific antibodies. Emergence of new, non-neutralizable viruses coincides with cyclical
episodes of disease in horses (Kono et al., 1973). Antigenic variation also occurs during the
persistent infection of sheep with visna virus (Narayan et al., 1977a, b) and probably also in
humans infected with HIV (Hahn et al., 1985). However there is no evidence for cyclical
episodes of disease in either of the latter two hosts. Fully virulent antigenic variants have been
recovered from sheep experimentally infected with plaque-purified virus. Variants of both visna
virus and HIV can be derived easily in cell cultures by the incorporation of immune serum from
infected hosts into the maintenance medium (Narayan et al., 1981; Reitz et al., 1988); this
phenomenon is unique to the lentiviruses. The variants are stable in cell culture and do not
undergo further variation unless subjected to selective pressures with neutralizing antibodies.
Studies on visna virus showed that it has multiple neutralization epitopes and variation is
caused by the genetically determined rearrangement of these epitopes in the viral envelope
(Narayan et al., 1986). Sheep vary in their antibody responses to these epitopes. Some infected
(or hyperimmunized) sheep develop antibodies to all of the epitopes. Sera from these animals
neutralize all visna viruses (at the typically slow rate of neutralization described above).
Antigenically variant viruses do not develop in such infected or immune animals and their sera
do not select antigenic variants in cell culture. Other infected sheep produce neutralizing
antibodies against a limited number of the epitopes; such antibodies neutralize only the
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O. N A R A Y A N AND J. E. C L E M E N T S
infecting virus but not other strains of the agent. Antigenic variants develop in these animals.
Furthermore, sera from these animals with limited neutralizing capabilities select for rapid
development of variant viruses in cell culture. Late sera from such animals collected 2 years or
more after infection have a broader spectrum of neutralizing antibodies and do not select for
new antigenic variants. Thus, depending on the rate of development of broad spectrum
neutralizing antibodies, these variants may or may not develop in individual animals. Emerging
antigenic variants of EIAV cause the cyclical episodes of a haemolytic crises in horses.
However, animals develop only three or four such crises and these occur during the first year of
the infection (Crawford et al., 1978). The broadening antibody spectrum induced by the variant
virus may be responsible for the limited number of such crises.
The biological importance of antigenic variation in these viruses is not understood. The
phenomenon does not seem to be essential for either the persistence of the agent or the induction
of disease. Antigenic variation may be more important for survival of the virus in nature, given
its narrow host range and its inefficient mechanism for spread to new hosts. It is possible that
mutations and other selective pressures may lead to viruses with differences in tropism for cells,
tissues and hosts and also possibly with differences in virulence. This may provide a mechanism
for derivation of viruses with variable tissue tropisms in individual hosts such as neurotropic and
lymphotropic viruses in humans (Koyanagi et al., 1987) and arthro-, neuro- and pneumotropic
viruses in sheep (Narayan & Cork, 1985). Mutation and selection may also provide the basis for
a change in virulence for different host species as indicated among viruses from sheep and goats
and between humans and macaques. It is possible that SIVma e may be the progeny of an HIV-2
strain of virus which was introduced into macaques and mutated into its uniquely pathogenic
phenotype. On the other hand HIV-2 may be a mutant of the lentivirus of free-ranging
mangabey monkeys in West Africa (P. Marx, personal communication).
MECHANISMS OF HISTOLOGICAL LESIONS FORMATION
Whereas the loss of helper T lymphocytes may be responsible for secondary disease, the
infection in macrophages may be the basis for primary disease, causing a variety of different
lesions.
Lytic infection in EIA
The highly productive virus replication in macrophage populations in the liver and spleen is
associated with acute necrosis in these cells (Konno & Yamamoto, 1970) and may be the first
step in the induction of acute disease.
Immune complex disease in EIA
Antibodies bind to cell-free virus in plasma and the immune complexes are either deposited in
specific areas such as the glomeruli of the kidneys and cause immune complex disease or are
taken up by specific macrophage populations that clear such complexes. Association of immune
complexes with circulating red blood ceils leads also to a haemolysis of the cells, resulting in
chronic anaemia. Infectious HIV and SIVma e also circulate in the blood but it is not known
whether this leads to the type of lesion seen in horses. It is of interest, however, that
disappearance of antigenanaemia in both humans and monkeys heralds the onset of disease.
Maturation differentiaiion of macrophages
Studies on the pathogenesis of visna suggested that replication of the virus in monocytemacrophage cells is dependent on the maturation/differentiation of the cells. Latent infection in
pro-monocytes in the bone marrow becomes productive when the monocytes mature into tissue
macrophages. This concept may be applicable to the other lentivirus-host systems with
activation confined to certain populations of macrophages. These vary from host to host. The
highly permissive macrophages in the liver and spleen of horses infected with EIAV, the
permissive brain macrophages of humans and macaques infected with HIV and SIC . . . .
respectively, the permissive alveolar macrophages of humans and sheep infected with HIV and
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maedi viruses, respectively, and permissive synovial and colostral macrophages of sheep and
goats infected with the ruminant lentiviruses are examples of this phenomenon.
Effects of breeds on the permissiveness of tissue macrophages
Icelandic sheep are much more susceptible to CNS disease than are British sheep (Dawson,
1980; Kennedy et al., 1988). Sheep inoculated intracerebrally with the same stock of Icelandic
visna virus showed that viral genes were transcribed much more extensively in the brain cells of
Icelandic sheep than in British sheep and that encephalitic changes were much more severe in
Icelandic sheep. Thus genetic factors in the host may regulate the extent of viral gene expression
in specific cell types and thereby influence the organ specificity of the lesions.
Possible role of cytokines and autoimmunity
Lymphadenopathy and follicular hyperplasia in lymph nodes and spleen are prominent
lesions following natural and experimented infection with EIAV, maedi-visna, CAEV, SIV ....
FIV and BIV. Lymphadenopathy is also a clinical manifestation of HIV infection in humans.
The lesions are associated frequently with polyclonal B cell activation. The mechanisms of these
processes are not understood, but in all cases infected macrophages can be found in the tissues.
The lesions may be caused by cytokines produced in excess by infected macrophage or
dysregulation of cytokine production resulting in the pathological proliferation of subsets of
lymphoid cells (such as cytotoxic T lymphocytes) and suppression of others (such as helper T
lymphocytes).
The active-chronic inflammatory lesions caused by maedi-visna and CAE viruses are the
most severe seen in any lentivirus disease (Narayan & Cork, 1985). The inflammatory cells
include monocytes-macrophages, cytotoxic T lymphocytes, plasma cells and follicular
accumulations of lymphoid cells. Similar lesions are found in kid goats developing acute
encephalitis and in children with AIDS. In sheep, the macrophage is the only cell type that
harbours the viral genome in these lesions (Kennedy-Stoskopf et al., 1987). Many of these cells
are Ia-positive, indicating immunological activation. Previous studies had shown that
interaction of T lymphocytes with infected macrophages resulted in the production of interferon
(Narayan et al., 1985). Fluid containing this cytokine caused enhanced expression of Ia antigens
in macrophages and caused reduction in replication of the virus in these cells. It is not known
whether the other lentiviruses induce a similar type of interferon. It is of interest that SIVmae
infection in macaque macrophages results in the expression of Ia by the cells without the
participation of interferon (Kannagi et al., 1987). The lentivirus infections may thus directly or
indirectly lead to unnaturally high levels of expression of MHC class II genes. This sets the stage
not only for abnormal proliferation of lymphoid cells, but these activated antigen-presenting
ceils may inadvertently begin to present host antigens to lymphocytes. This could result in
autoimmune lesions.
IMMUNIZATION AGAINST LENTIVIRUS INFECTIONS
Controlled studies on immunization against lentivirus infection are still in their infancy. In
the established animal models in horses and ruminants, control of disease by immunization has
never been pursued enthusiastically because of the expense and the relative lack of efficacy of
vaccines in contrast to the greater effectiveness of eradication and prevention programmes. The
available results can be summarized as follows. Sheep hyperimmunized with disrupted visna
virus and virus-infected cells developed broad spectrum neutralizing antibodies and two such
animals resisted infection after intracerebral challenge with the homologous infectious virus
(Narayan et al., 1981 ; O. Narayan, unpublished results). Similarly immunized animals had not
been challenged with antigenic variant viruses or heterologous viruses of any kind. Horses that
recover from episodic disease induced by the mildly pathogenic Wyoming strain of EIAV
remain persistently infected at a subclinical level. Injection of such animals with extremely
virulent antigenically distinct field isolate viruses failed to cause disease. (R. Montelaro,
personal communication). Goats immunized with visna virus became immune to challenge with
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O. N A R A Y A N A N D J. E. C L E M E N T S
the homologous virus but remained susceptible to infection with CAEV. CAEV failed to induce
protective immunity in goats after multiple injections of purified inactivated virus, live virus,
detergent-disrupted virus, virus-infected cells or detergent-treated virus-infected cells. (Narayan
et al., 1984). Finally, macaques immunized with inactivated SIVr~ac2Sl developed neutralizing
antibodies but in the initial test groups, the animals succumbed to infection and disease after
challenge with a high dose of virus given intravenously (Letvin et al., 1987; R. C. Desrosiers,
personal communication).
These preliminary studies thus suggest that although animals do not recover from infection
with lentiviruses, hyperimmunization with appropriate antigens of these agents may lead to
protective immunity against infection with homologous viruses of some members of this family.
The phenomenon of infection and immunity seen in horses occurs also in protozoan infections in
many animals, but its mechanism in either type of infection is not understood. Given the
disappointing results on immunization obtained so far with the lentiviruses, it would be of
interest to determine whether infection in primates with avirulent viruses would protect the
animals against challenge with virulent virus.
We thank Linda Kelly and Carol Thacker for preparing the manuscript. These studies were supported by grants
NS12127, AI25774, NS23039, NSl6145 and NS21916 from the National Institutes of Health.
REFERENCES
ADAMS, D. S., OLIVER, R. E., AMEGHINO, E., DE MARTINI, J. C., VERWOERD, D. W., HOUWERS, D. I., WAGHELA,S.,
GORHAM, I. R., HYLLSETH, B., DAWSON, M., TRIGO, F. & McGUIRE, T. C. (1984). Global survey of serologic
evidence of caprine arthritis-encephalitis virus infections. Veterinary Record 115, 493-495.
AHMAD,N. & VENKATESAN,S. (1988). Nefprotein of HIV- 1 is a transcriptional repressor of HIV- 1 LTR. Science241,
1481-1485.
ARYA, S. K., BEAVER, B., JAGODZINSKI,L., ENSOLI, B., KANKI, P. J., ALBERT,J., FENYO, E. M., BIBERFELD, G., ZAGURY,
J. F., LAURE, F., ESSEX, M., NORRBY, E., WONG-STAAL,F. & GALLO, R. C. (1987). New h u m a n and simian HIVrelated retroviruses possess functional transactivator (tat) gene. Nature, London 328, 548-550.
BARRI~-SINOUSSI,F., CHERMANN,J. C., REY, F., NUGEYRE, M. T., CHAMARET,S., CRUEST,J., DAUGNET,C., AXLER-BLIN,
C., VEZINET-BRUN,F., ROUZIOUS,C., ROSENBAUM,W. & MONTAGNIER,L. 0983). Isolation of a T-lymphotropic
retrovirus from a patient at risk for acquired i m m u n e deficiency syndrome (AIDS). Science 220, 868-871.
BENVENISTE, R. E., ARTHUR,L. O., TSAI,C. C.~ SOWDER, R. & COPELAND~T. D. (1986). Isolation of a lentivirus from a
macaque with l y m p h o m a : comparison with HTLV-III/LAV and other lentiviruses. Journalof Virology 60,
483-490.
CHAKRABARTI,L., GUYADER, M., ALIZON, M., DANIEL, M. D., DESROSIERS, R. C., TIOLLAIS, P. & SONIGO, P. (1987).
Sequence of simian immunodeficiency virus from m a c a q u e and its relationship to other h u m a n simian
retroviruses. Nature, London 328, 543-547.
CHALIFOUX, L. V., KING, N. W. & LETVIN, N. L. (1984). Morphologic changes in l y m p h nodes of macaques with an
immunodeficiency syndrome. Laboratory Investigation 51, 22-26.
CHALIFOUX,L. V., RINGLER, D. J., KING, N. W., SEHGAL,P. K., DESROSIERS,R. C., DANIEL,M. D. & LETVIN,N. L. (1987).
Lymphadenopathy in macaques experimentally infected with the simian immunodeficiency virus (SIV).
American Journal of Pathology 128, 104-110.
CHEEVERS, W. P. & McGUIRE, T. C. (1985). Equine infectious anemia virus: immunopathogenesis and persistence.
Reviews of Infectious Diseases 7, 83-88.
CHIU, I.-M., YANIV,M., DAHLBERG,J. E., GAZIT, A., SKUNTZ,S. F., TRONICK,S. R. & AARONSON,S. A. (1985). Nucleotide
sequence evidence for relationship of AIDS retrovirus to lentiviruses. Nature, London 317, 366-368.
CLAVEL, F., GUETARD, D., BRUN-VEZINET,F., CHAMARET,S. & REY, M. A. (1986). Isolation of a new h u m a n retrovirus
from West African patients with AIDS. Science 233, 343-346.
CLEMENTS,J. E. & NARAYAN,O. (1981). A physical m a p of the linear unintegrated D N A of visna virus. Virology 113,
412-415.
CLEMENTS, J. E. & NARAYAN,O., GRIFFIN, D. E. & JOHNSON, R. T. (1979). T h e synthesis a n d structure of visna virus
D N A . Virology93, 377-386.
CLEMEm'S, J. E., GOOVIN, S. L., MorCrELARO, R. C. & NARAYAN,O. (1988a). Antigenic variation in lentiviral diseases.
Annual Review of Immunology 6, 139-159.
CLEME/CrS, J. IL, DAVIS, J., I-roSS, J. & SMALL,J. (1988b). Viral and cellular factors which activate in trans the visna
viral LTR. In The ControlofHIVGene Expression, pp. 291-302. Edited by B. Cullen, R. Franza & F. WongStaal. New York: Cold Spring Harbor Laboratory.
CONNOR, E. M., MINNEFOR, A. B. & OLESKE, J. M. (1987). H u m a n immunodeficiency virus in infants and children. In
Current Topics in AIDS, vol. 1, pp. 185-209. Edited by M. S. Gottlieb, D. J. Jeffries, D. Mildvan, A. J.
Pinching, T. C. Quinn & R. A. Weiss. New York: John Wiley & Sons.
CORK, L. C., HADLOW, W. J., GORHAM, J. R., PYPER, R. C. & CRAWFORD, T. B. (1974). Infectious
leukoencephalomyelitis of goats (CAEV). Journal of Infectious Diseases 129, 134-141.
Downloaded from www.microbiologyresearch.org by
IP: 88.99.165.207
On: Sat, 17 Jun 2017 13:11:43
Review: Lentiviruses
1635
CRANE, S. E., CLEMENTS,J. E. & NARAYAN,O. (1988). Separate epitopes in the envelope of visna virus are responsible
for fusion and neutralization: biological implications for anti-fusion antibodies in limiting virus replication.
Journal of Virology 62, 2680-2685.
CRAWFORD,T. It. & ADAMS,D. S. (1981). Caprine arthritis-encephalitis: clinical features and presence of antibody in
selected goat populations. Journal of the American Veterinary Medical Association 178, 713-719.
CRAWFORD, T. B., CHEEVERS, W. P., KLEVJER-ANDERSON, P. & McGUIRE, T. C. (1978). Equine infectious anemia:
virion characteristics, virion-cell interaction and host response. In Persistent Viruses, UCLA Symposium on
Molecular and Cellular Biology, pp. 727-749. Edited by J. Stevens, G. Todaro & C. F. Fox. N e w York:
Academic Press.
CULLEN, 13. R. (1986). Trans-activation of h u m a n immunodeficiency virus occurs via a bimodal mechanism. Cell
46, 973-982.
DANIEL, M. D., LETVIN, N. L., KING, N. W., KANNAGI, M., SEHGAL, P. K., HUNT, R D., KANKI, P. J., ESSEX, M. &
DESROSIERS, R. C. (1985). Isolation of T-cell tropic HTLV-III-like retrovirus from macaques. Science 228,
1201-1206.
DANIEL, M. D., LETVIN, N. L., SEHGAL, P. K., SCHMIDT,D. K., SILVA, D. P., SOLOMON,K. R., HODI, F. S., RINGLER, D. J.,
HUNT, R. D., KING, N. W. & DESROSIERS,R. C. (1988). Prevalence of antibodies to 3 retroviruses in captive colony
of macaque monkeys. International Journal of Cancer 41, 601-608.
DAVIS, I. L., MOLI~AUX, S. & CLEMErrrS, J. E. (1987). Visna virus exhibits a complex transcriptional pattern: one
aspect of gene expression shared with the acquired immunodeficiency syndrome retrovirus. Journal of
Virology 61, 1325-1331.
DAWSON, M. (1980). Maedi/visna: a review. Veterinary Record 106, 212-216.
DERSE, D., DORN, P. L., LEVY, L., STEPHENS, R. M., RICE, N R. & CASE, I. W. (1987). Characterization o f equine
infectious anemia virus long terminal repeat. Journal of Virology 61, 743-747.
DESROSlERS, R. C. (1988). Simian immunodeficiency viruses. Annual Review of Microbiology 42, 607~525.
DESROSIERS, R. C. & LETVIN, N. L. (1987). Animal models for acquired immunodeficiency syndrome. Reviews of
Infectious Diseases 9, 438-446.
DORN, P. L. & DERSE, D. (1988). Cis- and trans-acting regulation of gene expression of equine infectious anemia
virus. Journal of Virology 62, 3522-3526.
DUBOIS-DALCQ,M., REISE, T. S. & NARAYAN,O. (1976). M e m b r a n e changes associated with assembly of visna virus.
Virology 74, 520-530.
EPSTEIN, L. G., SHARER, L. R., CHO, E. S., MYENHOFER, M., NAVIA, B. & PRICE, R. W. (1984). HTLV-III-Iike retrovirus
particles in the brains of patients with AIDS encephalopathy. AIDS Research 1, 447-454.
EAUCI, A. S. (1988). The h u m a n immunodeficiency virus: infectivity and m e c h a n i s m s of pathogenesis. Science 239,
617-622.
FAUCI, A. S., MASUR, H., GELMANN, E. P., MARKHAM, P. D., HAHN, It. H. & LANE, H. C. (1985). The acquired
immunodeficiency syndrome: an update. Annals of Internal Medicine 102, 800-813.
FEINBERG, M. It., JARRETT, R. F., ALDOVINI, A., GALLO, R. C. & WONG-STAAL,F. (1986). HTLV-III expression and
production involve complex regulation at the levels of splicing and translation of viral R N A . Cell46, 807-817.
FUJIWARA, T. & MIZUUCHI, K. (1988). Retroviral D N A integration: structure of an integration intermediate. Cell
Biology 54, 497-504.
FULTZ, P. N., McCLURE, H. M., ANDERSON,D. C. SWENSON, R. B. & ANAUD,R. (1986). Isolation of a T-lymphotropic
retrovirus from naturally infected sooty m a n g a b e y monkeys (Cerecocebus atys). Proceedings of the National
Academy of Sciences, U.S.A. 83, 5286-5290.
GARTNER, S., MARKOVITS,P., MARKOVITS,D. M., KAPLAN, M. B., GALLO, R. C. & POPOVIC, C. M. (1986). The role of
mononuclear phagocytes in HTLV-III/LAV infection. Science 233, 215-219.
GENDELMAN,H. E., NARAYAN,O., MOLINEAUX,S., CLEMEN'I~,J. E. & GHOTBI, Z. (1985). Slow persistent replication of
lentiviruses: role of macrophages and macrophage precursors in bone marrow. Proceedings of the National
Academy of Sciences, U.S.A. 82, 7086-7090.
GENDELMAN,H. E., NARAYAN, O., KENNEDY-STOSKOPF,S., KENNEDY, P. G. E., GHOTBI, Z., CLEMENTS,J. E., STANLEY,I.
& PEZESHKAPOUR,G. (1986). Tropism of sheep lentiviruses for monocytes: susceptibility to infection and virus
gene expression increase during maturation of moncytes to macrophages. Journal of Virology 58, 67-74.
GONDA, M. A., WONG-STAAL,F., GALLO,R. C., CLEMENTS,J. E., NARAYAN,O. & GILDEN, R. (1985). Sequence homology
and morphologic similarity of HTLV-III and visna virus, a pathogenic lentivirus. Science 227, 173-177.
GONDA, M. A., BRAUN,M. J., CLEMENTS,J. E., PYPER, J. M., CASEY,J. W., WONG-STKAL,F., GALLO,R. C. & GILDEN, R. V.
(1986). HTLV-III shares sequence homology with a family of pathogenic lentiviruses. Proceedings of the
National Academy of Sciences, U.S.A. 83, 4007-4011.
GONDA, M. A., BRAUN,M. J., CARTER,S. G., KOST,T. A. & BESS,J. W. (1987). Characterization and molecular cloning of
a bovine lentivirus related to h u m a n immunodefiency virus. Nature, London 330, 388-391.
GUY, B., KIENY, M. P., RIVIERE, Y., LE PEUCH, C., DOTT, K., GIRARD, M., MONTAGNIER,L. & LECOCQ, J. P. (1987). H I V
F/3' O R F encodes a phosphorylated G T P - b i n d i n g protein resembling an oncogene product. Nature, London
330, 266-269.
HAASE, A. T., STOWRING, L., HARRIS, J. D., TRAYNOR,It., VENTURA, P., PELUSO, R. & ItRAHIC, M. (1982). Visna D N A
synthesis and the tempo of infection in vitro. Virology 119, 399-410.
HAHN, B. H., GONDA, M. A., SHAW, G. M., POPOVIC, M., HOXIE, J. A., GALLO, R. C. & WONG-STAAL,F. (1985). G e n o m i c
diversity of the acquired i m m u n e deficiency syndrome virus HTLV-III: different viruses exhibit greatest
divergence in their envelope genes. Proceedings of the National Academy of Sciences, U.S.A. 82, 4813-4817.
Downloaded from www.microbiologyresearch.org by
IP: 88.99.165.207
On: Sat, 17 Jun 2017 13:11:43
1636
O. N A R A Y A N A N D J. E. C L E M E N T S
HAHN, B. H., SHAW, G. M., TAYLOR, M. E., REDFIELD, R. R., MARKHAM,P D., SALAHUDDIN,S. Z., WONG-STAAL,F.,
GALLO, R. C., PARKS, E. S. & PARKS, W. P. (1986). Genetic variation in HTLV-III/LAV over time in patients
with AIDS or at risk for AIDS. Science 232, 1548-1553.
HARRIS, J. D., SCOTT, J. V., TRAYNOR, B., BRAHIC,M., STOWRING, L., VENTURA, P., HAASE,A. T. & PELUSO, R. (1981).
Visna virus D N A : discovery of a novel gapped structure. Virology 113, 573-583.
HARTER, D. H. & CHOPPIN, P. W. (1967). Cell fusing activity of visna virus particles. Virology 31, 279-288.
HESS, J. L., CLEMENTS, J. E. & NARAYAN,O. (1985). Cis- and trans-acting transcriptional regulation of visna virus.
Science 229, 482-485.
HESS, J. L., PYPER, J. M. & CLEMENTS,J. E. (1986). Nucleotide sequence and transcriptional activity of the C A E V long
terminal repeat. Journal of Virology 60, 385-393.
HO, D. D., SCHOOLEY,R. T. & ROTA, T. R. (1984). HTLV-III in the semen and blood of a healthy homosexual man.
Science 226, 451-453.
HO, 0. D., ROTA, T. R. & HIRSCH, M. S. (1986). Infection of monocyte/macrophages by h u m a n T-lymphotropic virus
type III. Journal of Clinical Investigation 77, 1712-1715.
HO, D. D., POMERANTZ,R. J. & KAPLAN, J. C. (1987). Pathogenesis of infection with the h u m a n immunodeficiency
virus. New England Journal of Medicine 317, 278 286.
HOUWERS, D. J. (1985). Experimental maedi/visna control in the Netherlands. In Slow Viruses in Sheep, Goats and
Cattle, pp. 115-121. Edited by J. M. Sharp & R. Hoff-Jorgensen. Luxembourg: Commission of the European
Communities.
HUNT, R. D., BLAKE, B. J., CHALIFOUX, L. V., SEHGAL, P. K., KING, N. W. & LETVIN, N. L. (1983). Transmission of
naturally occurring lymphoma in macaque monkeys. Proceedingsof the NationalAcademy of Sciences, U.S.A.
80, 5085 5089.
HUSO, D. L., NARAYAN,O. & HART, G. (1988). Sialic acids on the surface of C A E V define the biological properties of
the virus. Journal of Virology 62, 1974.
JOHNSON, R. T., McARTHUR, J. C. & NARAYAN, O. (1988). The neurobiology of h u m a n immunodeficiency virus
infections. FASEB 2, 2970-2981.
JOLLY, P. E., HUSO, D. & NARAYAN, O. (1989). M e c h a n i s m s of persistent replication of lentiviruses in
immunocompetent hosts. In Concepts in ViralPathogenesislll(in press). Edited by A. L. Notkins & M. B. A.
Oldstone. Basel: S. Karger.
JOSHI, V. V., OLESKE, J. & MIN~EEOR, A. B. (1985). Pathologic pulmonary findings in children with AIDS. Human
Pathology 16, 241.
KANNAGI,M., KIYOTAKI,M., KING, N. W., LORD, C. I. & LETVIN, N. L. (1987). Simian immunodeficiency virus induces
expression of class II major histocompatibility complex structures on infected target cells in vitro. Journalof
Virology 61, 1421-1426.
KENNEDY, P. G. E., NARAYAN, O., GHOTBI, Z., HOPKINS, J., GENDELMAN, H. & CLEMENTS, J. E. (1985). Persistent
expression of Ia antigen on viral genome in visna-maedi virus-induced inflammatory cells. Possible role of
lentivirus induced interferon. Journal of Experimental Medicine 162, 1970-1982.
KENNEDY, P. G. E., NARAYAN,O., ZINK, M. C., HESS, J., CLEMENTS, J. E. & ADAMS,R. J. (1989). The pathogenesis of
visna, a lentivirus induced immunopathologic disease of the central nervous system. In Clinicaland Molecular
Aspects of Viral Illness of the Nervous System, pp. 394-421. Edited by D. H. GildeD & H. Lipton. Boston:
Martinus Nijhoff.
KENNEDY-STOSKOPF,S. & NARAYAN,O. (1986). Neutralizing antibodies to visna lentivirus: m e c h a n i s m of action and
possible role in virus persistence. Journal of Virology 59, 37-44.
KENNEDY-STOSKOPF, S., NARAYAN, O. & STRANDBERG, J. D. (1985). The m a m m a r y gland as a target organ for
infection with caprine arthritis encephalitis virus. Journal of Comparative Pathology 95, 609-617.
KENNEDY-STOSKOPF,S., ZINK, M. C., JOLLY, P. E. & NARAYAN,O. (1987). Lentivirus-induced arthritis: chronic disease
caused by a covert pathogen. Rheumatic Disease Clinics of North America 13, 235-247.
KING, N. W. (1986). Simian models of acquired immunodeficiency syndrome (AIDS): a review. Veterinary
Pathology 23, 345-353.
KLATZMANN,D. F., BARRI~-SINOUSSI,M. T., NUGEYRE, C., DANGUET, E., VALMER~C., GRISELLI, F.~ BRUN-VEZINET~F.,
ROUZIOUS, J. C., GLUCKMAN, J. C., CHERMANN, J. G. & MONTAGNIER, L. (1984). Selective tropism of
lymphadenopathy associated virus (LAV) for helper inducer T lymphocytes. Science 225, 59-62.
KNIGHT, D. i . , FLOMERFELT,F. A. & GHRAYEB,J. (1987). Expression of A R T / T R S protein of HIV and study of its
role in viral envelope synthesis. Science 236, 837-840.
KOENIG, S., GENDELMAN,H. E., ORENSTEIN, J. M., DAL CANTO,M., PEZESHKPOUR,G. H., YUNGBLUTH,M., JANOTTA~F.,
AKSAMIT,A., MARTIN,M. A. & FAUCI, A. S. (1986). Detection of AIDS virus in macrophages in brain tissue from
AIDS patients with encephalopathy. Science 233, 1089-1093.
KONNO, S. & YAMAMOTO,H. (1970). Pathology of equine infectious anemia. Cornell Veterinarian 60, 393-449.
KONO, Y. (1988). Antigenic variation of equine infectious anemia virus as detected by virus neutralization. Archives
of Virology 98, 91-97.
KONO, Y., KOBAYASHI,K. & FUKUNAGA,Y. (1973). Antigenic drift of equine infectious anemia virus in chronically
infected horses. Archivf~r die gesamte Virusforschung41, 1-10.
KOYANAGI,Y., MILES, S., MITSUYASU,R. T., MERRILL,J. E., VINTERS,H. V. & CHEN, I. S. Y. (1987). Dual infection of the
central nervous system by AIDS viruses with distinct cellular tropisms. Science 236, 819-822.
LETVIN, N. L. & KING, N. W. (1984). Clinical and pathologic features of an acquired i m m u n e deficiency syndrome
(AIDS) in macaque monkeys. Advances in Veterinary Sciences and of Comparative Medicine 28, 237-265.
Downloaded from www.microbiologyresearch.org by
IP: 88.99.165.207
On: Sat, 17 Jun 2017 13:11:43
Review: Lentiviruses
1637
LETVIN, N. L., DANIEL, M. D., SEHGAL, P. K., DESROSIERS, R. C., HUNT, R. D., WALDRON,L. M., MACKEY,J. J., SCHMIDT,
D. K., CHALIFOUX,L. V. & KING, N. W. (1985). Induction of AIDS-like disease in macaque monkeys with T-cell
tropic retrovirus STLV-III. Science 230, 71-73.
LETVIN, N. L., DANIEL,M. D., KING, N. W., KIYOTAK1,M., KANNAGI,M., CHALIFOUX,L. V., SEHGAL, P. K. & DESROSIERS,
R. C. (1987). AIDS like disease in macaque monkeys induced by simian immunodeficiency virus: a vaccine
trial. In Vaccines "87, 209-214. Edited by M. Chanock, R. A. Lerner & F. Brown. New York: Cold Spring
Harbor Laboratory.
LIFSON, J. D. & CURRAN, S. W. (1987). Epidemiology of AIDS: current trends and prevention. In Current Topics in
AIDS, vol. 1, pp. 7-30. Edited by M. S. Gottlieb. N e w York: John Wiley.
LIFSON, J. O., CONTRES, S., HUANG, E. & ENGELMAN, E. (1986a). Role of envelope glycoprotein carbohydrate in
h u m a n immunodeficiency virus (HIV) infectivity and virus-induced cell fusion. Journal of Experimental
Medicine 164, 2101.
LIFSON, J. D., FEINBERG, M. B., REYES, G. R., RABIN, L., BANAPOUR, B., CHAKRABARTI, S., MOSS, B., WONG-STAAL, F.,
STEINER, K. S. & ENGELMAN, E. G. (1986b). Induction of C D 4 dependent cell fusion by HTLV-III/LAV
envelope glycoprotein. Nature, London 323, 725-728.
LOWENSTEIN, L. J., PEDERSEN, N. C., HIGGINS, J., PALLIS, K. C. & UYEDA, A. (1986). Seroepidemiologic survey of
captive Old World primates for antibodies to h u m a n and simian retroviruses, and isolation of a lentivirus
from sooty mangabeys (Cerocebus atys). International Journal of Cancer 38, 563-574.
McARTHUR, J. C. (1988). Neurologic manifestations of AIDS. Medicine 66, 407-537.
McCLURE, M. O. & WEISS, R. A. (1987). H u m a n immunodeficiency virus a n d related viruses. In Current Topics in
AIDS, vol. 1, pp. 95-117. Edited by M. S. Gottlieb. New York: John Wiley.
McGUIRE, T. C., CRAWFORD, T. B. & HENSON, I. B. (1971). Immunofluorescent localization of equine infectious
anemia virus in tissue. American Journal of Pathology 62, 283-292.
McGUIRE, T. C., ADAMS, D. C., JOHNSON, G. C., KLEVJER-ANDERSON, P., BARBEE, D. E. & GORttAM, J. R. (1986).
Retrovirus challenge of vaccinated or persistently infected goats causes acute arthritis. American Journal of
Veterinary Research 47, 537-540.
MOLINEAUX,S. & CLEMENTS,J. E. (1983). Molecular cloning of unintegrated visna viral D N A and characterization
of frequent deletions in the 3' terminus. Gene 23, 137-148.
MUESING, M. A., SMITH, D. H. & CAPON, D. J. (1987). Regulation of m R N A accumulation by a h u m a n
immunodeficiency virus trans-activator protein, Cell 48, 691-701.
MURPHEY-CORB,M., MARTIN,L. N., RANGAN,S. R. S., BASKIN, G. B. & GORMUS,B. J. (1986). Isolation of an HTLV-IIIrelated retrovirus from macaques with simian AIDS and its possible origin in asymptomatic mangabeys.
Nature, London 321, 435-437.
NABEL, G. & BALTIMORE, D. (1987). A n inducible transcription factor activates expression of h u m a n
immunodeficiency virus in T cells. Nature, London 326, 711-713.
NARA, P., HATCH, W., DUNLOP, N., ARTHUR, L., WATERS, D. & FISCHINGER, P. (1987). The immunobiology of HIV-1
infection in chimpanzees and its relationship to h u m a n AIDS. Abstracts. Symposium on Non-human Primates
for AIDS (Atlanta, Georgia), p. 29.
NARAYAN,O. & CLEMENTS,J. E. (1988). Biology and pathogenesis of lentiviruses of ruminant animals. In Retrovirus
Biology. An Emerging Role in Human Biology, pp. 117-147. Edited by F. Wong-Staal & R. C. Gallo. N e w
York: Marcel Dekker.
NARAYAN,O. & CORK, L. C. (1985). Lentiviral diseases of sheep and goats: chronic pneumonia leukoencephalomyelitis and arthritis. Reviews of Infectious Diseases 7, 89-98.
NARAYAN,O. & ZINK, M. C. (1988). Role of macrophages in lentivirus infections. Advances in Veterinary Science and
Comparative Medicine 32, 129-148.
NARAYAN, O., GRIFFIN, D. E. & SILVERSTEIN, A. (1977a). Slow virus infection: replication and m e c h a n i s m s of
persistence of virus in sheep. Journal of Infectious Diseases 135, 800-806.
NARAYAN,O., GRIFFIN, D. E. ~ CHASE,J. (1977 b). Antigenic drift of visna virus in persistently infected sheep. Science
197, 376-378.
NARAYAN,O., CLEMENTS,J. E., STRANDBERG,J. D., CORK, L. C. & GRIFFIN, D. E. (1980). Biological characterization of
the virus causing leukoencephalitis and arthritis in goats. Journal of General Virology 50, 69-79.
NARAYAN, O., C;~EMENTS, J. E., GRIrEIN, D. E. & WOLINSKY, J. S. (1981). Neutralizing antibody spectrum determines the antigenic profiles of emerging m u t a n t s of visna virus. Infection and Immunity 32, 10451050.
NARAYAN,O., WOLINSKY,J. S., CLEMENTS, J. E., STRANDBERG,J. D., GRIFFIN, D. E. & CORK, L. C. (1982). Slow virus
replication: the role of macrophages in the persistence and expression of visna viruses of sheep and goats.
Journal of General Virology 59, 345-356.
NARAYAN,O., KENNEDY-STOSKOPF,S., SHEFFER, D., GRIFFIN, D. E. & CLEMENTS, J. E. (1983). Activation of caprine
arthritis encephalitis virus expression during maturation of monocytes to macrophages. Infection and
Immunity 41, 67-73.
NARAYAN,O., SHEFFER, D., GRIFFIN, D. E., CLEMENTS,J. E. & HESS, J. (1984). Lack of neutralizing antibody to caprine
arthritis-encephalitis lentivirus in persistently infected goats can be overcome by immunization with
inactivated mycobacterium tuberculosis. Journal of Virology 49, 349-355.
NARAYAN,O., SHEFFER, D., CLEMENTS,L E. & TENNEKOON, G. (1985). Restricted replication of lentiviruses: visna
viruses induce a unique interferon during interaction between lymphocytes and infected macrophages.
Journal of Experimental Medicine 162, 1954--1969.
Downloaded from www.microbiologyresearch.org by
IP: 88.99.165.207
On: Sat, 17 Jun 2017 13:11:43
1638
O. N A R A Y A N A N D J. E. C L E M E N T S
NARAYAN,O., CLEMENTS,J. E., KENNEDY-STOSKOPF,S. & ROYAL, W. (1986). Antigenic variation in the lentiviruses
that cause visna-maedi in sheep and arthritis-encephalitis in goats. In Antigenic Variation in Infectious
Diseases, pp. 35-40. Edited by T. H. Birkbeck & C. W. Penn. Oxford & Washington, D.C. : I R L Press.
NARAYAN, O., CLEMENTS, J. E., KENNEDY-STOSKOPF, S. & ROYAL, R. (1987). Mechanisms of escape of visna
lentiviruses from immunological control. Contributions to Microbiology and Immunology 8, 60-76.
NARAYAN,O., ZINK, M. C., HUSO, D., SHEFFER, D., CRANE, S., KENNEDY-STOSKOPF,S., JOLLY, P. E. & CLEMENTS,J. E.
(1988). Lentiviruses of animals are biological models of immunodeficiency viruses. Microbial Pathogenesis 5,
149-157.
OHTA, M., OHTA,K., MORI, F., NISHITANI, H. & SAIDA, T. (1986). Sera from patients with multiple sclerosis react with
h u m a n T cell lymphtropic virus-1 gag proteins but not env proteins-Western blotting analysis. Journal of
Immunology 137, 3440-3443.
OHTA, Y., MASUDA,T., TSUJIMOTO,H., ISHIKAWA,K., KODAMA,T., MORIKAWA,S., HAKAI,M., HONJO, S. & HAYANI, M.
(1988). Isolation of simian immunodeficiency virus from African green monkeys and seroepidemiologic
.survey of the virus in various n o n - h u m a n primates. International Journal of Cancer 41, 115-122.
PANGANIBAN,A. T. & TEMIN, H. M. (1983). The terminal nucleotides of retrovirus D N A are required for integration
but not virus production. Nature, London 306, 155-160.
PEDERSON, N. C., HO, E. W., BROWN, M. L. & YAMAMOTO,J. K. (1987). Isolation of a T-lymphotropic virus from
domestic cats with an immunodeficiency-like syndrome. Science 235, 790-793.
PoPovIc, M., SARNGADHARAN,M. G., READ, E. & GALLO,R. C. (1984). Detection, isolation and continuous production
of cytopathic retroviruses HTLV-III from patients with AIDS and pre-AIDS. Science 224, 497-500.
PRICE, R. W., BREW, B., SIDTIS, J., ROSENBLUM,M., SCHECK, A. C. & CLEARY, P. (1988). The brain in AIDS: central
nervous system HIV-1 infection and AIDS dementia complex. Science 239, 586-592.
PRUSINER, S. B. (1982). Novel proteinaceous infectious particles cause scrapie. Science 216, 136-144.
PYPER, J. M., CLEMENTS, J. E., MOLINEAUX,S. M. & NARAYAN,O. (1984). Genetic variation among ovine-caprine
lentiviruses: homology between visna virus and caprine arthritis encephalitis virus is confined to the 5' gagpol region and a small portion of the env gene. Journal of Virology 51, 713-721.
PYPER, J. M., CLEMENTS, J. E., GONDA, M. A. & NARAYAN,O. (1986). Sequence homology between cloned caprine
arthritis-encephalitis virus and visna virus, two neurotropic lentiviruses. Journal of Virology 58, 665-670.
QUERAT, G., BARBAN,V., SAUZE, N., FILIPPI, P., VIGNE, R., RUSSO, P. & VITU, C. (1984). Highly lytic and persistent
lentiviruses naturally present in sheep with progressive p n e u m o n i a are genetically distinct. Journal of Virology
52, 672-679.
RABSON, A. B., DAUGHERTY,D. F., VENKATESAN,S., BAULUKOS,K. E., BENN, S. I., FOLKS, T. M., FEORINO, P. & MARTIN,
M. A. (1985). Transcription of novel open reading frames of AIDS retrovirus during infection of lymphocytes.
Science 229, 1388-1390.
RATNER, L., HASELTINE,W., PATARCA,R., LIVAK, K. J., STARCHICH,B., JOSEPHS, S. F., DORAN, E. R., RAFALSKI,J. A.,
WHITEHORN, E. A,, BAUMEISTER,K., IVANOFF,L., PETTEWA,S. R, JR., PEARSON,M. L., LAVTEblBERGER,J. A., PAPAS,
T. S., GHRAYEB, J., CHANG, N. T., GALLO,R. C. & WONG-STAAL,F. (1985). Complete nucleotide sequence of the
AIDS virus, HTLV-III. Nature, London 313, 277-284.
REITZ, M. S., WILSON, C., NAUGLE, C. H., GALLO,R. C. & ROBERT-GUROFF,M. (1988). Generation of a neutralizationresistant variant of HIV is due to selection for a point mutation in the env gene. Cell 54, 57-63.
RINGLER, D. J., MURPHY,G. F. & KING, N. W. (1986). An erythematous maculopapular eruption in macaques infected
with an HTLV-III-like virus (STLV-III). Journal of Investigative Dermatology 87, 674-677.
ROBERSON,S. M., McGUIRE,T. C., KLEVJER-ANDERSON,P., GORHAM,I. R. & CHEEVERS,W. P. (1982). Caprine, arthritisencephalitis virus is distinct from visna and progressive p n e u m o n i a viruses as measured by genome sequence
homology. Journal of Virology 44, 755-758.
ROBERT-GUROFF, M., BROWN, M. & GALLO, R. C. (1985). HTLV-III neutralizing antibodies in patients with AIDS
and AIDS-related complex. Nature, London 316, 72-74.
ROSEN, C. A., SODROSKI,J. G. & HASELTINE,W. A. (1985). The location ofcis-acting regulatory sequences in the h u m a n
T cell lymphotropic virus type III (HTLV-III/LAV) long terminal repeat. Cell 41, 813-823.
RUSHLOW, K., OLSEN, K., STEIGLER, G., PAYNE, S. L., MONTELARO,R. C. & ISSEL, C. J. (1986). Lentivirus genomic
organization: the complete nucleotide sequence of the env region of equine infectious anemia virus. Virology
155, 309-321,
SALAHUDDIN,S. Z., ROSE, R. M., GROOPMAN,J. E., MARKHAM,P. D. & GALLO, R. C. (1986). HTLV-III infection of
h u m a n alveolar macrophages. Blood 68, 281-284.
SANCHEZ-PESCADOR,R., POWER, M. D., BARR, P. J., STEIMER,K. S., STEMPIEN,M. M., BROWN-SHIMER,S. L., GEE, W. W.,
RENARD, A., RANDOLPH,A., LEVY, J. A. & LUCIW, P. A. (1985). Nucleotide sequence and expression of an AIDSassociated retrovirus (ARV-2). Science 227, 484-492.
SCOTT, J. V., STOWRING, L., BRAHIC, M., HAASE,A. T., NARAYAN,O. & VIGNE, R. (1979). Antigenic variation in visna
virus. Cell 18, 321-327.
SIGURDSSON, B. 0954). Observations on three slow infections of sheep, maedi, paratuberculosis, rida, a slow
encephalitis of sheep with general remarks on infections which develop slowly and some of their special
characteristics. British Veterinary Journal 110, 255-270, 307-322, 341-354.
SODROSKI, J. G., PATARCA, R., ROSEN, C. A., WONG-STAAL, F. & HASELTINE, W. A. (1985). Location of the
transactivating region of the genome of h u m a n T-cell lymphotropic virus type IIl. Science 229, 74-77.
SOOROSKI,J. G., GOH, W. C., ROSEN,C. A. & HASELTINE,W. A. (1986a). Role of HTLV-III/LAV envelope in syncytium
formation and cytopathicity. Nature, London 322, 470-474.
Downloaded from www.microbiologyresearch.org by
IP: 88.99.165.207
On: Sat, 17 Jun 2017 13:11:43
Review: Lentiviruses
1639
SODROSKI, J. G., GOH, W. C., ROSEN, C. A., DAYTON,A., TERWILLIGER, E. & HASELTINE, W. A. (1986b). A second posttranslational trans-activator gene required for HTLV-III replication. Nature, London 321, 412-417.
SOMASUNDARAN,M. & ROBINSON, H. L. (1988). Unexpectedly high levels of HIV-1 R N A and protein synthesis in a
cytocidal infection. Science 242, 1554-1557.
SONIGO, P., ALIZON, M., STASKUS,K., KLATZMAN,D. F., COLE, S., DANOS,O., RETZEL, E., TIOLLAIS,P., HAASE,A. T. &
WAIN-HOBSON, S. (1985). Nucleotide sequence of visna lentivirus: relationship to the AIDS virus. Cell 42,
369-382.
TAKEDA,A., TUAZON,C. U. & ENNIS, F. A. (1988). Antibody-enhanced infection by HIV-I via Fc receptor-mediated
entry. Science 242, 580-583.
TmRY, L., GOLDBF-RGER,S. & JONCKHEER, T. (1985). Isolation of AIDS virus from cell free breast milk of three
healthy virus carriers. Lancet ii, 891-892.
THORMAR, H. (1963). The growth cycle of visna virus in monolayer cultures of sheep cells. Virology 19, 273-278.
TrlORMAR,H. (1976). Visna-maedi virus infection in cell cultures and in laboratory animals. In Slow Virus Diseases
of Animals and Man, pp. 97-114. Edited by R. H. K i m b e d i n . A m s t e r d a m : North-Holland.
TSUJIMOTO,H., COOPER, R. W., KODAMA,T., FUKASAWA,M., MIURA,T., OHTA, Y., ISHIKAWA,K. I., NAKAI,M., FROST,E.,
ROELANTS, G. E., ROFFI, J. & HAYAMI,M. (1988). Isolation and characterization of simian immunodeficiency
virus from mandril in Africa and its relation to other h u m a n and simian immunodeficiency viruses. Journal of
Virology 62, 4044-4050.
VALLEE, H. & CARRE, H. (1904). Sur la nature infectieuse de l'anemie du cheval. Compte rendu de l'Acad~mie des
sciences 139, 331-333.
VAN DER MAATEN, M. J., BOOTHE, A. D. & SEGER, C. L. (1972). Isolation of a virus from cattle with persistent
lymphocytosis. Journal of the National Cancer Institute 49, 1649-1657.
VIGNE, R., FILIPPI, R., QUERAT, G., SAUZE, N., VITU, C., RUSSO, P. & DELORI, P. (1982). Precursor polypeptides to
structural proteins of visna virus. Journal of Virology 42, 1046-1056.
WAIN-HOBSON,S., SONGIO,P., DANOS,O., COLE, S. & ALIZON, i . (1985). Nucleotide sequence of the AIDS virus, LAV.
Cell 40, 9-17.
WEISS, R. A., TEICH, N. M., VARMUS,H. & COFFIN, J. (editors) (1982). RNA Tumor Viruses: Molecular Biology of Tumor
Viruses, 2nd edn. New York: Cold Spring Harbor Laboratory.
WEISS, R. A., CLAPHAM,P. R., CHEINGSONG-POPOV,R., DALGLEISH,A. G., CARNE,C. A., WELLER, I. V. D. & TEDDER.,R. S.
(1985). Neutralization of h u m a n Tqymphotropic virus type III by sera of AIDS and AIDS-risk patients.
Nature, London 316, 69-72.
YANIV, A., DAHLBERG, J. E., TRONICK, S. R., CHIU, I. M. & AARONSON,S. A. (1985). Molecular cloning of integrated
caprine arthritis-encephalitis. Virology 145, 340-345.
ZINK, M. C., NARAYAN,O., KENNEDY, P. G. E. & CLEMENTS, J. E. (1987). Pathogenesis of visna/maedi and caprine
arthritis-encephalitis: new leads on the m e c h a n i s m of restricted virus replication and persistent
inflammation. Veterinary Immunology and Immunopathology 15, 167-180.
Downloaded from www.microbiologyresearch.org by
IP: 88.99.165.207
On: Sat, 17 Jun 2017 13:11:43