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Journal of Antimicrobial Chemotherapy (1996) 37, Suppl. B, 1-11
Retrovirus classification and cell interactions
Robin A. Weiss
Institute of Cancer Research, Chester Beatty Laboratories, 237 Fulham Road,
London SW3 6JB, UK
Retroviruses cause a variety of diseases such as cancer, AIDS, autoimmunity and
diseases of central nervous system, bone and joints. Some retroviruses are apparently
harmless and some retroviral genomes are even inherited as host mendelian traits.
Whereas oncoviruses generally have a low virus load, so that antiviral therapy would
not greatly affect disease progression, lentiviruses like HIV have high load and
turnover. The cell interactions of retroviruses largely determine their pathogenesis.
Finally, retroviruses are being exploited therapeutically as vectors for gene therapy.
Introduction
Retroviruses infect a wide variety of vertebrates ranging from fish to humans (Weiss
et al., 1985; Levy, 1992-4). Some retroviruses cause diseases (Table I) of agricultural
and economic importance, e.g. leukosis of cattle and chickens. Of course, the greatest
impact has come from AIDS, a disease which was not recognised until 1981. Human
immunodeficiency virus (HIV) is the topic of this symposium and this article is to
introduce retroviruses in general and to explore their interactions with host cells.
Retrovirus replication
Retroviruses acquired their name when the discovery in 1970 of reverse transcriptase
(RNA dependent DNA polymerase) showed that their RNA genomes are copied into
DNA. This RNA to DNA conversion was the first example of a 'backwards' direction
of genetic information in biological systems. It has formed the basis of the first clinically
applied antivirals for retroviruses, because drugs such as azidothymidine, dideoxycytidine and lamivudine (3TC) are selectively incorporated as DNA chain terminators
by viral reverse transcriptase and not by host DNA polymerases. Now we know that
a broader group of genetic elements than retroviruses utilise reverse transcription at
some stage of replication; these include hepadnaviruses (including hepatitis B virus),
cauliflower mosaic virus and retrotransposons of eukaryotes and prokaryotes. Indeed
lamivudine may find a place in the treatment of hepatitis B infection as well as HIV.
A simplified version of the replication cycle of a retrovirus is shown in Figure 1. The
virus particle is diploid, i.e. it carries two genome copies in its core. Reverse transcriptase
is also packaged in the core but does not become enzymatically active until penetration
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R. A. Weiss
Table I. Retroviral diseases
Malignancies
myeloid leukaemia
erythroid leukaemia
lymphoid leukaemia
lymphoma
sarcoma
mammary carcinoma
renal carcinoma
Haematological deficiencies
aplastic anaemia
haemolytic anaemia
autoimmune disease
immunodeficiency
Bone and joint disease
osteopetrosis
arthritis
Neurological disease
peripheral neuropathy
encephalopathy
degeneration
dementia
Pulmonary disease
pneumonia
adenomatosis
and uncoating of the virion takes place. The primers for reverse transcription are
cellular transfer RNA molecules that hybridize with the viral RNA genome, tRNAlys
for HIV. From these primers nascent DNA chains are formed. Reverse transcriptase
also has an RNaseH activity that removes the parental RNA from the DNA, which
then forms the template for second strand DNA synthesis to form a double-stranded
DNA 'provirus'. This provirus is haploid but has sequences derived from both RNA
Receptor
Figure 1. Simplified replication cycle of a retrovirus.
Retrovirus classification and cell interactions
3
strands through a copy-choice mechanism to provide long terminal repeats (LTR) at
each end of the DNA genome (Skalka & Goff, 1993).
The provirus then integrates into host chromosomal DNA, catalysed by another viral
enzyme, integrase. Integration is not host-site specific but occurs preferentially in
euchromatin. The integrated provirus may remain latent and will be replicated along
with the rest of host DNA if the infected cell is proliferating. Expression of the provirus,
however, provides mRNA for translation into viral proteins and full length transcripts
provide genomic RNA for packaging into virions. The transcriptional control of viral
RNA from the integrated DNA provirus depends on cellular transcriptional regulators,
e.g. NFkB for HIV. Complex retroviruses (see below) like HIV also require viral
regulatory proteins, such as tat for efficient RNA transcription, and rev which aids
transport of the larger viral transcripts from nucleus to cytoplasm.
In virion maturation the core and matrix proteins are formed from the gag protein
precursor which is cleaved by viral protease at a late stage of virion budding into
the major structural proteins. The envelope glycoproteins, gp41 transmembrane
(TM) and gpl20 surface (SU) proteins in the case of HIV, are synthesised in the
rough endoplasmic reticulum and are cleaved by cellular furin-like enzymes during
processing through the Golgi to the cell surface, where they are incorporated into
budding virions.
Retrovirus classification
Retroviruses are broadly classified into three subfamilies, oncoviruses, lentiviruses and
spumaviruses (Table II), based on electron microscopic morphology of virions and
analysis of genome sequences. Oncoviruses are further subclassified into B- C- and
D-type particles morphologically (A-type particles are cytoplasmic cores of B- and
D-type particles). Not all retroviruses classed as oncoviruses are oncogenic. Some are
apparently harmless in their natural hosts; others such as the D type simian retroviruses
related to Mason-Pfizer monkey virus induce an immune deficiency which can be as
severe as those caused by HIV and SIV. Foamy viruses (spumaviruses) frequently occur
in monkeys and great apes, especially in the central nervous system, but the status of
human foamy virus has become uncertain. They are not known to be pathogenic in vivo,
Table II. Retrovirus classification
Subfamily
Oncovirus
B-type
C-type
D-type
Lcntivirus
Spumavirus
Examples
Murine mammary tumour virus
(MMTV)
Human T-ccll leukaemia virus
Avian leukosis and sarcoma viruses
Salmon lymphoma virus
Mason-Pfizer monkey virus
Human immunodeficiency viruses
Ovine maedi-visna virus
Equine infectious anaemia virus
Simian foamy viruses
(HTLV)
(ALSV)
(MPMV)
(HIV)
(MVV)
(EIAV)
(SFV)
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R. A. Weiss
despite the fact that they are more cytopathic in vitro than any other retroviruses,
forming large, vacuolated syncytia with a foamy appearance.
An alternative broad classification of retroviruses that has recently come into
vogue is to divide them according to genome organisation into 'simple' and 'complex'
viruses. Simple retroviruses contain only gag pol and env genes, while complex
retroviruses contain extra non-structural genes having regulatory or auxiliary functions.
The genome organisation of some typical retroviruses is shown in Figure 2. gag,
pol and env encode the core proteins, viral enzymes and envelope glycoproteins
respectively. The regulatory genes include transcriptional activators such as tat of
HIV, tax of human T cell leukaemia virus (HTLV-I) and bel-\ of human foamy virus
(HFV) which upregulate viral transcription. They may also transactivate cellular genes;
for example, tax protein acts indirectly to enhance expression of the p55 chain of
the interleukin-2 receptor which is overexpressed in the T-cell leukaemia induced by
this vims.
1
MLV
1.i K-—-
HTLV-1
nef
HIV-1
bell
HFV
LTR
kb
ML..
6
8
10
12
Figure 2. Proviral genomes of different classes. The simple oncovirus, mouse leukaemia virus (MLV)
possesses only gag, pol and enc genes whereas the complex viruses shown (HTLV-I, H1V-I and HFV) have
accessory genes which aid viral replication. All the genes or their products are potential targets for anti-viral
drugs.
Retrovirus classification and cell interactions
S
Retrovinis transmission
Retroviruses are transmitted horizontally, vertically, and genetically as integrated DNA
proviruses in germ cells. HIV can be transmitted horizontally both as a cell-free virus,
or as infected cells, whereas HTLV is only cell-associated. Hence the frequent presence
of both HTLV and HIV in injecting drug users, but only HIV in haemophiliacs (before
screening was introduced).
Horizontal transmission is well adapted to the hosts being infected. Thus some
retroviruses are transmitted through biting and scratching (e.g. leukaemia vims among
cats, SIV among macaques), via water and gill wounds among fish, and via biting flies
among horses in equine infectious anaemia virus (EIAV).
Vertical transmission of infectious virus can occur prenatally, perinatally and
post-natally, as known for HIV. The majority of paediatric infections appear to occur
perinatally but milk transmission also occurs, particularly on primary maternal
infection during lactation. Milk transmission is the principle means of infection for
HTLV-I, and for the murine mammary tumour virus (MMTV). Indeed, MMTV is
adapted to high expression in lactating mammary gland cells by possessing enhancer
sequences in its LTR that are upregulated by host hormones. Upon infection of suckling
mice (probably via gut lymphoid cells), MMTV is carried in T-lymphocytes which are
activated to proliferate by a viral gene encoding a superantigen. The virus then colonises
the mammary gland of females (and the epididymis of males) upon sexual maturity.
Avian leukosis virus is similarly adapted for congenital transmission by its high
production in ovalbumen-secreting cells in the hen's oviducts.
Mendelian genetic inheritance is perhaps the most ingenious and economical means
of viral transmission known. Various oncoviruses have become integrated into germ
cells during vertebrate evolution and are thus passed on to the next host generation in
the eggs and sperm. Such 'endogenous' retroviral genomes as they are called, may
remain latent for many host generations, or they may later be expressed and cause
disease. Thus MMTV and murine leukaemia virus have been integrated into certain
mouse inbred lines (GR and AKR, respectively) during their derivation and selection
as high incidence cancer mouse strains. We have shown that an endogenous leukosis
virus genome of chickens entered the germ-line before their domestication thousands
of years ago in China, as the virus is present in the red jungle fowl (Gallus gallus), but
was acquired after the diversification of the Gallus genus, as it is not present in the DNA
of the other extant species.
Human DNA contains thousands of endogenous retroviral genomes, most of which
were acquired relatively early in primate evolution since they are widely represented in
old world monkeys. In general they have become defective, with numerous stop codons
in the viral genes. However, a few open reading frames are conserved, and some human
cells produce non-infectious virions containing RNA, reverse transcriptase and gag
proteins. We have recently studied a human endogenous retroviral genome which has
a conserved env gene expressed as glycoprotein in the syncytiotrophoblast of the normal
human placenta (Venables el a/., 1995).
Human retroviruses
Table III lists the known human retroviruses. The first 'human' retrovirus to be isolated
in 1971 was human foamy virus (HFV) from a nasopharyngeal carcinoma line.
R. A. Weiss
Table III. Human retroviruses
Virus
Oncovirus
HTLV-I
HTLV-II
Disease
Adult T-cell leukaemia
Tropical spastic paraparesis
Hairy cell leukaemia?
Neurodegeneration?
Lentivirus
HIV-1
HIV-2
Acquired immune deficiency syndrome
Acquired immune deficiency syndrome
Spumavirus
HFV?
None
Immunofluorescence studies indicated that sera collected from humans in East Africa
and Polynesia had HFV antibodies, and various claims have been made that HFV is
associated with CNS disease and autoimmune thyroid diseases (Graves and De
Quervain thyroditis). However, recent PCR and ELISA tests have not upheld the earlier
evidence of HFV infection, and the original HFV genome sequence is almost
indistinguishable from chimpanzee simian foamy virus (SFV-6). SFVs are common
among old world monkeys and apes and there are now a handful of authenticated, PCR
positive human infections among primate handlers, all of whom remain in good health.
Human T-cell leukaemia virus type I (HTLV-I) was first isolated in 1980 and is found
to be endemic in southwest Japan, West Africa and among black people in or from the
New World. It causes adult T-cell leukaemia and is associated with some other less well
defined malignancies of mature T-helper lymphocytes. It is also causally linked with
tropical spastic paraparesis (TSP), known in Japan as HTLV-I associated myelopathy
(HAM), and with a variety of other central and peripheral neurological symptoms.
Intensive searches for related retroviruses in multiple sclerosis have not reliably detected
retrovirus to date despite several positive reports.
HTLV-II was first found in 1982 in a T-cell line from a patient with hairy cell
leukaemia, and later among injecting drug users. Now it is known to be endemic among
many native American communities in North, Central and South America and also
among some African pygmy tribes. It is related to HTLV-I in genome organisation with
approximately 40% sequence similarity, but it has not as yet definitively been linked
to malignant or neurological disease.
HIV-1 was first isolated in 1983 by Francoise Barre-Sinoussi and her colleagues in
France and rapidly became established as the principal cause of AIDS. HIV-2 was
isolated in 1986 from West African and Portuguese patients with AIDS-like symptoms
who had been found to carry antibodies cross-reacting with simian immunodeficiency
viruses (SIV). Clearly, it does cause AIDS, although it tends to produce a lower virus
load, possibly, no maternal-to-child transmission, and some infected persons remain
well for many years.
Both the HTLV and HIV groups of human retroviruses are closely related to simian
counterparts. They probably originated as human endemic and epidemic infections by
zoonoses from monkeys (HTLV-I, HIV-2) and possibly from chimpanzees (HIV-1). The
Retrovirus classification and cell interactions
7
HTLVs may have been present in humans for thousands of generations, whereas the
HIVs appear to be recent introductions during the past few decades.
Humans also harbour endogenous oncoviral genomes as already discussed,
resembling C-type and D-type retroviruses. Recently, an oncovirus has been found in
immunosuppressed bone marrow transplant patients, through screening for recovery of
replication-competent retroviral vectors. There is also some evidence of a virus related
to D-type retroviruses in Sjogren's syndrome and normal salivary gland biopsies. These
candidates for new human retroviruses require much further characterisation. They
serve to remind us that they may be further human retroviruses awaiting discovery.
Retroviral pathogenesis
Retroviruses elicit so many different diseases and symptoms (Table I) that it is not
possible to review them in detail here. However, from the antiviral point of view, it is
worth distinguishing those diseases that result from an ongoing, persistent viral burden
and might therefore be prevented by arresting or slowing viral replication, from those
that arise as late sequelae of early retrovirus infection. The latter include several but
not all the retroviral malignancies.
Viral oncogenesis can be induced by three main molecular mechanisms, depicted in
Figure 3. The transduction of cellular oncogenes has thrown much light on human
malignancy because it led to the original discovery of oncogenes—in chickens, cats and
mice—but transduction only very rarely occurs in nature and thus is not of practical
value in considering antiviral therapy. Retrovirus proviral integration next to cellular
oncogenes (thus activating them through the viral LTR) is a special case of insertional
mutagenesis. Since viral integration is not specifically targetted to oncogene loci in the
LTR gag
pol
env
LTR
tax
Figure 3. Activation of transforming genes by oncogenic retroviruses. A. Integration of an avian, murine
or feline leukaemia virus adjacent to a cellular oncogene (c-onc). Promoter sequences in the LTR leads to
uncontrolled expression of c-onc. Cellular oncogenes can also be activated through enhancer sequences in
the LTR, in which case the retrovirus could also act when integrated downstream of c-onc. B. A sarcoma
virus carrying a viral oncogene (v-onc) in its genome. This genome is defective, lacking full length gag, pol
and enc genes; therefore these essential proteins must be provided in 'trans' by a non-defective 'helper' virus
such as genome A. By the same principle retroviral vectors are engineered to carry therapeutic genes in place
of v-onc. C. HTLV-I (and related HTLV-II and bovine leukosis virus) express the tax protein which acts in
trans not only to upregulate the LTR, but also cellular genes for proliferation such as IL-2 receptor (analogous
to c-onc) located at other sites and chromosomes.
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R. A. Weiss
chromosomes, the higher the virus load in the target tissue, the higher the chance that
one cell among millions infected will integrate its provirus in such a dangerous locus
that monoclonal malignancy ensues. Studies of leukosis in chickens have shown that
this occurs in B-cells in the bursa of Fabricius during primary infection, so subsequent
antiviral treatment would presumably be of no avail. In mice and cats, however,
multiple recombination of infectiously spreading leukaemia virus with related yet
distinct endogenous envelope genes appear to be required before the typical T-cell
lymphomas are initiated. Hence antiviral therapy should suppress leukaemogenesis. In
fact the best in-vivo mouse model for testing antiretrovirals (it provided the earliest
evidence for azidothymidine) is Friend or Rauscher erythroid leukaemia in which
splenomegaly is rapidly caused by an oncogene-carrying defective virus coupled with
an infectiously spreading helper virus.
Human T-cell leukaemia exerts its oncogenic effect neither by transducing an
oncogene nor by integrating into DNA next to an oncogene. Rather, its tax gene
transactivates cellular genes such as the IL-2 receptor (Figure 3) as already mentioned.
Tax activity, however, is clearly insufficient to cause leukaemia since it is expressed in
the majority of infected, activated T-lymphoblasts, which must number tens of millions
in HTLV-infected persons, yet only about 3% of such individuals develop T-cell
leukaemia during a life-time's infection acquired through their mother's milk. The other
events, chromosome translocations and the like, remain obscure for this type of
leukaemia. Persistent lymphocytosis is seen in a number of patients over the course of
many years, but once the malignant clone emerges it is refractory to chemotherapy.
Whether antiviral therapy in seropositive individuals would reduce leukaemia incidence
is unknown. Viral load of infected cells, however, is several orders of magnitude lower
than in lentivirus infections, as is virus turnover. This means that targetting inhibitors
to viral replication is less important; on the other hand, the opportunities for the virus
to evolve resistance are also much less.
Lentiviruses, as their name implies, are slow to cause disease, but infection is not
latent. Progress to disease depends on several viral parameters (Table IV). As has
become evident from recent analyses of patients treated with non-nucleoside reverse
transcriptase inhibitors and protease inhibitors (Ho et al., 1995; Wei et al., 1995), at
least by the time of early symptomatic infection there is both a high turnover of virus
in the blood and of virus-infected cells. Since approximately one-third of the 10' infected
T-lymphocytes are replaced every day. These dynamics of virus and infected cells
Table IV. Changing parameters of HIV infection
during progression to
AIDS
Quantitative
viral burden
viral dynamics
Qualitative
genome diversity
antigen variation
cellular tropism
virulence
Retrovirus classification and cell interactions
Table V. Comparative attributes of lentivirus infection
Virus
(and host)
Syndrome
Cell tropism
Receptor
HIV and SIV Immune deficiency
(primates)
Wasting
CNS disease
CD4 T-lymphocytes
Macrophages, microglia
Dendritic cells
CD4
FIV
(cats)
Immune deficiency
Wasting
CNS disease
CD4 T-lymphocytes
Macrophages, microglia
CD9
MW
(sheep)
Wasting
CNS disease
Macrophages, microglia
MHC-II?
EIAV
(horses)
Haemolytic anaemia
Wasting
CNS disease
Monocytes, macrophages 7
emphasise the great importance of using therapies that will inhibit viral replication.
Indeed, immune restoration therapy may only make things worse by providing more
activated T-lymphocytes for HIV to replicate within (Coffin, 1995), unless accompanied
by antiviral treatment.
Despite these new insights into viral dynamics we still do not know precisely how HIV
causes AIDS (Weiss, 1993). HIV infects T-helper lymphocytes, macrophages and also
dendritic cells (Patterson el al., 1995). Escape from virus neutralization can change
cellular tropism and vice versa (McKnight et al., 1995). Maedi-visna virus ( M W ) , on
the other hand, infects just the antigen-presenting cells. M W disease in sheep resembles
a subset of the AIDS syndrome, namely the CNS disease and wasting disease (Table V).
It seems reasonable, therefore, to attribute the severe immune deficiency seen in HIV
and feline immunodeficiency virus infection to the infection and depletion of T-helper
lymphocytes, and the CNS and wasting syndrome to infection of macrophages,
including the microglia in the brain.
Cell tropism of retroviruses is determined by cell surface receptors allowing binding
and entry, and further by tissue-specific transcriptional regulation acting on the proviral
LTR. Retroviruses use diverse receptors such as CD4 by HIV and SIV, amino-acid and
phosphate transporter molecules by mammalian C type retroviruses and low-density
lipoprotein related molecules by avian leukosis viruses (Wimmer, 1994). HIV also binds
to the glycolipid, galactosylceramide, which may be relevant to CNS disease. The
distinctive tropism of HIV-1 for T-lymphocytes versus macrophages is determined in
part by the V3 loop of gpl20 which is thought to interact with secondary cellular
receptors following the CD4 interaction (Wimmer, 1994; McKnight et al., 1995).
Controlling retroviral disease
As argued above, controlling lentiviral infection demands efficacious antiviral drugs in
order to keep viral load and turnover down. Yet the very high turnover allows the rapid
evolution of drug-resistant strains within each infected individual. The hope must
therefore lie in combination antiviral therapy and possibly in early treatment during
primary infection, if it is apparent.
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R. A. Weiss
For the same reason as the limited success of antiviral treatment, vaccines protecting
against lentivirus infection will have to show protection against the myriad
(quasi-species) of substrains present in the infected host populations. One may roughly
calculate that HIV varies over the course of a 10-year infection period within a singly
infected person as much as HTLV-I has done over 100,000 years of co-evolution with
its human hosts worldwide. Whereas a vaccine protective against HTLV-I, based on
env antigens appears quite feasible (as it protects against HTLV-I infection in
experimentally infected rabbits and macaques), the development of HIV vaccines will
be much more problematic.
But that is not to say that efficacious HIV vaccination will be impossible. A small
proportion of African prostitutes exposed to HIV have developed cell-mediated
immunity which appears to protect them although they are repeatedly at sexual risk of
infection (Rowland-Jones et al., 1995). These individuals have never seroconverted to
HIV and lack PCR-detectable HIV genomes in the blood, although they may have been
infected locally in the genital tract. There are also a few individuals who have
seroconverted and who have detectable virus, albeit at relatively low load, who,
nevertheless, remain well and maintain high CD4 T-lymphocytes levels (Cao et al., 1995;
Pantaleo et al., 1995). Several of the monkey species which naturally harbour SIV
(e.g. sooty mangabeys and African green monkeys) also appear to remain well
indefinitely. If we could gain a greater understanding of the reason for human and
simian long-term non-progression we could perhaps enable the less fortunate majority
of HIV-infected people to stay well, and tip the balance of power between the immune
system and the lentivirus in favour of the host.
Therapeutic retroviruses
The foregoing discussion has dealt with naturally occurring retroviruses. It is worth
reminding the reader, too, that retroviruses can be turned to therapeutic use as vectors
in gene therapy. The property of retroviruses in causing persistent infection with genome
integration allows genes to be delivered to cells and tissues. Just as retroviruses have
themselves transduced host oncogenes (Figure 3), so can gene therapists insert genes for
replacement therapy in inherited disorders (Lever & Goodfellow, 1995). Thus, the initial
clinical trials of gene therapy for adenosine deaminase deficiency have used retroviral
vectors derived from disabled murine leukaemia virus genomes. For cancer treatment
the gene for herpes simplex thymidine kinase has been delivered to the tumour so that
systemically administered ganciclovir is selectively activated in the tumour tissue.
Thus it is satisfying to virologists that a viral vector delivering a gene activating an
antiviral prodrug may prove useful in treating a non-viral disease. However, there is
a long way to go to improve both the safety and efficacy of retroviral vectors. This
propensity to integrate is both part of their benefit and a cause of anxiety lest they cause
tumours via insertional mutagenesis. Their delivery is still not sufficient to infect the
majority of the target cells. Improvements are underway to use selective receptors and
tissue-specific gene promotors to restrict expression to target cells (Lever & Goodfellow,
1995). In-vivo delivery is limited by titre and by the observation that human
complement rapidly inactivates murine leukaemia virus envelopes. We have recently
found ways to obviate complement resistance that may lead to a new generation of
retroviral vectors (Takeuchi et al., 1994).
Retro virus classification and cell interactions
11
Acknowledgements
The work of the author is supported by the Medical Research Council and the Cancer
Research Campaign.
References
Note: The retrovirus literature is voluminous. Therefore some key text books and review articles
are cited together with selected articles of topical interest.
Cao, Y., Qin, L., Zhang, L., Safrit, J. & Ho, D. D. (1995). Virological and immunological
characterization of long-term survivors of human immunodeficiency virus type 1 infection.
New England Journal of Medicine 332, 201-8.
Coffin, J. M. (1995). HIV population dynamics in vivo: implications for genetic variation,
pathogenesis, and therapy. Science 267, 483-9.
Ho, D. D., Neumann, A. U., Perelson, A. S., Chen, W., Leonard, J. M. & Markowitz, M. (1995).
Rapid turnover of plasma virions and CD4 lymphocytes in HIV-1 infection. Nature 373,
123-6.
Lever, A. M. L. & Goodfellow, P. N. (1995). Gene therapy. British Medical Bulletin 51, 1-242.
Levy, J. A. (1992^1). The Retroviridae. Plenum Press, New York.
McKnight, A., Weiss, R. A., Shotton, C , Takeuchi, Y., Hoshino, H. & Clapham, P. R. (1995).
Change in tropism upon immune escape by human immunodeficiency virus. Journal of
Virology 69, 3167-70.
Pantaleo, G., Menzo, S., Vaccareqzza, M., Graziosi, C , Cohen, O. J., Demarest, J. F. et al.
(1995). Studies in subjects with long-term nonprogressive human immunodeficiency virus
infection. New England Journal of Medicine 332, 209-16.
Patterson, S., Gross, J., English, N., Stackpole, A., Bedford, P. & Knight, S. C. (1995). CD4
expression on dendritic cells and their infection by human immunodeficiency virus. Journal
of General Virology 76, 1155-63.
Rowland-Jones, S., Sutton, J., Ariyoshi, K., Dong, T., Gotch, F., McAdam, S. et al. (1995).
HIV-specific cytotoxic T-cells in HIV-exposed but uninfected Gambian women. Nature
Medicine 1, 59-64.
Skalka, A. M. & Goff, P. S. (1993). Reverse Transcriptase, pp. 1^492. Cold Spring Harbor
Laboratory Press, New York.
Takeuchi, Y., Cosset, F.-L. C , Lachmann, P. J., Okada, H., Weiss, R. A. & Collins, M. K. L.
(1994). Type C retrovirus inactivation by human complement is determined by both the viral
genome and the producer cell. Journal of Virology 68, 8001-7.
Venables, P. J. W., Brookes, S. M., Griffiths, D., Weiss,' R. A. & Boyd, M. T. (1995). Abundance
of an endogenous retroviral envelope protein in placental trophoblasts suggests a biological
function. Virology 211, 589-592.
Wei, X. P., Ghosh, S. K., Taylor, M. E., Johnson, V. A., Emini, E. A., Deutsch, P. (1995). Viral
dynamics in human immunodeficiency virus type 1 infection. Nature 373, 117-22.
Weiss, R. A. (1993). How does HIV cause AIDS? Science 260, 1273-9.
Weiss, R. A., Teich, N. M., Varmus, H. E. & Coffin, J. M. (1985). RNA Tumor Viruses, 2 vols,
pp. 1-1121; 1-1306. Cold Spring Harbor Laboratory Press, New York.
Wimmer, E. (1994). Cellular Receptors for Animal Viruses. Cold Spring Harbor Laboratory Press,
New York.