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Nature Reviews Microbiology 2, 401-413 (2004); doi:10.1038/nrmicro878
[1110K]
CONTROL OF HIV-1 INFECTION BY SOLUBLE FACTORS OF THE IMMUNE RESPONSE
Anthony L. DeVico & Robert C. Gallo
about the authors
Institute of Human Virology, University of Maryland Biotechnology Institute, Baltimore, Maryland 21202, USA.
correspondence to: Robert C. Gallo [email protected]
An increasing body of evidence indicates that the immune system uses a range of soluble molecules to suppress certain viral
infections without killing infected host cells. Recent studies indicate that such factors might have an especially important role
in the immune response to HIV-1. Accordingly, this review uses HIV-1 as a model to explore the diversity of non-cytolytic
antiviral factors and considers how these molecules might be used to develop new therapeutic and prophylactic strategies to
fight viral infections.
Viruses and immune systems play microscopic games of 'hide-and-seek' during the course of an infection. The virus attempts to find and
enter its host cell, replicate its genome, assemble new particles and spread to new target cells, while minimizing its exposure to the immune
system. At the same time, the immune system attempts to recognize and eliminate the invading viruses as quickly as possible and without
causing damage to the host. In cases of chronic viral infections, or when viruses (such as retroviruses) use cells of the immune system as
their hosts, this game can be very complicated indeed.
To gain an advantage, the immune system uses overlapping effector mechanisms, which are activated by viral infection and suppress one or
more steps in the virus life cycle (Fig. 1). NATURAL KILLER CELLS (NK cells)1, 2, granulocytes and, possibly,
-T CELLS3-5 provide the initial line of
defence when stimulated by chemical signals that are released at sites of infection. All of these cells produce immunoregulatory molecules:
neutrophils produce antimicrobial defensins; and NK cells and
-T cells can kill infected cells through cytolytic mechanisms 1-5. Host
macrophages and dendritic cells also have important roles in this early stage by taking up and presenting viral antigens and by secreting
several soluble CYTOKINES and CHEMOKINES that help to amplify the immune response. These early processes are called INNATE IMMUNE
RESPONSES because they can act immediately using extant receptors and do not require the induction of major histocompatibility complex
(MHC) gene products or antigen presentation in the context of MHC molecules. Over time, the innate response gives way to an adaptive
response, which requires viral antigen presentation by cell-surface MHC molecules. Adaptive immunity is carried out by several effector-cell
subsets, including CD8+ T CELLS, CD4+ HELPER T CELLS, and B cells. These cells establish important cell–cell communication mechanisms by
releasing a wide range of soluble molecules. The cellular arm of adaptive immunity is active at an early stage ( 1 week post-infection) and
has an important role in fighting most viral infections. CELLULAR IMMUNE RESPONSES are mediated by CD8+ cytotoxic T lymphocytes (CTLs) that
have been primed by dendritic cells and other cell subsets that present viral antigens in conjunction with Class I MHC molecules. Once primed
by MHC–antigen complexes and co-stimulatory signals, CTL clones target infected tissues and attempt to kill infected cells before they can
produce progeny viruses. To do this, the CTL must interact with viral antigens in conjunction with Class I MHC molecules on the surface of an
infected cell. The CTL then delivers pro-apoptotic signals and soluble cytolytic enzymes that destroy the infected target. Several weeks after
infection, the humoral arm of adaptive immunity joins the cellular response in combating infection. HUMORAL IMMUNE RESPONSES arise as a
result of interactions between antigen-specific B cells and CD4+ helper T cells that have been stimulated by viral antigens in conjunction with
MHC Class II antigens. Ultimately, the interacting B cells release antibodies that react with specific epitopes on the viral antigens. In most
cases, antiviral antibodies prevent the intercellular transmission of virions and the reinfection of the host, although in some instances they can
also contribute to the direct suppression of viral replication. Overall, the conventional view of the immune system holds that the control and
prevention of viral infections rests with one or more of these defence mechanisms, depending on the virus in question.
Figure 1 | A working model of an antiviral immune response that uses cytolytic cell killing,
antibodies and soluble non-cytolytic factors as a means to suppress infection.
In the first phase of an infection, viruses infect susceptible host cells. In response to infection, the innate
immune response mediates several antiviral mechanisms, including cytolytic cell killing by NKcells, which lyse
infected cells. Several soluble factors are also released, which directly suppress infection without killing
infected host cells. Infected cells or virions that escape the innate response are controlled by the humoral and
cellular adaptive immune responses. However, non-cytolytic antiviral mechanisms continue to have a crucial
role in suppressing viral replication. Infected host cells are shown in red and uninfected cells in green. IFN,
interferon; NK, natural killer; TNF, tumour necrosis factor.
However, this view is being reconsidered. We are beginning to understand that both innate and adaptive responses to viral infections can be
supplemented by NON-CYTOLYTIC SOLUBLE SUPPRESSOR FACTORS, which, remarkably, can be antiviral either by accident or design. This new
perspective has emerged primarily from four lines of evidence. First, it has become clear that certain immunoregulatory cytokines, including
INTERFERONS (IFNs) and tumour necrosis factor (TNF), not only induce apoptosis and necrosis of certain cell types on infection, but also
activate a number of intracellular pathways that directly suppress viral replication without killing the host cell 6-18. Interferons have been
shown to suppress hepatitis B virus (HBV), hepatitis C virus (HCV), herpes simplex virus, vesicular stomatitis virus (VSV), vaccinia virus,
picornaviruses, retroviruses, influenza viruses and other types of viruses in vitro in a non-cytolytic manner6-13, 17. These broad antiviral effects
are mediated by several mechanisms that rely on receptor-mediated gene-expression pathways, including the JAK/STAT (Janus kinase/signal
transducer and activator of transcription) signal-transduction cascade6-11, 18, 19. In the presence of double-stranded RNA, IFN- and IFNmediate well-characterized antiviral mechanisms that either degrade viral RNA transcripts or inhibit viral protein synthesis. Other mechanisms
inhibit the attachment, entry or assembly of certain viruses. IFNis likely to activate overlapping pathways as well as non-redundant
pathways and comparable antiviral mechanisms8, 11, 18, 19. Second, many cell subsets of both the innate and adaptive responses, including NK
cells, mononuclear phagocytes,
-T cells, CD4+ T cells and CTLs, have been shown to secrete non-cytolytic antiviral molecules, such as IFN
and TNF- , in response to stimulation by viral antigens10. Third, a substantial amount of data from experiments with HBV transgenic mice
indicate that the primary mechanism for the control and clearance of HBV infection is provided by the direct non-cytolytic antiviral activity of
soluble factors that are released by CTLs and/or NK cells10, 14, 15. In this transgenic system, the animals exhibit hepatic HBV gene expression,
but do not mount an immune response (anti-self) against HBV antigens. Furthermore, the data do not support cell–cell virus spread and
reinfection by HBV. So, these animals are highly useful for specific analyses of effector subsets. Adoptive transfer experiments carried out in
these mice showed that HBV-specific CTL clones suppress viral replication in many infected cells through non-cytolytic antiviral activities that
are mediated by IFNand, perhaps, TNF- 20-23. Fourth, cell subsets other than CTLs have been shown to release soluble factors with noncytolytic antiviral activity. CD4+ T cells have been shown to suppress influenza, VSV, HBV and vaccinia infections in mice24-30, and HIV-1
infections in human lymphocyte cultures31, through the release of soluble factors. NK cells have also been observed to suppress certain viral
infections by releasing non-cytolytic antiviral factors32-37. The production of soluble suppressor factors by
the protection of macaques from simian immunodeficiency virus (SIV)38.
-T cells has been correlated with
Given these findings, a new model for antiviral immunity has emerged, which includes the direct antiviral effects of soluble non-cytolytic
factors as an effector mechanism. In this model, the array of soluble mediator factors that are released in response to infection includes
factors that diffuse through the site of infection and directly suppress virus replication without killing infected cells (Fig. 1). As will be
discussed below, this working model accounts for the possibility that some of the virus suppressor molecules might also perform
immunoregulatory roles. In these cases, the relative importance of antiviral versus immunoregulatory function varies depending on the
infecting virus and the nature of the adaptive response.
In theory, this model presents three advantages for the infected host. First, a soluble/diffusible non-cytolytic effector function would boost the
antiviral potency of a CTL beyond its destructive capacity, which is inherently limited by the frequency of effector–target-cell contacts. So, a
CTL would be able to more rapidly clear an infection in tissues where it is outnumbered by infected cells. Second, NK cells and CTLs could
suppress infection in vital organs without having to destroy a large number of important cells. Third, an immune response to one virus might
suppress other viruses in the area by bystander effects that are mediated through the diffusion of soluble antiviral factors. For example, the
release of IFN by CTLs in response to one type of virus might partially 'sterilize' the area to other sensitive viruses. In the past such a
phenomenon was difficult to show in experimental viral systems. In mice, CTL clones that are specific for lymphocytic choriomeningitis virus
(LCMV) were passively transferred to animals that were then co-challenged with LCMV and the related pichinde arenavirus. Although the
animals were protected from LCMV, they were still infected by pichinde 39. Similarly, passive transfer of CTLs that are specific for influenza
haemagglutinin HA2 protected mice from influenza virus but not from concomitant challenge with influenza haemagglutinin HA 1 (Ref. 40).
Such specificity indicates that if soluble non-cytolytic factors are released by antiviral CD8+ T lymphocytes, they might be active only over
very short distances. On the other hand, it was shown that hepatocellular HBV gene expression was potently suppressed during LCMV
infection in HBV transgenic mice41. Such suppression was non-cytolytic and principally mediated by TNF- and IFN- /
produced by LCMVinfected intrahepatic macrophages41. Similarly, clinical studies have provided evidence that HBV replication is suppressed by acute hepatitis A
virus (HAV)-induced production of soluble factors including IFNcertain tissues and viral systems.
42, 43
. So, soluble 'bystander' suppression may indeed occur more readily in
In recent years, HIV-1 has been characterized as a virus that is highly sensitive to non-cytolytic suppression by soluble factors. Indeed, the
nature of soluble HIV-1 suppressor activity might reflect an intimate link between viral replication and the immune system. So, HIV-1
infection is an ideal model for appreciating the capacities of soluble factors to mediate antiviral immunity. Accordingly, the following sections
focus on HIV-1 suppressor factors, their activities and their relevance to natural infection.
Soluble HIV-1 suppressor activity
The first observations of non-cytolytic HIV-1 suppressor activity were made almost two decades ago in the context of CD8+ T-cell responses4446
. At that time, it was recognized that peripheral blood mononuclear cells (PBMCs) taken from seropositive asymptomatic individuals often
failed to manifest HIV-1 replication in vitro. In 1986, Walker et al.44 showed that this suppression of viral replication was linked to the
presence of CD8+ T cells in the cultures. Selective removal of these cells resulted in an elevation of viral replication, whereas depletion of
other cell types, such as CD16+ cells (including NK cells), had no effect44. Furthermore, reconstitution of depleted cultures with autologous
CD8+ T cells re-established suppression of HIV-1 replication in a concentration-dependent manner without altering the proliferation or viability
of CD4+ HIV-1 host cells45-49. Taken together, these data show that CD8 + T cells are able to block active HIV-1 replication through noncytolytic virus-suppressive mechanisms. Later studies revealed two more significant characteristics of this activity. First, the factor(s) that are
responsible for HIV-1 suppressor activity are soluble45, 46, 50. Experiments carried out in transwell chambers clearly showed that non-cytolytic
suppression was achieved even when the CD8+ T cells were separated from the CD4+ host cells by semi-permeable membranes50, 51. Other
experiments showed that HIV-1 suppression was mediated by filtered supernatants from cultures of CD8 + T cells that had been activated with
mitogen or anti-CD3 antibody and interleukin (IL)-2 (Refs 45,51,52). Second, the soluble factor(s) are capable of suppressing many, if not all,
primary HIV-1 strains46, 47. CD8+ cell supernatants suppressed infection in infectivity systems that used cell-free virus stocks, as well as in
experiments that used CD4+ T cells derived from HIV-positive individuals as the source of primary virus.
Taken together, these findings indicate that the immunological control of HIV-1 might involve non-cytolytic antiviral mechanisms, such as
those shown in Fig. 1. As CD8+ T cells release the factor(s) with suppressive activity, it was reasonable to suspect that this activity is most
relevant to cellular responses against HIV-1. So, the soluble suppressive factor was eventually named CD8 ANTIVIRAL FACTOR, or 'CAF', on the
basis of the narrow assumption that activity could be explained by a single molecule.
However, our perception of soluble HIV-1 suppressor activity has progressed beyond this simplistic concept in three significant ways. First, it
is now appreciated that soluble HIV-1 suppressor activity reflects the collective action of multiple factors. This characteristic was revealed in
1995, when it was determined that the chemokines RANTES and macrophage inflammatory proteins 1 and 1
(MIP-1 AND MIP-1 ) are
involved in the suppressor activity when released by activated CD8 + T cells53. Specifically, it was shown that neutralizing anti-chemokine
antibodies completely abrogate the HIV-1 suppressor activity of activated CD8+ T cells from HIV-1 seropositive, asymptomatic individuals.
Notably, antibodies against any one of the chemokines had little effect on suppressor activity against the test isolate, HIV-1Bal. However, a
mixture of antibodies against all three chemokines reversed the suppression of the virus (Fig. 2). This important observation showed that
RANTES, MIP-1
and MIP-1
were responsible for nearly all of the HIV-1Bal suppressor activity in the CD8+ T-cell-culture supernatants.
However, more extensive testing with a wider variety of isolates revealed that although RANTES, MIP-1 and MIP-1
always suppressed
what were then called MACROPHAGE-TROPIC viruses, they did not suppress T-TROPIC isolates, such as HIV-1IIIB53. This was in contrast to
+
unfractionated CD8 T-cell supernatants, which suppressed all strains of HIV-1 regardless of tropism. We now know that macrophage-tropic
viruses are selectively suppressed by RANTES, MIP-1 and MIP-1
owing to their specific requirements for entry. To enter target cells, HIV1 must first establish an envelope–receptor complex that includes the viral envelope glycoprotein (gp120) and cell-surface CD4 molecule. The
gp120–CD4 complex that is formed by macrophage-tropic viruses then binds selectively to a seven-transmembrane-spanning, G-proteincoupled surface co-receptor called CCR5 (Refs 54–58), which is also the natural receptor for RANTES, MIP-1 and MIP-1 . As a consequence
of this shared receptor usage, the entry of macrophage-tropic (now called R5) HIV-1 strains is blocked by the CCR5 ligands53, 59-61.
Conversely, the T-tropic (now designated X4) strains enter cells using a different chemokine receptor known as CXCR4, which is not bound by
CCR5 ligands58, 62 but instead by the chemokine stromal-cell-derived factor or SDF-1 (Ref. 63). This preference renders X4 strains immune to
inhibition by CCR5 ligands. So-called DUAL-TROPIC (R5X4) strains can use either co-receptor type, depending on target-cell expression
patterns, but are inhibited by CCR5 ligands whenever CCR5 is the operative co-receptor. So, RANTES, MIP-1 and MIP-1
collectively
account for the CD8-derived suppression of R5 viruses (and R5X4 viruses in a CCR5-dependent system), whereas other, unknown factors are
responsible for inhibiting the isolates that must use the CXCR4 co-receptor (Fig. 3). In riposte, 'CAF' is now defined as the portion of CD8derived suppressor activity that suppresses X4 HIV-1 strains (or R5X4 strains in a CCR5-minus system), or any suppressive molecule other
than RANTES, MIP-1 or MIP-1
non-R5 (X4 or R5X4) isolates.
17, 64, 65
. In general, it is now common to categorize factors according to whether they suppress R5 versus
Figure 2 | RANTES, MIP-1 and MIP-1
are primarily responsible for the suppression of
macrophage-tropic (R5) HIV-1 replication by CD8+ T-cell-culture supernatants.
In this experiment, the treatment of CD8 supernatants from four HIV-positive donors with a mixture of
neutralizing antibodies to RANTES, MIP-1 and MIP-1
extensively abrogates the suppression of HIV-1BaL
replication. HIV-SF, HIV suppressive factors. Reproduced with permission from Ref. 53 © (1995) American
Association for the Advancement of Science.
Figure 3 | A schematic representation of the multipartite nature of the soluble HIV-1 suppressor
activity produced by CD8+ T cells.
RANTES, MIP-1 and MIP-1
account for the suppression of R5 viruses. Unidentified factors suppress X4
and R5X4 HIV-1 isolates in a CCR5-negative system. CAF, CD8 antiviral factor.
Second, it is clear that bulk CD8+ T cells are not the only human cell sources of soluble non-cytolytic HIV-suppressor activities/factors (Fig.
4). For example, naive CD4+ T cells stimulated with immobilized anti-CD3 and anti-CD28 antibodies66-68 or co-cultured with antigen-pulsed
dendritic cells31, NK cells stimulated with IL-15 and IL-12 or cytokine and anti-CD16 (Refs 35–37),
-T cells69, and antigen-specific CD4+ T
cell clones70 have all been reported to secrete antiviral concentrations of RANTES, MIP-1 and MIP-1
together with unassigned activities
that suppress R5 and/or X4 isolates. CD4- or CD8-depleted PBMCs that are stimulated by live, inactivated influenza virus 71 produce HIVsuppressive levels of IFN- together with unidentified factors that suppress both R5 and X4 HIV-1 isolates. Alloantigen-stimulated whole
PBMC72 release a partially unassigned factor with antiviral activity that suppresses diverse HIV-1 strains. CTL clones that are stimulated by
autologous antigen-presenting cells or anti-CD3 antibodies also release a soluble non-cytolytic factor with antiviral activity that comprises
RANTES, MIP-1 , MIP-1
and unknown X4 suppressor factors73-78. These cells release RANTES, MIP-1 and MIP-1
from their cytoplasmic
granules as part of a larger glycosaminoglycan (GAG) complex75. Although the immunological significance of these chemokine–GAG
complexes is unclear, in the case of RANTES, MIP-1 and MIP-1
the antiviral activity is preserved after GAG binding, whereas the receptoractivating function is inhibited79. Notably, placental stromal cells were also shown to release a factor with HIV-suppressive activity80. In
accordance, leukaemia inhibitory factor, which is expressed in the placenta, was shown to inhibit multiple HIV-1 strains81.
Figure 4 | A variety of primary cell subsets secrete soluble HIV-1 suppressor activities in response to various
stimuli.
Candidate suppressor factors that are 'relevant' to these activities are shown. In this case, CCR5 ligands refers to RANTES,
MIP-1 and MIP-1 . The HIV-1 phenotype (which is defined by co-receptor preference) that has been reported to be most
sensitive to the various suppressor factors or activities is shown. CTL, cytotoxic T lymphocytes; EDN, eosinophil-derived
neurotoxin; MDC, macrophage-derived chemokine; NK, natural killer; PBMC, peripheral blood mononuclear cells.
Third, the composition of the suppressor factor(s) that are released in a given system might change over time. For example, four days after
addition of antigen co-cultures of naive CD4+ T cells and dendritic cells31 secrete a factor with suppressive activity that comprises RANTES,
MIP-1 , MIP-1
and macrophage-derived chemokine (MDC), which is another HIV-suppressive chemokine82-86. The suppressive activity of
the 4-day-old supernatant is almost entirely abrogated by neutralizing antibodies to these chemokines 31. However, culture supernatant that is
collected after stimulation is less sensitive to the neutralizing anti-chemokine antibodies. Furthermore, supernatants that are collected early
(1 day) after addition of antigen suppress HIV-1 in a manner that is completely insensitive to these antibodies. So, the cultures release
unknown inhibitors at certain time points and known suppressor factors at others. Such changes might be explained by the differentiation of
cells into distinct subsets over time. As a result, the culture supernatants reflect the presence of a dynamic collection of HIV-1 suppressive
molecules, some of which have yet to be identified.
Overall, these findings indicate that both innate and adaptive immune responses use soluble non-cytolytic antiviral activity to control HIV-1
replication. Findings that multiple cell subsets produce factors with antiviral activity indicate that there is a degree of redundancy in such
responses. However, it seems almost certain that soluble suppressor activity is always due to the actions of multiple components (possibly
providing another level of redundancy), although the nature of the composition might vary according to the cell subset and response pathway
in question.
The quest for other HIV-1 suppressor factors
To fully understand the immunological significance and practical value of soluble antiviral activity, the responsible factors must be identified
beyond rantes, MIP-1
and MIP-1
. Accordingly, efforts have been made to assign a molecular identity to 'CAF' and HIV-1 suppressor
activities. Early studies52, 87 focused on IFN- , and and TNF- , because they were already known to suppress a number of viruses
(see above), including HIV-1 (Refs 52,88–96), when tested as reagents. However, two studies found that treatment of CD8 + T-cell
supernatants with neutralizing antibodies against these cytokines, or other HIV-1 inhibitors, such as transforming growth factor (TGF)and
IL-4, did not abrogate 'CAF' activity52, 87. These studies indicated that an unknown factor is responsible for 'CAF' activity, but did not eliminate
the possibility that 'CAF' is a collection of known antiviral cytokines with redundant functions. Indeed, a later study showed that a combination
of antibodies to IL-10, IL-13, IFN- and IFNwas able to appreciably reverse HIV-1 suppressor activity in CD8+ T-cell-derived
supernatants97. However, the antibody mix did not achieve complete reversal of X4 HIV-1 suppression, indicating that additional unknown
suppressor factors were involved.
Fortunately, recent technological advances have greatly increased the chances of successfully identifying soluble HIV-1 suppressor factors.
The development of herpesvirus saimiri (HVS)- and human T lymphotrophic virus (HTLV)- immortalized T-cell lines that secrete factor(s) with
soluble suppressor activity53, 82, 98-100 has been particularly helpful because they provide continuous sources of antiviral factors, which is
necessary for protein purification and sequencing efforts. More recent refinements in genomic and microanalytical techniques have facilitated
direct examinations of primary cells for suppressor factors. Given these new tools, a number of additional candidate HIV-1 suppressor
factors82, 101-104 have been identified in recent years (Fig. 4).
Nevertheless, the identification of immunologically relevant suppressor factors remains a tricky business. Many molecules, including
substances present in commercial media or sera used to culture cells rather than T-cell-derived factors101, will suppress HIV-1 replication
under certain conditions and/or at sufficient concentrations. Therefore, it is essential to determine if a candidate factor is produced by primary
cells at effective antiviral concentrations. The most reliable method is to treat conditioned media with cognate antibodies that either neutralize
biological activity or clear the native antigen from solution. Abrogation of HIV-1 suppressor activity by such treatment unambiguously shows
that the candidate factor is active at the concentrations secreted by primary cells and therefore might be 'relevant' to a natural immune
response. Of course, such analyses will not address the presence of redundant factors unless an appropriate mixture of antibodies is used.
On the basis of antibody-neutralization experiments, most of the candidate human suppressor factors have been characterized as potentially
relevant to soluble suppressor activity from at least one source (Fig. 4). At the same time, it is also clear that relevance is system-dependent.
For example, IFN- contributes significantly to the activity of influenza-A-stimulated PBMCs71, yet IFNs do not seem to be important
components of factors with suppressor activity that are released by CD8 + T cells52, 87. In the case of PBMC-derived activities, relevance is also
determined by the nature of the antigenic stimulus. So, the main suppressor factor in influenza-A-stimulated PBMC cultures is IFN- 71,
whereas in alloantigen-stimulated PBMC cultures104 it is a heat-stable ribonuclease known as eosinophil-derived neurotoxin (EDN). This
variability is perhaps not surprising given that PBMCs can contain mixtures of cell subsets with different specificities and response profiles.
Overall, RANTES, MIP-1
and MIP-1
provide the most overlap among systems (Fig. 4).
But the big question remains: what factors are responsible for the CD8 + T-cell-derived suppressor activity that is not explained by RANTES,
MIP-1 and MIP-1 ? Notably, the anti-chemokine antibody experiments (Fig. 2) indicate that these unknown factors must be significantly
less potent against R5 HIV-1, as CD8+ cell-culture supernatants treated with anti-chemokine antibodies do not exhibit residual R5 suppressor
activity. If these other factors were able to suppress R5 infection, their antiviral activities should have been apparent after the chemokines
were neutralized, yet this was not the case. Possibly, the unknown factors are not present in the supernatants at sufficient concentrations to
block R5 HIV-1 replication. On the other hand, they might need to synergize with one of the R5 ligands to mediate R5 suppression. Of course,
these possibilities cannot be explored until the unknown factors have been identified.
Early on, the CXCR4 ligand SDF-1 was considered to be a logical candidate for 'CAF' when it was determined that it binds to CXCR4 coreceptors and blocks the entry of both X4 and dual-tropic viruses in CCR5-minus systems63. But lymphocytes produce little or no SDF-1 and
these levels do not correlate with CD8+ cell-derived suppressor activity105. Another early candidate for 'CAF' was the cytokine IL-16. This
cytokine is constitutively produced by CD4+ and CD8+ T cells106, and inhibits HIV-1 replication in vitro when tested as a recombinant
molecule103, 106-109. However, IL-16 is not considered relevant to 'CAF' as it was shown that the concentrations of cytokine that are released by
CD8+ cells do not correlate with levels of HIV-1 suppressor activity in culture supernatants. Furthermore, neutralizing anti-IL-16 antibodies do
not reverse the soluble HIV-1 suppressor activities that are derived from CD8 + cell cultures107. Other reports have suggested that 'CAF'
activity might be attributed to a fragment of bovine antithrombin III 101, or to a catalytically inactive amino-terminal peptide fragment of
urokinase-type plasminogen activator (ATF-uPA)110, 111. These possibilities remain to be explored. Recently, Ho and colleagues attributed 'CAF'
activity to the -defensins 1, 2 and 3 (Ref. 97). Defensins are well known as neutrophil-derived antibiotic factors and others had already
observed that they inactivate certain enveloped viruses 112-114, including HIV-1 (Ref. 115). However, the assertion that 'CAF' is explained by a
combination of RANTES, MIP-1 , MIP-1
and –defensins102, has not 'stood the test of time'. Following evidence that the antiviral
properties of 'CAF' and -defensins are discordant116-119, the Ho group revealed that the -defensins present in their cultures were released
by contaminating neutrophils and not by CD8+ T cells120, and therefore could not contribute to 'CAF'. So, the search for a specific CD8 + T-cellderived HIV-1 suppressor factor that is active against X4 viruses continues.
Although the nature of the unknown CD8-derived factors remains obscure, there are tantalizing indications that protease activity is involved.
A recent study showed that certain protease inhibitors abrogate the suppressor activity in CD8 + T-cell supernatants that act on X4 isolates121.
In accordance, it was suggested that the HIV-suppressive fragment of bovine antithrombin III is generated by a proteolytic activity that is
greater in CD8+ T-cell supernatants from HIV-infected donors than from seronegative donors101. Of course, this protease has no clinical
relevance until it is shown to process human substrate into an antiviral form.
Mechanisms of non-cytolytic HIV-1 suppression
Soluble suppressor activities suppress many HIV-1 strains. Such breadth of activity is consistent with the presence of multiple suppressor
mechanisms, which could selectively become activated according to viral phenotype and tropism (Fig. 5). In accordance with this view,
suppressor factors collectively exhibit a diverse range of antiviral mechanisms. MDC inhibits the replication of R5 viruses in macrophages, but
does not interfere in proviral DNA accumulation 84. However, MDC suppresses X4 viruses at the level of reverse transcription in primary T cells.
The X4-suppressive effects involve a G-protein-coupled signalling pathway (C. Kleinman, A.L.D. and A. Garzino-Demo, unpublished
observations) that is linked either to the MDC receptor CCR4 or to an unidentified receptor that might be used by a naturally truncated form
of the chemokine83. EDN ribonuclease is associated with a mechanism that blocks replication prior to reverse transcription72, 104, 122. The exact
mechanism of suppression is not known, but it might be similar to the RNase-dependent pathways that are induced by IFNs6-11. IFN- also
blocks HIV-1 replication prior to reverse transcription71, in part due to the downregulation of the CXCR4 co-receptor12, 13, and also at the
budding and assembly steps123. ATF-uPA also interferes with the budding and assembly steps of HIV-1 replication through receptor-mediated
pathways110, 111. The -defensins also suppress HIV-1 by altering the host-cell environment116, although they can directly bind and inactivate
other viruses113. In the case of HIV-1, suppression occurs at a post-entry step that might be as late as proviral integration 116. IL-16 is an
interesting case because it is a ligand for CD4 (Ref. 106). However, this binding does not prevent virus attachment or gp120 interactions.
Instead, CD4 crosslinking by IL-16 homodimers or homotetramers generates several second messengers that ultimately inhibit HIV-1 gene
transcription106, 108 and, possibly, the entry of virions into macrophages and dendritic cells109. Notably, IL-16 has also been shown to suppress
HIV-1 replication, even when present intracellularly 124. As discussed above, RANTES, MIP-1 and MIP-1
suppress the entry of R5 isolates;
details of this process have been exhaustively covered in several excellent reviews (for example, Ref. 58) and need not be described further.
However, it should be noted that three other CCR5 ligand — monocyte chemoattractant protein (MCP)-2 (Ref. 59), LD78
60
and a natural
fragment of human
-CC-chemokine (HCC)-1 (Ref. 61) — also suppress R5 HIV-1 strains at the level of entry, although these molecules
have not yet been formally linked to a soluble suppressor activity.
Figure 5 | Soluble factors might suppress HIV-1 at multiple replication steps through several
mechanisms.
Candidate factors and the replication steps they target are shown. ATF-uPa, amino-terminal peptide fragment
of urokinase-type plasminogen activator; EDN, eosinophil-derived neurotoxin; IFN, interferon; IL, interleukin;
LTR, long terminal repeat; MDC, macrophage-derived chemokine; STAT, signal transducer and activator of
transcription; CD87/u-PAR, urokinase-type plasminogen activator receptor.
Crude CD8+ T-cell supernatants contain yet another antiviral activity that has not been assigned to any known factor. This activity blocks HIV1 LONG TERMINAL REPEAT (LTR)-driven transcription17, 116, 125-131, presumably through signal-transduction pathways that are modulated by
receptor–ligand interactions. However, human CD8+ cell supernatants also suppress transcription that is driven by other retroviral
promoters127, which indicates that the responsible antiviral agent(s) is not specific to lentiviruses. In vitro assays indicate that nuclear factor
(NF)- B, nuclear factor of activated T cells (NFAT), and STAT1 might be involved in the suppressive mechanism 17, 127, 128, although
suppression of a SIV mutant was observed in the absence of a NF- B binding domain in the LTR131. The inhibition of LTR-driven transcription
is reminiscent of HIV-1 suppression by IL-16, IFN- , IFNand TGF; however, as discussed above, these molecules do not apparently
explain the CD8-derived activity. Therefore, it is still assumed that a single unknown factor that is released by CD8 + cells mediates the
transcriptional block. However, in the spirit of Ephraim Racker's tenet "Do not waste clean thinking on dirty enzymes", cauti on should be
exercised when assigning functional mechanisms to crude material. It is possible that the antiviral effects of crude CD8+ cell medium, which is
the definition of CAF, reflect the collective action of several factors, which might act in an indirect manner — for example, cause the release of
IFN and IL-16. It is also unclear how this mechanism would relate to the apparent link between CD8-derived HIV-1 suppression and protease
activity (see above).
Relevance of HIV-1 suppressor factors
The studies discussed in the previous section imply that, at least in some viral infections, soluble non-cytolytic antiviral factors might come
from multiple sources, under multiple conditions and target multiple steps in the virus life cycle. Given this redundancy, it seems possible that
soluble suppressor factors are able to produce a barrier web that would make the average spider blush. But is there any evidence that such a
web is catching bugs in vivo? The answer to this question is found in the clinic.
The first evidence that non-cytolytic activities might be clinically relevant was provided by studies that showed that CD8 + T cells from
asymptomatic HIV-1-infected individuals suppress HIV-1 replication more efficiently than cells from patients with AIDS45, 46, 133-135. Similarly,
lymphoid tissue CD8+ T cells from infected persons who remain clinically healthy for extended periods of time without clinical intervention
(known as LONG-TERM NON-PROGRESSORS) were shown to mediate more potent suppression than cells from AIDS patients 135. More recent
studies have focused on candidate factors rather than gross suppressor activity. Numerous clinical studies have compared the concentrations
of RANTES, MIP-1
or MIP-1
released from PBMCs and CD8+ T cells in vitro with the clinical status of the cell donor136-141. These studies
have repeatedly shown a statistically significant correlation between increased production of MIP-1 and/or MIP-1
from activated cells in
vitro and favourable clinical profiles, such as increased CD4 + T-cell counts or reduced viral loads. In accordance, genetic analyses have
uncovered polymorphisms in the human RANTES promoter that increase mRNA transcription and also correlate with slower HIV-1 disease
progression139, 142-145. Notably, a recent study found that HIV-infected patients who controlled their infection better after structured
interruption of therapy harboured R5 viruses that were significantly more susceptible to suppression by RANTES 146.
These data support the concept that soluble non-cytolytic antiviral activities dampen HIV-1 infection in vivo, although mainly in patients with
an intrinsic capacity to release high levels of suppressor factors. This proposal is consistent with the general model for soluble non-cytolytic
antiviral responses that is shown in Fig. 1. However, it is important to recognize that concentrations of CCR5 ligands and/or 'CAF' correlate
with disease status even when non-HIV-1 antigens or mitogens are used to stimulate the cells45, 46, 133-135, 137-141. Furthermore, studies on
CTLs derived from infected patients showed that the release of HIV-1 suppressor factors is not restricted to HIV-1-specific cells77. So, the
activation of the immune system might be sufficient to suppress HIV-1 through soluble mechanisms, particularly in patients that naturally
release increased concentrations of suppressor factors. Of course, the magnitude of this 'bystander' suppressive effect would depend on the
nature of the antigenic stimulus and the frequencies of cognate responder cells that release suppressor factors. The ratio of naive to memory
cells might also have an effect as memory cells should rapidly release soluble suppressor factors by degranulation, whereas naive cells
produce them more slowly de novo.
The available data further indicates that an intrinsic capacity to secrete high concentrations of HIV-1 suppressor factors might afford a certain
level of resistance to primary HIV-1 infection. Lymphocytes from HIV-1 seronegative people produce variable levels of soluble HIV-1
suppressor activity following stimulation with mitogen or other non-HIV-1 antigens31, 47, 71, 72, 98, 104, 122, 140, 141, 147-155. Adult individuals with
lymphocytes that release abnormally high concentrations of RANTES, MIP-1 or MIP-1
seem to remain uninfected despite repeated
exposure to HIV-1 (Refs 150,151). Uninfected children born to HIV-1-positive mothers exhibited the same trait 152. This intrinsic capacity
might be genetic or acquired owing to previous immunological perturbations.
There is also evidence that certain microorganisms elicit immune responses that dampen clinical HIV-1 infection via soluble non-cytolytic
suppressor factors. The situation seems analogous to what has been reported for HBV suppression during LCMV infection in transgenic mice41
or acute HAV infection in humans42, 43. Some individuals who are simultaneously infected with HIV-1 and either dengue157, Orientia
tsutsugamushi (the causative agent of scrub typhus) 157-159, hepatitis G/GB virus C160-164 and measles morbillivirus165 have reduced HIV-1 viral
loads and/or increased CD4+ T-cell counts compared with patients who are infected only with HIV-1 or with HIV-1 and other pathogens. As
passive transfer of cell-free plasma from donors with mild O. tsutsugamushi infection has been shown to reduce viral loads in HIV-1-infected
recipients and suppress HIV-1 replication in vitro158, a soluble factor is responsible for the effect. The activity has not been linked to HIVreactive antibodies. Furthermore, in vitro stimulation of PBMCs with O. tsutsugamushi induced the production of rantes and generated
resistance to R5, but not X4 or R5X4, HIV-1 infection159. In the case of hepatitis G virus (HGV), binding of the serum HGV E2 protein to CD81
led to increased RANTES secretion and reduced CCR5 expression 164. Notably, both dengue virus and HGV are flaviviruses and therefore might
induce the release of suppressor factors through similar immunological mechanisms. A prospective study of commercial sex workers in
Senegal showed that HIV-2 infection reduces the risk of HIV-1 infection166. Stimulated cells from these persons secreted abnormally high
concentrations of RANTES, MIP-1 and MIP-1
and resisted infection by R5 HIV-1 strains166). In vitro studies indicate that HTLV-II infection
might upregulate the production of MIP-1 167. Given these findings, it can be envisioned that some microbial infections efficiently elicit the
secretion of soluble HIV-1 suppressor factors at antiviral concentrations within reach of HIV-1 replication sites (Fig. 1). These concepts
warrant further experimental evaluation.
On the other hand, there are certain clinical observations that remain difficult to reconcile with the concept of soluble suppressor activity as a
mechanism of immunity. The infection of CD4 + T cells by HIV-1 is an example. As discussed above, naive and antigen-stimulated CD4+
subsets release soluble suppressor factors. Yet one report suggests that the HIV-1-specific CD4+ T-cell population contains more viral DNA
than other memory CD4+ T-cell pools168. It is possible that the close and prolonged proximity of these cells to actively replicating HIV-1
overcomes the suppressive capacities of soluble factors. Nevertheless, it is important to recognize that most antigen-responsive HIV-1specific CD4+ T cells are not infected by HIV-1 (Ref. 168), despite their increased chances of exposure to virus. This leaves the possibility that
soluble factors provide resistance to a fraction of cells under certain conditions. Likewise, a subset of CD3 - CD56+ CD4+ NK cells is persistently
infected with HIV-1 in vivo even though bulk CD56+ NK cells release soluble suppressor factors, including RANTES, MIP-1 and MIP-1 169.
However, other NK-cell subsets might be protected by soluble suppressor activity given the resistance of the bulk NK cell population to HIV-1
infection in vitro35-37. In other words, NK cells might represent a case of selective resistance to infection according to viral phenotype. In any
case, it seems clear that the impact of soluble suppressor factors in vitro will depend on a variety of parameters, including duration and
proximity to infection, viral replication kinetics versus the kinetics of production and uptake, and local viral phenotype.
Practical applications of suppressor factors
In view of the available evidence, it is logical to consider soluble non-cytolytic suppressor activity as a model for developing therapeutic and
prophylactic antiviral agents. Some measure of support for this proposal has been provided by HBV vaccine studies carried out in both mice
and humans. DNA-based HBV vaccines were shown to control viral replication in HBV-transgenic mice through the release of soluble noncytolytic factors from CD4+ and CD8+ lymphocytes170-172. Although therapeutic HBV vaccination of humans has not provided significant clinical
benefit, in some studies it was associated with reduced serum HBV DNA levels and enhanced T-cell proliferative responses that produced high
concentrations of TNF-
and IFN-
171, 172
. The direct administration of IFN-
is a successful treatment for HCV infection.
In the case of HIV-1 infection, the arguments for exploiting soluble suppressor factors are obvious. The factors are non-toxic to target cells
and, unlike antibodies or CTLs, they suppress diverse HIV-1 strains. Moreover, a significant portion of the bulk antiviral activity of primary
cells is derived from factors that suppress HIV-1 as a consequence of normal physiological functions. So, RANTES, MIP-1 and MIP-1
become highly selective antiviral agents against R5 HIV-1 strains as a consequence of their roles in an immune response.
One approach towards exploiting these features is to design antiretroviral drugs that mimic the activities of soluble suppressor factors.
Indeed, entry inhibitors that target CCR5 are likely to represent the most promising category of new antiretroviral agents. Another approach
might be to deliberately modulate the immune system to enhance the release of soluble suppressor factors from effector cells. A recent study
showed that the bacterial G1 cytostatic agent rapamycin causes PBMCs to secrete increased concentrations of rantes, MIP-1 and MIP-1 173
and to downregulate the CCR5 co-receptor. This effect rendered PBMCs and macrophages resistant to infection by R5 strains. Similarly, it was
shown that cells treated with other agents that inhibit the G1 phase of the cell cycle, such as hydroxyurea, secreted increased concentrations
of soluble HIV-1 suppressor factors, particularly RANTES, MIP-1 and MIP-1 174. Rapamycin has been used in humans to treat transplant
rejection and hydroxyurea has been tested in clinical trials in combination with anti-HIV-1 drugs. Therefore, these compounds might provide a
feasible and expedient means to clinically evaluate this concept. Furthermore, these agents might be used in combination with CCR5-targeted
drugs to produce a potent, synergistic antiviral effect.
Going a step further, a few research groups, including our own, have proposed the concept of using HIV-1 vaccines to enhance the capacity of
the immune system to release soluble HIV-1 suppressor activity together with classical immune responses. Fortunately, primate models can
be used to evaluate this concept as CD8+ T cells from chimpanzees, baboons and macaques secrete a primate equivalent of 'CAF' that
suppresses HIV-1, HIV-2 and SIV, respectively175-177. So far, primate vaccine strategies that are based on non-pathogenic strains, live
attenuated viruses or SIV antigens delivered to iliac lymph nodes have associated protection from virus challenge with the enhanced cellular
capacity to release CD8-derived soluble suppressor factors, particularly RANTES, MIP-1 and MIP-1 38, 178-184. The aim is to translate these
findings into a vaccine strategy that might be used in humans. Lehner and co-workers showed that allo-immunization of women (to prevent
spontaneous recurrent abortion) caused cells to upregulate the release of CD8-derived soluble suppressor factors and CCR5 ligands. In
addition, cells from these women became less susceptible to infection by HIV-1 and exhibited lower frequencies of co-receptor expression185.
These provocative results indicate that a prophylactic level of soluble factor release might be achieved with a vaccine that does not
necessarily contain HIV-1 antigens.
Concluding remarks
Viruses have evolved replication processes that allow them to coexist with the immune systems of their hosts. So, no single viral system can
be used to fully define 'antiviral immunity'. It is only through studies of different viral systems that we can fully appreciate the capacity of the
immune system to mediate antiviral immunity. Research on primate lentiretroviruses and other types of viruses, such as HBV, have indicated
that soluble non-cytolytic activity might provide an important mechanism for controlling at least some viral infections. Yet it is also possible
that the non-cytolytic suppression of antigen production might provide a virus with a method to persist in its host. Indeed, some viruses
might have evolved to coexist with such suppression as it does not immediately kill the virus or the host. On the other hand, there are likely
to be some viral infections that do not involve soluble non-cytolytic factors at all.
Nevertheless, it is entirely reasonable to view the soluble non-cytolytic antiviral activity as a promising basis for developing treatments for
viral infections. In the case of HIV-1 infection, it has become evident that soluble suppressor activity is mediated by diverse arrays of
molecules that are produced by a variety of cell subsets. This reality may not be as captivating as the concept of a single 'magic bullet' factor
that suppresses HIV-1 in multiple settings, but the possibilities that are provided by this diversity significantly expand the potential for
developing therapeutic or prophylactic antiviral strategies based on the mechanisms revealed by soluble, non-cytolytic immunity. This
potential will be realized and expanded as more suppressor factors are identified, characterized in the context of natural immune responses
and their mechanism of viral suppression unravelled.
Links
DATABASES
Entrez: hepatitis A virus | hepatitis B virus | HIV-1 | human T lymphotrophic virus | simian immunodeficiency virus | vaccinia virus |
vesicular stomatitis virus
LocusLink: CCR5 | CXCR4 | IFNs | TNF
SwissProt: eosinophil-derived neurotoxin | MIP-1
| MIP-1
References
1.
2.
3.
4.
5.
6.
7.
8.
9.
10.
11.
12.
13.
Biron, C. A., Nguyen, K. B., Pien, G. C., Cousens, L. P. & Salazar-Mather, T. P. Natural killer cells in antiviral defense: function and
regulation by innate cytokines. Annu. Rev. Immunol. 17, 189–220 (1999). | Article | PubMed | ISI | ChemPort |
Biron, C. A. & Brossay, L. NK cells and NKT cells in innate defence against viral infections. Curr. Opin. Immunol. 13, 458–464
(2001). | Article | PubMed | ISI | ChemPort |
Wallace, M., Malkovsky, M. & Carding, S. R.
(1995). | PubMed | ISI | ChemPort |
/ T lymphocytes in viral infections. J. Leukoc. Biol. 58, 277–283
Welsh, R. M. et al.
and
T-cell networks and their roles in natural resistance to viral infections. Immunol. Rev. 159, 79–93
(1997). | PubMed | ISI | ChemPort |
Selin, L. K., Santolucito, P. A., Pinto, A. K., Szomolanyi-Tsuda, E. & Welsh, R. M. Innate immunity to viruses: control of vaccinia virus
infection by
T cells. J. Immunol. 166, 6784–6794 (2001). | PubMed | ISI | ChemPort |
Isaacs, A. & Lindemann, J. Virus interference I. The interferon. Proc. Natl Acad. Sci. USA 147, 258 (1957). | ChemPort |
Vilcek, J. & Sen, G. C. in Virology (eds Fields B. N., Knipe, D. M. & Howley, P. M.) 375 (Lippencott–Raven, Philadelphia, 1996).
Kalvakolanu, D. V. & Borden, E. C. An overview of the interferon system: signal transduction and mechanism of action. Cancer Invest.
14, 25–53 (1996). | PubMed | ISI | ChemPort |
Stark, G. R., Kerr, I. M., Williams, B. R., Silverman, R. H. & Schreiber, R. D. How cells respond to interferons. Annu. Rev. Biochem. 67.
227–264 (1998). | Article | PubMed | ISI | ChemPort |
Guidotti, L. G. & Chisari, F. V. Noncytolytic control of viral infections by the innate and adaptive immune response. Annu. Rev. Immunol.
19, 65–91 (2001).
Excellent review of the role of soluble virus suppressor factors in HBV and other viral
infections. | Article | PubMed | ISI | ChemPort |
Katze, M. G., He, Y. & Gale, M. Viruses and interferon: a fight for supremacy. Nature Rev. Immunol. 2, 675–687 (2002). | Article
| PubMed | ISI | ChemPort |
Shirazi, Y. & Pitha, P. M. Intereferon -mediated inhibition of human immunodeficiency virus type 1 provirus synthesis in T-cells.
Virology 193, 303–312 (1993). | Article | PubMed | ISI | ChemPort |
Shirazi, Y. & Pitha, P. M. Interferon downregulates CXCR4 (fusin) gene expression in peripheral blood mononuclear cells. J. Human. Virol.
2, 69–76 (1998).
14.
Guidotti, L. G, Guilhot, S. & Chisari, F. V. Interleukin 2 and interferon /
negatively regulates hepatitis B virus gene expression in vivo
by tumor necrosis factor dependent and independent pathways. J. Virol. 68, 1265–1270 (1994). | PubMed | ISI | ChemPort |
15. Gilles, P. N., Fey, G. & Chisari, F. V. Tumor necrosis factor- negatively regulates hepatitis B virus gene expression in transgenic mice. J.
Virol. 66, 3955–3960 (1992). | PubMed | ISI | ChemPort |
16. Herbein, G. & O'Brien, W. A. Tumor necrosis factor (TNF)- and TNF receptors in viral pathogenesis Proc. Soc. Exp. Biol. Med. 223, 241–
257 (2000). | Article | PubMed | ISI | ChemPort |
17. Chang, T. L.-Y., Mosoian, A., Pine, R., Klotman, M. E. & Moore, J. P. A soluble factor(s) secreted from CD8 + T lymphocytes inhibits
human immunodeficiency virus type 1 replication through STAT1 activation. J. Virol. 76, 569–581
(2002). | Article | PubMed | ISI | ChemPort |
18. Patterson, J. B., Thomis, D. C., Hans, S. L. & Samuel, C. E. Mechanism of interferon action: double stranded RNA-specific adenosine
deaminase from human cells is inducible by
19.
Bovolenta, C. et al. A selective defect of IFN-
and
interferons. Virology 210, 508–511 (1995). | Article | PubMed | ISI | ChemPort |
- but not of IFN- -induced JAK/STAT pathway in a subset of U937 clones prevents the
antiretroviral effect of IFNagainst HIV-1. J. Immunol. 162, 323–330 (1999). | PubMed | ISI | ChemPort |
20. Guidotti, L. G. et al. Cytotoxic T lymphocytes inhibit hepatitis B virus gene expression by a noncytolytic mechanism in transgenic mice.
Proc. Natl Acad. Sci. USA 91, 3764–3768 (1994). | PubMed | ChemPort |
21. Guidotti, L. G. et al. Intracellular inactivation of the hepatitis B by cytotoxic T lymphocytes. Immunity 4, 25–36
(1996). | PubMed | ISI | ChemPort |
22. Guidotti, L. G. The role of cytotoxic T cells and cytokines in the control of hepatitis B virus infection. Vaccine 4, 80–82 (2002). | Article |
23. Nakamoto, Y., Guidotti, L. G., Pasquetto, V., Schreiber, R. D. & Chisari, F. V. Differential target cell sensitivity to cytotoxic T lymphocyte-
activated death pathways in vivo. J. Immunol. 158, 5692–5697 (1997). | PubMed | ISI | ChemPort |
24. Binder, D. & Kundig, T. Antiviral protection by CD8 + versus CD4+ T cells: CD8+ T cells correlating with cytotoxic activity in vitro are more
effective in antivaccinia virus protection than CD4-dependent interleukins. J. Immunol. 146, 4301–4307
(1991). | PubMed | ISI | ChemPort |
25. Eichelberger, M., Allan, W., Zijlstra, M., Jaenisch, R. & Doherty, P. C. Clearance of influenza virus respiratory infection in mice lacking
Class I major histocompatibility complex-restricted CD8+ T cells. J. Exp. Med. 174, 875–880 (1991). | PubMed | ISI | ChemPort |
26.
Kundig, T. M., Hengartner, H. & Zinkernagel, R. M. T-cell dependent interferon
exerts an antiviral effect in central nervous system but
not in peripheral solid organs. J. Immunol. 150, 2316–2321 (1992). | ISI |
27. Scherle, P. A., Palladino, G. & Gerhard, W. Mice can recover from pulmonary influenza virus infection in the absence of class I-restricted
cytotoxic T cells. J. Immunol. 148, 212–217 (1992). | PubMed | ISI | ChemPort |
28.
Spriggs, M. K. et al.
2-microglobulin-, CD8+ T-cell-deficient mice survive inoculation with hogh doses of vaccinia virus and exhibit
altered IgG responses Proc. Natl Acad. Sci. USA 89, 6070–6074 (1992). | PubMed | ChemPort |
29. Franco, A., Guidotti, L. G., Hobbs, M. V., Pasquetto, V. & Chisari, F. V. Pathogenic effector function of CD4 + T-helper-1 cells in hepatitis B
virus transgenic mice. J. Immunol. 159, 2001–2008 (1997). | PubMed | ISI | ChemPort |
30. Maloy, K. J. et al. CD4+ T-cell subsets during virus infection. Protective capacity depends on effector cytokine secretion and on migratory
capability. J. Exp. Med. 191, 2159–2170 (2000). | Article | PubMed | ISI | ChemPort |
31. Abdelwahab, S. F. et al. HIV-1-suppressive factors are secreted by CD4+ T cells during primary immune responses. Proc. Natl Acad. Sci.
USA 100, 15006–15010 (2003). | Article | PubMed | ChemPort |
32. Biron, C. A., Nguyen, K. B., Pien, G. C., Cousens, L. P. & Salazar-Mather, T. P. Natural killer cells in antiviral defense: function and
regulation by innate cytokines. Annu. Rev. Immunol. 17, 189–220 (1999). | Article | PubMed | ISI | ChemPort |
33.
Orange, J. S., Wang, B., Terhorst, C. & Biron, C. A. Requirement for natural killer cell-produced interferon
in defense against murine
cytomegalovirus infection and enhancement in defense pathway by interleukin 12 administration. J. Exp. Med. 182, 1045–1056
(1995). | PubMed | ISI | ChemPort |
34.
Orange, J. S. & Biron, C. A. Characterization of early IL-12, IFN- / , and TNF effects on antiviral state and NK responses during murine
cytomegalovirus infection. J. Immunol. 156, 4746–4756 (1996). | PubMed | ISI | ChemPort |
35. Fehniger, T. A. et al. Natural killer cells from HIV-1+ patients produce C-C chemokines and inhibit HIV-1 infection. J. Immunol. 161,
6433–6438 (1998). | PubMed | ISI | ChemPort |
36. Oliva, A. et al. Natural killer cells from human immunodeficiency virus (HIV)-infected individuals are an important source of CCchemokines and suppress HIV-1 entry and replication in vitro. J. Clin. Invest. 102, 223–231 (1998). | PubMed | ISI | ChemPort |
37. Kottilil, S. et al. Innate immunity in human immunodeficiency virus infection: effect of viremia on natural killer cell function. J. Infect.
Dis. 187, 1038–1045 (2003). | Article | PubMed | ISI |
38.
Lehner, T. et al. The role of
/ T cells in generating antiviral factors and
-chemokines in protection against mucosal simian
immunodeficiency virus infection. Eur. J. Immunol. 30, 2245–2256 (2000). | Article | PubMed | ISI | ChemPort |
39. Lukacher, A. E., Braciale, V. L. & Braciale, T. J. In vivo effector function of influenza virus-specific cytotoxic T lymphocyte clones is highly
specific. J. Exp. Med. 160, 814–825 (1984). | PubMed | ISI | ChemPort |
40. McIntyre, K. W., Bukowski, J. F. & Welsh, R. M. Exquisite specificity of adoptive immunization in arenavirus-infected mice. Antiviral Res.
5, 299–305 (1985). | Article | PubMed | ISI | ChemPort |
41. Guidotti, L. G. et al. Viral cross talk: intracellular inactivation of the hepatitis B virus during an unrelated infection of the liver. Proc. Natl
Acad. Sci. USA 93, 4589–4594 (1996). | Article | PubMed | ChemPort |
42. Tassopoulos, N. et al. Double infections with hepatitis A and B viruses. Liver 5, 348–353 (1985). | PubMed | ISI | ChemPort |
43. Van Nunen, A. B., Pontesilli, O., Uytdehaag, F., Osterhaus, A. D. & de Man, R. A. Suppression of hepatitis B virus replication mediated by
hepatitis A-induced cytokine production. Liver 21, 45–49. (2001). | Article | PubMed | ISI | ChemPort |
44. Walker, C. M., Moody, D. J., Stites, D. P. & Levy, J. A. CD8 + lymphocytes can control HIV infection in vitro by suppressing virus
replication. Science 234, 1563–1566 (1986).
Provides the first description of soluble HIV suppressor activity released by CD8 + T cells. This activity was later called
CAF. | PubMed | ISI | ChemPort |
45. Mackewicz, C. E. & Levy, J. A. CD8+ cell anti-HIV activity: noncytolytic suppression of virus replication. AIDS Res. Hum. Retrovir. 8,
1039–1050 (1992). | PubMed | ISI | ChemPort |
46. Levy, J. A., Mackewicz, C. E. & Barker, E. Controlling HIV pathogenesis: the role of the noncytotoxic anti-HIV response of CD8+ T cells.
Immunol. Today 17, 217–224 (1996). | Article | PubMed | ISI | ChemPort |
47. Barker, T. D., Weissman, D., Daucher, J. A., Roche, K. M. & Fauci, A. S. Identification of multiple and distinct CD8 + T cell suppressor
48.
49.
50.
51.
52.
53.
54.
activities: dichotomy between infected and uninfected individuals, evolution with progression of disease, and sensitivity to
irradiation.
J. Immunol. 156, 4476–4483 (1996) | PubMed | ISI | ChemPort |
+
+
Wiviott, L. D., Walker, C. M. & Levy, J. A. CD8 lymphocytes suppress HIV production by autologous CD4 cells without eliminating the
infected cells from culture. Cell. Immunol. 128, 628–634 (1990). | PubMed | ISI | ChemPort |
Walker, C. M., Erickson, A. L., Hsueh, F. C. & Levy, J. A. Inhibition of human immunodeficiency virus replication in acutely infected CD4+
cells by CD8+ cells involves a noncytotoxic mechanism. J. Virol. 65, 5921–5927 (1991). | PubMed | ISI | ChemPort |
Walker, C. M. & Levy, J. A. A diffusible lymphokine produced by CD8 + T lymphocytes suppresses HIV replication. Immunology 66, 628–
630 (1989). | PubMed | ISI | ChemPort |
Brinchmann, J. E., Gaudernack, G. & Vartdal, F. CD8 + T cells inhibit HIV replication in naturally infected CD4 + T cells. J. Immunol. 144,
2961–2966 (1990). | PubMed | ISI | ChemPort |
Mackewicz, C. E., Ortega, H. W. & Levy, J. A. Effect of cytokines on HIV replication in CD4 + lymphocytes: lack of identity with the CD8 +
cell antiviral factor. Cell. Immunol. 153, 329–343 (1994).
Provides evidence that the antiviral effect of CAF was not entirely due to any of the non-cytolytic antiviral cytokines known
at the time. | Article | PubMed | ISI | ChemPort |
Cocchi, F. et al. Identification of RANTES, MIP-1 , and MIP-1
as the major HIV-suppressive factors produced by CD8+ T cells. Science
270, 1811–1815 (1995).
The first report to identify a new HIV suppressor factor and reveal that certain chemokines are components of CAF. The
paper also showed that soluble suppressor activities are composed of multiple components. | PubMed | ISI | ChemPort |
Alkhatib, G. et al. CC CKR5: a RANTES, MIP-1 , MIP-1
receptor as a fusion cofactor for macrophage-tropic HIV-1. Science 272, 1955–
1958 (1996). | PubMed | ISI | ChemPort |
55. Dragic, T. et al. HIV-1 entry into CD4 1 cells is mediated by the chemokine receptor CC-CKR–5. Nature 381, 667–673 (1996). | Article
| PubMed | ISI | ChemPort |
56.
Choe, H. et al. The
-chemokine receptors CCR3 and CCR5 facilitate infection by primary HIV-1 isolates. Cell 85, 1135–1148
(1996). | Article | PubMed | ISI | ChemPort |
57. Deng, H. K. et al. Identification of a major co-receptor for primary isolates of HIV-1. Nature 381, 661–666 (1996). | Article
| PubMed | ISI | ChemPort |
58. Berger, E. A., Murphy, P. M. & Farber, J. M. Chemokine receptors as HIV-1 coreceptors: roles in viral entry, tropism, and disease. . Annu.
Rev. Immunol. 17, 657–700 (1999). | Article | PubMed | ISI | ChemPort |
59. Gong, W. et al. Monocyte chemotactic protein-2 activates CCR5 and blocks CD4/CCR5-mediated HIV-1 entry/replication. J. Biol. Chem.
273, 4289–4292 (1998). | Article | PubMed | ISI | ChemPort |
60. Bertini, R. et al. Identification of MIP-1 /LD78 as a monocyte chemoattractant released by the HTLV-I-transformed cell line MT4. AIDS
Res Hum Retrovir. 11, 155–160 (1995). | PubMed | ISI | ChemPort |
61. Detheux, M. et al. Natural proteolytic processing of hemofiltrate CC chemokine 1 generates a potent CC chemokine receptor (CCR)1 and
CCR5 agonist with anti-HIV properties. J. Exp. Med. 192, 1501–1508 (2000). | Article | PubMed | ISI | ChemPort |
62. Feng, Y., Broder, C. C., Kennedy, P. E. & Berger, E. A. HIV-1 entry cofactor: functional cDNA cloning of a seven-transmembrane, Gprotein coupled receptor. Science 272, 872–877 (1996).
This seminal paper demonstrates that certain chemokine receptors act as entry co-receptors for HIV1. | PubMed | ISI | ChemPort |
63. Bleul, C. C. et al. The lymphocyte chemoattractant SDF-1 is a ligand for LESTR/fusin and blocks HIV-1 entry. Nature 382, 829–833
(1996). | Article | PubMed | ISI | ChemPort |
64. Mackewicz, C. E., Craik, C. S. & Levy, J. A. The CD8+ cell noncytotoxic anti-HIV response can be blocked by protease inhibitors. Proc.
Natl Acad. Sci. USA 100, 3433–3438 (2003). | Article | PubMed | ChemPort |
65. Mackewicz, C. E. et al. Lack of the CD8+ cell anti-HIV factor in CD8+ cell granules. Blood 102, 180–183
(2003). | Article | PubMed | ISI | ChemPort |
66. Mengozzi, M. et al. Naive CD4 T cells inhibit CD28-costimulated R5 HIV replication in memory CD4 T cells. Proc. Natl Acad. Sci. USA 98,
11644–11649 (2001). | Article | PubMed | ChemPort |
67. Levine, B. L. et al. Antiviral effect and ex vivo CD4+ T cell proliferation in HIV-positive patients as a result of CD28 costimulation. Science
272, 1939–1943 (1996). | PubMed | ISI | ChemPort |
68. Riley, J. L. et al. Intrinsic resistance to T cell infection with HIV type 1 induced by CD28 costimulation. J. Immunol. 158, 5545–5553
(1997). | PubMed | ISI | ChemPort |
69.
Poccia, F. et al. Phospohoantigen-reactive V 9 2 T lymphocytes suppress in vitro human immunodeficiency virus type 1 replication by
cell-released antiviral factors including CC chemokines. J. Infect. Dis. 180, 858–861 (1999). | Article | PubMed | ISI | ChemPort |
70. Furci, L. et al. Antigen-driven C-C chemokine-mediated HIV-1 suppression by CD4+ T cells from exposed uninfected individuals
expressing wild-type CCR-5 allele. J. Exp. Med. 186, 455–460 (1997). | Article | PubMed | ISI | ChemPort |
71. Pinto, L. A. et al. Inhibition of human immunodeficiency virus type 1 replication prior to reverse transcription by influenza virus
stimulation. J. Virol. 74, 4505–4511 (2000).
Identifies IFN as an important component of the soluble HIV-1 suppressor factor that is released following influenza virus
stimulation. | Article | PubMed | ISI | ChemPort |
72. Pinto, L. A., Sharpe, S., Cohen, D. I. & Shearer, G. M. Alloantigen-stimulated anti-HIV activity. Blood 92, 3346–3354
(1998). | PubMed | ISI | ChemPort |
73. Roso, J. F. et al. Oligoclonal CD8 lymphocytes from persons with asymptomatic human immunodeficiency virus (HIV) type 1 infection
inhibit HIV-1 replication. J. Infect. Dis. 172, 964–973 (1995). | PubMed |
74. Yang, O. O. et al. Suppression of human immunodeficiency virus type 1 replication by CD8+ cells: evidence for HLA class I-restricted
triggering of cytolytic and noncytolytic mechanisms. J. Virol. 71, 3120–3128 (1997). | PubMed | ISI | ChemPort |
75.
Wagner, L. et al.
-chemokines are released from HIV-1-specific cytolytic T-cell granules complexed to proteoglycans. Nature 391,
908–911 (1998). | Article | PubMed | ISI | ChemPort |
76.
Price, D. A. et al. Antigen-specific release of
-chemokines by anti-HIV-1 cytotoxic T lymphocytes. Curr. Biol. 8, 355–358
(1998). | PubMed | ISI | ChemPort |
77. Van Baalen, C. A. et al. Kinetics of antiviral activity by human immunodeficiency virus type 1-specific cytotoxic T lymphocytes (CTL) and
rapid selection of CTL escape virus in vitro. J. Virol. 72, 6851–6857 (1998). | PubMed | ISI | ChemPort |
78. Le Borgne, S., Fevrier, M., Callebaut, C., Lee, S. P. & Riviere, Y. CD8-cell antiviral factor activity is not restricted to human
immunodeficiency virus (HIV)-specific T cells and can block HIV replication after initiation of reverse transcription. J. Virol. 74, 4456–
4464 (2000).
Demonstrates that CTLs against non-HIV antigens also release active concentrations of non-cytolytic HIV-1 suppressor
factors. | Article | PubMed | ISI | ChemPort |
79. Burns, J. M., Lewis, G. K. & DeVico, A. L. Soluble complexes of regulated upon activation, normal T cells expressed and secreted
(RANTES) and glycosaminoglycans suppress HIV-1 infection but do not induce Ca2+ signaling. Proc. Natl Acad. Sci. USA 96, 14499–
14504 (1999). | Article | PubMed | ChemPort |
80. Sharma, U. K. et al. A novel factor produced by placental cells with activity against HIV-1. J. Immunol. 161, 6404–6412 (1998).
81. Patterson, B. K. et al. Leukemia inhibitory factor inhibits HIV-1 replication and is upregulated in placentae from nontransmitting women.
J. Clin. Invest. 107, 287–294 (2001). | PubMed | ISI | ChemPort |
82.
Pal, R. et al. Inhibition of HIV-1 infection by the
-chemokine MDC. Science 278, 695–698 (1997). | Article | PubMed | ISI | ChemPort |
83. Struyf, S. et al. Enhanced anti-HIV-1 activity and altered chemotactic potency of NH2-terminally processed macrophage-derived
chemokine (MDC) imply an additional MDC receptor. J. Immunol. 161, 2672–2675 (1998). | PubMed | ISI | ChemPort |
84. Cota, M. et al. Selective inhibition of HIV replication in primary macrophages but not T lymphocytes by macrophage-derived chemokine.
Proc. Natl Acad. Sci. USA 97, 9162–9167 (2000). | Article | PubMed | ChemPort |
85. Agrawal, L., Vanhorn-Ali, Z. & Alkhatib, G. Multiple determinants are involved in HIV coreceptor use as demonstrated by CCR4/CCL22
interaction in peripheral blood mononuclear cells (PBMCs). J. Leukoc. Biol. 72, 1063–1074 (2002). | PubMed | ISI | ChemPort |
86. Moriuchi, H. & Moriuchi, M. Dichotomous effects of macrophage-derived chemokine on HIV infection. AIDS 28, 994–996 (1999). | Article |
87. Brinchmann, J. E., Gaudernack, G. & Vartdal, F. In vitro replication of HIV-1 in naturally infected CD4+ T cells is inhibited by rIFN 2 and
88.
by a soluble factor secreted by activated CD8 + T cells, but not by rIFN
Immune Defic. Syndr. 4, 480–488 (1991). | PubMed | ISI | ChemPort |
, rIFN
, or recombinant tumor necrosis factor- . J. Acquir.
Yamamoto, J. K., Barre-Sinoussi, F., Bolton, V., Pedersen, N. C. & Gardner, M. B. Human - and
-interferon but not
- suppress the
in vitro replication of LAV, HTLV-III, and ARV-2. J. Interferon Res. 6, 143–152 (1986). | PubMed | ISI | ChemPort |
89. Hammer, S. M., Gillis, J. M., Groopman, J. E. & Rose, R. M. In vitro modification of human immunodeficiency virus infection by
90.
granulocyte-macrophage colony-stimulating factor and
(1986). | PubMed | ChemPort |
interferon. Proc. Natl Acad. Sci. USA 83, 8734–8738
Nakashima, H., Yoshida, T., Harada, S & Yamamoto, H. Recombinant human interferon
suppresses HTLV-III replication in vitro. Int. J.
Cancer 38, 433–436 (1986). | PubMed | ISI | ChemPort |
91. Poli, G., Orenstein, J. M., Kinter, A., Folks, T. M. & Fauci, A. S. Interferon- but not AZT suppresses HIV expression in chronically
infected cell lines. Science 244, 575–577 (1989). | PubMed | ISI | ChemPort |
92. Wong, G. H., Krwoka, J. F., Stites, D. P. & Goeddel, D. V. In vitro anti-human immunodeficiency virus activities of tumor necrosis factor93.
and interferon-
. J. Immunol. 40, 120–124 (1988).
Williams, G. J. & Colby, C. B. Recombinant human interferonsuppresses the replication of HIV and acts synergistically with AZT. J.
Interferon Res. 9, 709–718 (1989). | PubMed | ISI | ChemPort |
94. Gendelman, H. E. et al. Regulation of HIV replication in infected monocytes by IFN- . Mechanisms for viral restriction. J. Immunol. 145,
2669–2676 (1990). | PubMed | ISI | ChemPort |
95.
Hartshorn, K. L., Neumeyer, D., Vogt, M. W., Schooley, R. T. & Hirsch, M. S. Activity of interferons ,
, and
against human
immunodeficiency virus replication in vitro. AIDS Res. Hum. Retrovir. 3, 125–133 (1987). | PubMed | ISI | ChemPort |
96. Kornbluth, R. S., Oh, P. S., Munis, J. R., Cleveland, P. H. & Richman, D. D. The role of interferons in the control of HIV replication in
macrophages. Clin. Immunol. Immunopathol. 54, 200–219 (1990). | Article | PubMed | ISI | ChemPort |
97.
Moriuchi, H., Moriuchi, M., Combadiere, C., Murphy, P. M. & Fauci, A. S. CD8 + T-cell-derived soluble factor(s), but not
-chemokines
RANTES, MIP-1 , and MIP-1 , suppress HIV-1 replication in monocyte/macrophages. Proc. Natl Acad. Sci. USA. 93, 15341–15345
(1996). | Article | PubMed | ChemPort |
98.
Saha, K., Bentsman, G., Chess, L. & Volsky, D. J. Endogenous production of
-chemokines by CD4+, but not CD8+, T-cell clones
correlates with the clinical state of human immunodeficiency virus type 1 (HIV-1)-infected individuals and may be responsible for
blocking infection with non-syncytium-inducing HIV-1 in vitro. J. Virol. 72, 876–881 (1998). | PubMed | ISI | ChemPort |
99. Leith, J. G. et al. T cell-derived suppressive activity: evidence of autocrine noncytolytic control of HIV type 1 transcription and replication.
AIDS Res. Hum. Retrovir. 15, 1553–1561 (1999). | Article | PubMed | ISI | ChemPort |
100. Mosoian, A., Teixeira, A., Caron, E., Piwoz, J. & Klotman, M. E. CD8 cell lines isolated from HIV-1-infected children have potent soluble
HIV-1 inhibitory activity that differs from
-chemokines. Viral Immunol. 13, 481–495 (2000). | PubMed | ISI | ChemPort |
101. Geiben-Lynn, R., Brown, N., Walker, B. D. & Luster, A. D. Purification of a modified form of bovine antithrombin III as an HIV-1 CD8+ Tcell antiviral factor. J. Biol. Chem. 277, 42352–42357 (2002).
Demonstrates that components of commercial media or serum additives (perhaps generated by cellular proteases) might
contribute to soluble HIV-suppressor activities. | Article | PubMed | ISI | ChemPort |
102. Zhang, L. et al. Contribution of human defensin 1, 2,and 3 to the anti-HIV-1 activity of CD8 antiviral factor. Science 298, 995–1000
(2002). | Article | PubMed | ISI | ChemPort |
103. Baier, M., Werner, A., Bannert, N., Metzner, K. & Kurth, R. HIV suppression by interleukin-16. Nature 378, 563 (1995). | Article
| PubMed | ISI | ChemPort |
104. Rugeles, M. T. et al. Ribonuclease is partly responsible for the HIV-1 inhibitory effect activated by HLA alloantigen recognition. AIDS 17,
481–486 (2003).
Identifies EDN ribonuclease as an important soluble HIV-1 suppressor factor that is released by alloantigen-stimulated
cells. | Article | PubMed | ISI | ChemPort |
105. Lacey, S., McDanal, C. B., Horuk, R. & Greenberg, M. L. The CXC chemokine stromal cell derived factor 1 is not responsible for CD8+ T
cell suppression of syncytia-indicing strains of HIV-1. Proc. Natl Acad. Sci. USA 94, 9842–9847 (1997). | Article | PubMed | ChemPort |
106. Cruikshank, W. W., Kornfeld, H. & Center, D. M. Interleukin-16. J. Leukoc Biol. 67, 757–766 (2000). | PubMed | ISI | ChemPort |
107. Mackewicz, C. E., Levy, J. A., Cruikshank, W. W., Kornfeld, H. & Center, D. M. Role of IL-16 in HIV replication. Nature 383, 488–489
(1995). | Article | ISI |
108. Maciaszek, J. W. et al. IL-16 represses HIV-1 promoter activity. J. Immunol. 158, 5–8 (1997). | PubMed | ISI | ChemPort |
109. Truong, M. et al. Interleukin-16 inhibits human immunodeficiency virus type 1 entry and replication in macrophages and dendritic cells.
J. Virol. 73, 7008–7013 (1999). | PubMed | ISI | ChemPort |
110. Wada, M. et al. Amino-terminal fragment of urokinase-type plasminogen activator inhibits HIV-1 replication. Biochem. Biophys. Res.
Commun. 284, 346–351 (2001). | Article | PubMed | ISI | ChemPort |
111. Alfano, M., Sidenius, N., Panzeri, B., Blasi, F. & Poli, G. Urokinase-urokinase receptor interaction mediates an inhibitory signal for HIV-1
replication. Proc. Natl Acad. Sci. USA 99, 8862–8867 (2002). | Article | PubMed | ChemPort |
112. Sinha, S., Cheshenko, N., Lehrer, R. I. & Herold, B. C. NP-1, a rabbit -defensin, prevents the entry and intercellular spread of herpes
simplex virus type 2. Antimicrob. Agents Chemother. 47, 494–500 (2003). | Article | PubMed | ISI | ChemPort |
113. Daher, K. A., Selsted, M. E. & Lehrer, R. I. Direct inactivation of viruses by human granulocyte defensins. J. Virol. 60, 1068–1074
(1986). | PubMed | ISI | ChemPort |
114. Bastian, A. & Schafer, H. Human -defensin 1 (HNP-1) inhibits adenoviral infection in vitro. Regul. Pept. 101, 157–161
(2001). | Article | PubMed | ISI | ChemPort |
115. Nakashima, H., Yamamoto, N., Masuda, M. & Fujii, N. Defensins inhibit HIV replication in vitro. AIDS 7, 1129
(1993). | PubMed | ISI | ChemPort |
116. Chang, T. L., Francois, F., Mosoian, A. & Klotman, M. E. CAF-mediated human immunodeficiency virus (HIV) type 1 transcriptional
inhibition is distinct from -defensin-1 HIV inhibition. J. Virol. 77, 6777–6784 (2003). | Article | PubMed | ISI | ChemPort |
117. Mackewicz, C. E. et al. Lack of the CD8+ cell anti-HIV factor in CD8+ cell granules. Blood 102, 180–183
(2003). | Article | PubMed | ISI | ChemPort |
118. Borregaard, N. & Cowland, J. B. Granules of the human neutrophilic polymorphonuclear leukocyte. Blood 10, 3503–3521 (1997).
119. Mackewicz, C. E. et al. -defensins can have anti-HIV activity but are not CD8 cell anti-HIV factors. AIDS 17, 23–32
(2003). | Article | PubMed |
120. Zhang, L., Lopez, P., He, T., Yu, W. & Ho, D. D. Retraction of an interpretation. Science 303, 467
(2004). | Article | PubMed | ISI | ChemPort |
121. Mackewicz, C. E., Craik, C. S. & Levy, J. A. The CD8+ cell noncytotoxic anti-HIV response can be blocked by protease inhibitors. Proc.
Natl Acad. Sci. USA 100, 3433–3438 (2003). | Article | PubMed | ChemPort |
122. Pinto, L. A., Blazevic, V., Shearer, G. M., Patterson, B. K. & Dolan, M. J. Alloantigen-induced anti-HIV activity occurs prior to reverse
transcription and can be generated by leukocytes from HIV-infected individuals. Blood 95, 1875–1876 (2000). | PubMed | ISI | ChemPort |
123. Fernie, B. F., Poli, G. & Fauci, A. S. -interferon suppresses virion but not soluble human immunodeficiency virus antigen production in
chronically infected T-lymphocytic cells. J. Virol. 65, 3968–3971 (1991). | PubMed | ISI | ChemPort |
124. Zhou, P., Goldstein, S., Devadas, K., Tewari, D. & Notkins, A. Human CD4 + cells transfected with IL-16 cDNA are resistant to HIV-1
infection: inhibition of mRNA expression. Nature Med. 3, 659–664 (1997). | PubMed | ISI | ChemPort |
125. Chen, C. H., Weinhold, K. J., Bartlett, J. A., Bolognesi, D. P. & Greenberg, M. L. CD8 T lymphocyte-mediated inhibition of HIV-1 long
terminal repeat transcription: a novel antiviral mechanism. AIDS Res. Hum. Retrovir. 9, 1079–1086 (1993).
Shows that 'CAF' contains an unknown factor that inhibits HIV-1 transcription. | PubMed | ISI | ChemPort |
126. Mackewicz, C. E., Blackbourn, D. J. & Levy, J. A. CD8 T cells suppress human immunodeficiency virus replication by inhibiting viral
transcription. Proc. Natl Acad. Sci. USA 92, 2308–2312 (1995). | PubMed | ChemPort |
127. Copeland, K. F., McKay, P. J. & Rosenthal, K. L. Suppression of activation of the human immunodeficiency virus long terminal repeat by
CD8 T cells is not lentivirus specific. AIDS Res. Hum. Retrovir. 11, 1321–1326 (1995). | PubMed | ISI | ChemPort |
128. Copeland, K. F., McKay, P. J. & Rosenthal, K. L. Suppression of the human immunodeficiency virus long terminal repeat by CD8 T cells is
dependent on the NFAT-1 element. AIDS Res. Hum. Retrovir. 12, 143–148 (1996). | PubMed | ISI | ChemPort |
129. Leith, J. G. et al. T cell-derived suppressive activity: evidence of autocrine noncytolytic control of HIV type 1 transcription and replication.
AIDS Res. Hum. Retrovir. 15, 1553–1561 (1999). | Article | PubMed | ISI | ChemPort |
130. Tomaras, G. D. et al. CD8 T cell-mediated suppressive activity inhibits HIV-1 after virus entry with kinetics indicating effects on virus
gene expression. Proc. Natl Acad. Sci. USA 97, 3503–3508 (2000). | Article | PubMed | ChemPort |
131. Locher, C. P., Witt, S. A. & Levy, J. A. The nuclear factor B and Spl binding sites do not appear to be involved in virus suppression by
CD8 T lymphocytes. AIDS 15, 2455–2457 (2001). | Article | PubMed | ISI | ChemPort |
132. Walker, C. M., Moody, D. J., Stites, D. P. & Levy, J. A. CD8 + T lymphocyte control of HIV replication in cultured CD4 + cells varies among
infected individuals. Cell. Immunol. 119, 470–475 (1989). | PubMed | ISI | ChemPort |
133. Mackewicz, C. E., Ortega, H. W. & Levy, J. A. CD8 + cell anti-HIV activity correlates with the clinical state of the infected individual. J.
Clin. Invest. 87, 1462–1466 (1991).
Provides early evidence that the natural capacity to produce increased concentrations of HIV-1 suppressor factors
correlates with better clinical status in HIV-1 infection. | PubMed | ISI | ChemPort |
134. Stanford, S. A. et al. Lack of infection in HIV-exposed individuals is associated with a strong CD8+ cell noncytotoxic anti-HIV response.
Proc. Natl Acad. Sci. USA 96, 1030–1035 (1999). | Article | PubMed |
135. Blackbourn, D. J. et al. Suppression of HIV replication by lymphoid tissue CD8 + cells correlates with the clinical state of HIV-infected
individuals. Proc. Natl Acad. Sci. USA 93, 13125–13130 (1996). | Article | PubMed | ChemPort |
136. Garzino-Demo, A., DeVico, A. L. & Gallo, R. C. Chemokine receptors and chemokines in HIV infection. J. Clin. Immunol. 18, 243–255
(1998). | Article | PubMed | ISI | ChemPort |
137.
Garzino-Demo, A., DeVico, A. L., Cocchi, F. & Gallo, R. C.
-chemokines and protection from HIV type 1 disease. AIDS Res. Hum.
Retrovir. 14 (Suppl.), S177–S184 (1998). | PubMed | ISI | ChemPort |
138. Gallo, R. C., Garzino-Demo, A. & DeVico, A. L. HIV infection and pathogenesis: what about chemokines? J. Clin. Immunol. 19, 293–299
(1999). | Article | PubMed | ISI | ChemPort |
139. Garzino-Demo, A., DeVico, A. L., Conant, K. E. & Gallo, R. C. The role of chemokines in human immunodeficiency virus infection.
Immunol. Rev. 177, 79–87 (2000). | Article | PubMed | ISI | ChemPort |
140.
Garzino-Demo, A. et al. Spontaneous and antigen-induced production of HIV-inhibitory
-chemokines are associated with AIDS-free
status. Proc. Natl Acad. Sci. USA 96, 11986–11991 (1999). | Article | PubMed | ChemPort |
141.
Cocchi, F. et al. Higher macrophage inflammatory protein (MIP)-1 and MIP-1
levels from CD8+ T cells are associated with
asymptomatic HIV-1 infection. Proc. Natl Acad. Sci. USA 97, 13812–13817 (2000).
This cross-sectional study shows that a natural capacity to release increased concentrations of CCR5 ligands on
stimulation correlates with better clinical status in HIV-1 infection. | Article | PubMed | ChemPort |
142. Liu, H. et al. Polymorphism in RANTES chemokine promoter affects HIV-1 disease progression. Proc. Natl Acad. Sci. USA 96, 4581–4585
(1999). | Article | PubMed | ChemPort |
143. McDermott, D. H. et al. Chemokine RANTES promoter polymorphism affects risk of both HIV infection and disease progression in the
multicenter AIDS cohort study. AIDS 14, 2671–2678 (2000). | Article | PubMed | ISI | ChemPort |
144. Gonzales, E. et al. Global survey of genetic variation in CCR5, RANTES, and MIP-1 : impact on the epidemiology of the HIV-1 pandemic.
Proc. Natl Acad. Sci. USA 98, 51199–5204 (2001).
145. An, P. et al. Modulating influence on HIV/AIDS by interacting RANTES gene variants. Proc. Natl Acad. Sci. USA 99, 10002–10007
(2002). | Article | PubMed | ChemPort |
146. Swiss HIV Cohort Study. Human immunodeficiency virus type 1 fitness is a determining factor in viral rebound and set point in chronic
infection. J. Virol. 77, 13146–13155 (2003). | ISI |
147. Hsueh, F. W., Walker, C. M., Blackbourn, D. J. & Levy, J. A. Suppression of HIV replication by CD8 + cell clones derived from HIV-infected
and uninfected individuals. Cell. Immunol. 159, 271–279 (1994). | Article | PubMed | ISI | ChemPort |
148. Rosok, B. et al. CD8+ T cells from HIV type 1-seronegative individuals suppress virus replication in acutely infected cells. AIDS Res. Hum
Retrovir. 13, 79–85 (1997). | PubMed | ISI | ChemPort |
149. Levy, J. A., Hsueh, F., Blackbourn, D. J., Wara, D. & Weintrub, P. S. CD8 cell noncytotoxic antiviral activity in human immunodeficiency
virus-infected and-uninfected children. J. Infect. Dis. 177, 470–472 (1998). | PubMed | ISI | ChemPort |
150. Zagury, D. et al. C-C chemokines, pivotal in protection against HIV type 1 infection. Proc. Natl Acad. Sci. USA 95, 3857–3861
(1998). | Article | PubMed | ChemPort |
151. Paxton, W. A. et al. Reduced HIV-1 infectability of CD4+ lymphocytes from exposed-uninfected individuals: association with low
expression of CCR5 and high production of
-chemokines. Virology 244, 66–73 (1998).
Provides early evidence that patients who remain uninfected despite repeated exposure to HIV-1 have a natural capacity
to release high concentrations of soluble suppressor factors. | Article | PubMed | ISI | ChemPort |
152.
Wasik, T. J. et al. Protective role of
-chemokines associated with HIV-specific Th responses against perinatal HIV transmission. J.
Immunol. 162, 4355–4364 (1999). | PubMed | ISI | ChemPort |
153. Stranford, S. A. et al. Lack of infection in HIV-exposed individuals is associated with a strong CD8+ cell noncytotoxic anti-HIV response.
Proc. Natl Acad. Sci. USA 96, 1030–1035 (1999). | Article | PubMed | ChemPort |
154. Geiben-Lynn, R. et al. Noncytolytic inhibition of X4 virus by bulk CD8 + cells from human immunodeficiency virus type 1 (HIV-1)-infected
persons and HIV-1-specific cytotoxic T lymphocytes is not mediated by
-chemokines. J. Virol. 75, 8306–8316
(2001). | Article | PubMed | ISI | ChemPort |
155. Skurnick, J. H. et al. Correlates of nontransmission in US women at high risk of human immunodeficiency virus type 1 infection through
sexual exposure. J. Infect. Dis. 185, 428–438 (2002). | Article | PubMed | ISI |
156. Watt, G., Kantipong, P. & Jongsakul, K. Decrease in human immunodeficiency virus type 1 load during acute dengue fever. Clin. Infect.
Dis. 36, 1067–1069 (2003). | Article | PubMed | ISI |
157. Watt, G. et al. HIV-1 suppression during acute scrub-typhus infection. Lancet 356, 475–479 (2000). | Article | PubMed | ISI | ChemPort |
158. Watt, G., Kantipong, P., Jongsakul, K., de Souza, M. & Burnouf, T. Passive transfer of scrub typhus plasma to patients with AIDS: a
descriptive clinical study. Q. J. M. 94, 599–607 (2001). | Article | ChemPort |
159. Moriuchi, M., Tamura, A. & Moriuchi, H. In vitro reactivation of human immunodeficiency virus-1 upon stimulation with scrub typhus
rickettsial infection. Am. J. Trop. Med. Hyg. 68, 557–561 (2003). | PubMed | ISI |
160. Lefrere, J. J. et al. Carriage of GB virus C/hepatitis G virus RNA is associated with a slower immunologic, virologic, and clinical
progression of human immunodeficiency virus disease in coinfected persons. J. Infect. Dis. 179, 783–789
(1999). | Article | PubMed | ISI | ChemPort |
161. Yeo, A. E. et al. Effect of hepatitis G virus infection on progression of HIV infection in patients with hemophilia. Multicenter hemophilia
cohort study. Ann. Intern. Med. 132, 959–963 (2000). | PubMed | ISI | ChemPort |
162. Tillmann, H. L. et al. Infection with GB virus C and reduced mortality among HIV-infected patients. N. Engl. J. Med. 345, 715–724
(2001). | Article | PubMed | ISI | ChemPort |
163. Tillmann, H. L. & Manns, M. P. GB virus-C infection in patients infected with the human immunodeficiency virus. Antiviral Res. 52, 83–90
(2001). | Article | PubMed | ISI | ChemPort |
164. Nattermann, J. et al. Regulation of CC chemokine receptor 5 in hepatitis G virus infection. AIDS. 17, 1457–1462
(2003). | Article | PubMed | ISI | ChemPort |
165. Moss, W. J. et al. Suppression of human immunodeficiency virus replication during acute measles. J. Infect. Dis. 185, 1035–1042
(2002). | Article | PubMed | ISI |
166. Kokkotou, E. G. et al. In vitro correlates of HIV-2-mediated HIV-1 protection. Proc. Natl Acad. Sci. USA 97, 6797–6802
(2000). | Article | PubMed | ChemPort |
167. Casoli, C. et al. HTLV-II down-regulates HIV-1 replication in IL-2-stimulated primary PBMC of coinfected individuals through expression
of MIP-1 . Blood 95, 2760–2769 (2000). | PubMed | ISI | ChemPort |
168. Douek, D. C. et al. HIV preferentially infects HIV-specific CD4+ T cells. Nature 417, 95–98 (2002). | Article | PubMed | ISI | ChemPort |
169. Valentin, A. et al. Persistent HIV-1 infection of natural killer cells in patients receiving highly active antiretroviral therapy. Proc. Natl
Acad. Sci. USA 99, 7015–7020 (2002). | Article | PubMed | ChemPort |
170. Mancini, M., Hadchouel, M., Tiollais, P. & Michel, M. L. Regulation of hepatitis B virus mRNA expression in a hepatitis B surface antigen
transgenic mouse model by IFN- -secreting T cells after DNA-based immunization. J. Immunol. 161, 5564–5570
(1998). | PubMed | ISI | ChemPort |
171. Couillin, I. et al. Specific vaccine therapy in chronic hepatitis B: induction of T cell proliferative responses specific for envelope antigens.
J. Infect. Dis. 180, 15–26 (1999). | Article | PubMed | ISI | ChemPort |
172. Ren, F., et al. Cytokine-dependent anti-viral role of CD4-positive T cells in therapeutic vaccination against chronic hepatitis B viral
infection. J. Med. Virol. 71, 376–384 (2003). | Article | PubMed | ISI | ChemPort |
173.
Heredia, A. et al. Rapamycin causes down-regulation of CCR5 and accumulation of anti-HIV
-chemokines: an approach to suppress R5
strains of HIV-1. Proc. Natl Acad. Sci. USA 100, 10411–10416 (2003). | Article | PubMed | ChemPort |
174.
Heredia, A. et al. Induction of G1 cycle arrest in T lymphocytes results in increased extracellular levels of
-chemokines: a strategy to
inhibit R5 HIV-1. Proc. Natl Acad. Sci. USA 100, 4179–4184 (2003). | Article | PubMed | ChemPort |
175. Castro, B. A., Walker, C. M., Eichberg, J. W. & Levy, J. A. Suppression of human immunodeficiency virus replication by CD8 + cells from
infected and uninfected chimpanzees. Cell. Immunol. 132, 246–255 (1991). | PubMed | ISI | ChemPort |
176. Blackbourn, D. J. et al. CD8+ cells from HIV-2-infected baboons control HIV replication. AIDS 11, 737–746
(1997). | Article | PubMed | ISI | ChemPort |
177. Kannagi, M., Chalifoux, L. V., Lord, C. I. & Letvin, N. L. Suppression of simian immunodeficiency virus replication in vitro by CD8+
lymphocytes. J. Immunol. 140, 2237–2242 (1988). | PubMed | ISI | ChemPort |
178. Gauduin, M. C., Glickman, R. L., Means, R. & Johnson, R. P. Inhibition of simian immunodeficiency virus (SIV) replication by CD8+ T
lymphocytes from macaques immunized with attenuated SIV. J. Virol. 72, 6315–6324 (1988).
179.
Heeney, J. L. et al.
-chemokines and neutralizing antibody titers correlate with sterilizing immunity generated in HIV-1 vaccinated
macaques. Proc. Natl Acad. Sci. USA 95, 10803–10808 (1988). | Article |
+
180. Leno, M. et al. CD8 lymphocyte antiviral activity in monkeys immunized with SIV recombinant poxvirus vaccines: potential role in
vaccine efficacy. AIDS Res. Hum. Retrovir. 15, 461–470 (1999). | Article | PubMed | ISI | ChemPort |
181. Heeney, J. et al. HIV-1 vaccine-induced immune responses which correlate with protection from SHIV infection: compiled preclinical
efficacy datafrom trials with ten different HIV-1 vaccine candidates. Immunol. Lett. 66, 189–195
(1999). | Article | PubMed | ISI | ChemPort |
182.
Ahmed, R. K. et al.
-chemokine production in macaques vaccinated with live attenuated virus correlates with protection against simian
immunodeficiency virus (SIVsm) challenge. J. Gen. Virol. 80, 1569–1574 (1999). | PubMed | ISI | ChemPort |
183.
Lehner, T., et al. Up-regulation of
-chemokines and down-modulation of CCR5 co-receptors inhibit simian immunodeficiency virus
transmission in non-human primates. Immunology 99, 569–577 (2000).
Evidence from a primate infection model which indicates that vaccines might afford protection from HIV-1 infection by
modulating the capacity of the immune system to release soluble suppressor factors. | Article | PubMed | ISI | ChemPort |
184.
Ahmed, R. K. et al. Spontaneous production of RANTES and antigen-specific IFNproduction in macaques vaccinated with SHIV-4
correlates with protection against SIVsm challenge. Clin. Exp. Immunol. 129, 11–18 (2002). | Article | PubMed | ISI | ChemPort |
+
185. Wang, Y. et al. Allo-immunization elicits CD8 T cell-derived chemokines, HIV suppressor factors and resistance to HIV infection in
women. Nature Med. 5, 1004–1009 (1999). | Article | PubMed | ISI | ChemPort |
Competing interests statement. The authors declare that they have no competing financial interests.