Simian immunodeficiency virus SIVagm.sab infection of Caribbean African green monkeys: a new model for the study of SIV pathogenesis in natural hosts

Caribbean-born African green monkeys (AGMs) were classified as Chlorocebus sabaeus by cytochrome b sequencing. Guided by these phylogenetic analyses, we developed a new model for the study of simian immunodeficiency virus (SIV) infection in natural hosts by inoculating Caribbean AGMs with their species-specific SIVagm.sab. SIVagm.sab replicated efficiently in Caribbean AGM peripheral blood mononuclear cells in vitro. During SIVagm.sab primary infection of six Caribbean AGMs, the virus replicated at high levels, with peak viral loads (VLs) of 10(7) to 10(8) copies/ml occurring by day 8 to 10 postinfection (p.i.). Set-point values of up to 2 x 10(5) copies/ml were reached by day 42 p.i. and maintained throughout follow-up (through day 450 p.i.). CD4(+) T-cell counts in the blood showed a transient depletion at the peak of VL, and then returned to near preinfection values by day 28 p.i. and remained relatively stable during the chronic infection. Preservation of CD4 T cells was also found in lymph nodes (LNs) of chronic SIVagm.sab-infected Caribbean AGMs. No activation of CD4(+) T cells was detected in the periphery in SIV-infected Caribbean AGMs. These virological and immunological profiles from peripheral blood and LNs were identical to those previously reported in African-born AGMs infected with the same viral strain (SIVagm.sab92018). Due to these similarities, we conclude that Caribbean AGMs are a useful alternative to AGMs of African origin as a model for the study of SIV infection in natural African hosts.     

Short-lived infected cells support virus replication in sooty mangabeys naturally infected with simian immunodeficiency virus: implications for AIDS pathogenesis

Sooty mangabeys (SMs) naturally infected with simian immunodeficiency virus (SIV) do not develop AIDS despite high levels of virus replication. At present, the mechanisms underlying this disease resistance are poorly understood. Here we tested the hypothesis that SIV-infected SMs avoid immunodeficiency as a result of virus replication occurring in infected cells that live significantly longer than human immunodeficiency virus (HIV)-infected human cells. To this end, we treated six SIV-infected SMs with potent antiretroviral therapy (ART) and longitudinally measured the decline in plasma viremia. We applied the same mathematical models used in HIV-infected individuals and observed that SMs naturally infected with SIV also present a two-phase decay of viremia following ART, with the bulk (92 to 99%) of virus replication sustained by short-lived cells (average life span, 1.06 days), and only 1 to 8% occurring in longer-lived cells. In addition, we observed that ART had a limited impact on CD4(+) T cells and the prevailing level of T-cell activation and proliferation in SIV-infected SMs. Collectively, these results suggest that in SIV-infected SMs, similar to HIV type 1-infected humans, short-lived activated CD4(+) T cells, rather than macrophages, are the main source of virus production. These findings indicate that a short in vivo life span of infected cells is a common feature of both pathogenic and nonpathogenic primate lentivirus infections and support a model for AIDS pathogenesis whereby the direct killing of infected cells by HIV is not the main determinant of disease progression.     

High levels of viral replication during primary simian immunodeficiency virus SIVagm infection are rapidly and strongly controlled in African green monkeys

In contrast to pathogenic human immunodeficiency virus and simian immunodeficiency virus (SIV) infections, chronic SIVagm infections in African green monkeys (AGMs) are characterized by persistently low peripheral and tissue viral loads that correlate with the lack of disease observed in these animals. We report here data on the dynamics of acute SIVagm infection in AGMs that exhibit remarkable similarities with viral replication patterns observed in peripheral blood during the first 2 weeks of pathogenic SIVmac infections. Plasma viremia was evident at day 3 postinfection (p.i.) in AGMs, and rapid viral replication led by days 7 to 10 to peak viremias characterized by high levels of antigenemia (1.2 to 5 ng of p27/ml of plasma), peripheral DNA viral load (10(4) to 10(5) DNA copies/10(6) peripheral blood mononuclear cells [PBMC]), and plasma RNA viral load (2 x 10(6) to 2 x 10(8) RNA copies/ml). The lymph node (LN) RNA and DNA viral load patterns were similar to those in blood, with peaks observed between day 7 and day 14. These values in LNs (ranging from 3 x 10(5) to 3 x 10(6) RNA copies/10(6) LN cell [LNC] and 10(3) to 10(4) DNA copies/10(6) LNC) were at no time point higher than those observed in the blood. Both in LNs and in blood, rapid and significant decreases were observed in all infected animals after this peak of viral replication. Within 3 to 4 weeks p. i., antigenemia was no longer detectable and peripheral viral loads decreased to values similar to those characteristic of the chronic phase of infection (10(2) to 10(3) DNA copies/10(6) PBMC and 2 x 10(3) to 2 x 10(5) RNA copies/ml of plasma). In LNs, viral loads declined to 5 x 10(1) to 10(3) DNA copies and 10(4) to 3 x 10(5) RNA copies per 10(6) LNC at day 28 p.i. and continued to decrease until day 84 p.i. (<10 to 3 x 10(4) RNA copies/10(6) LNC). Despite extensive viremia during primary infection, neither follicular hyperplasia nor CD8(+) cell infiltration into LN germinal centers was detected. Altogether, these results indicate that the nonpathogenic outcome of SIVagm infection in its natural host is associated with a rapidly induced control of viral replication in response to SIVagm infection, rather than with a poorly replicating virus or a constitutive host genetic resistance to virus replication.     

Mucosal simian immunodeficiency virus transmission in African green monkeys: susceptibility to infection is proportional to target cell availability at mucosal sites

African green monkeys (AGMs) are naturally infected with a simian immunodeficiency virus (SIVagm) that is nonpathogenic in its host. Although SIVagm is common and widespread, little is known about the mechanisms that govern its transmission. Since the earliest virus-host interactions may provide key insights into the nonpathogenic phenotype of SIVagm, we developed a mucosal transmission model for this virus. Using plasma from an acutely infected AGM as the virus inoculum, we exposed adult and juvenile AGMs, as well as pigtailed macaques (PTMs) as a nonnatural host control, by mucosal routes to increasing titers of virus and compared the doses needed to establish a productive infection. Four juvenile and four adult AGMs as well as two PTMs were intrarectally (IR) exposed, while two additional adult female AGMs were intravaginally (IVAG) exposed. No animal became infected following exposure to 10(5) RNA copies. Both PTMs but none of the AGMs became infected following exposure to 10(6) RNA copies. Finally, all adult AGMs and two of the four juvenile AGMs became infected following exposure to 10(7) RNA copies, acquiring either one (2 IR infected juveniles, 1 IR infected adult, 2 IVAG infected adults) or two (3 IR infected adults) transmitted founder viruses. These results were consistent with immunophenotypic data, which revealed a significant correlation between the percentage of CD4(+) T cells expressing CCR5 in the mucosa and the susceptibility to infection, in terms of both the viral dose and the numbers of transmitted founder viruses. Moreover, studies of uninfected AGMs showed that the fraction of CCR5-expressing CD4(+) T cells increased significantly with age. These results indicate that (i) AGMs are readily infected with SIVagm by both intrarectal and intravaginal routes, (ii) susceptibility to infection is proportional to the number of available CCR5(+) CD4(+) target cells in the mucosa, and (iii) the paucity of CCR5(+) CD4(+) target cells in infant and juvenile AGMs may explain the near absence of vertical transmission.     

Simian immunodeficiency virus infection induces severe loss of intestinal central memory T cells which impairs CD4+ T-cell restoration during antiretroviral therapy

BACKGROUND: Simian immunodeficiency virus (SIV) infection leads to severe loss of intestinal CD4(+) T cells and, as compared to peripheral blood, restoration of these cells is slow during antiretroviral therapy (ART). Mechanisms for this delay have not been examined in context of which specific CD4(+) memory subsets or lost and fail to regenerate during ART. METHODS: Fifteen rhesus macaques were infected with SIV, five of which received ART (FTC/PMPA) for 30 weeks. Viral loads were measured by real-time PCR. Flow cytometric analysis determined changes in T-cell subsets and their proliferative state. RESULTS: Changes in proliferative CD4(+) memory subsets during infection accelerated their depletion. This reduced the central memory CD4(+) T-cell pool and contributed to slow CD4(+) T-cell restoration during ART. CONCLUSION: There was a lack of restoration of the CD4(+) central memory and effector memory T-cell subsets in gut-associated lymphoid tissue during ART, which may contribute to the altered intestinal T-cell homeostasis in SIV infection.     

Dynamics of CCR5 expression by CD4(+) T cells in lymphoid tissues during simian immunodeficiency virus infection

Early viral replication and profound CD4(+) T-cell depletion occur preferentially in intestinal tissues of macaques infected with simian immunodeficiency virus (SIV). Here we show that a much higher percentage of CD4(+) T cells in the intestine express CCR5 compared with those found in the peripheral blood, spleen, or lymph nodes. In addition, the selectivity and extent of the CD4(+) T-cell loss in SIV infection may depend upon these cells coexpressing CCR5 and having a "memory" phenotype (CD45RA(-)). Following intravenous infection with SIVmac251, memory CD4(+) CCR5(+) T cells were selectively eliminated within 14 days in all major lymphoid tissues (intestine, spleen, and lymph nodes). However, the effect on CD4(+) T-cell numbers was most profound in the intestine, where cells of this phenotype predominate. The CD4(+) T cells that remain after 14 days of infection lacked CCR5 and/or were naive (CD45RA(+)). Furthermore, when animals in the terminal stages of SIV infection (with AIDS) were examined, virtually no CCR5-expressing CD4(+) T cells were found in lymphoid tissues, and all of the remaining CD4(+) T cells were naive and coexpressed CXCR4. These findings suggest that chemokine receptor usage determines which cells are targeted for SIV infection and elimination in vivo.     

Simian immunodeficiency virus infection in neonatal macaques

Children with human immunodeficiency virus infection often have higher viral loads and progress to AIDS more rapidly than adults. Since the intestinal tract is a major site of early viral replication and CD4(+) T-cell depletion in adults, we examined the effects of simian immunodeficiency virus (SIV) on both peripheral and intestinal lymphocytes from 13 neonatal macaques infected with SIVmac239. Normal neonates had more CD4(+) T cells and fewer CD8(+) T cells in all tissues than adults. Surprisingly, neonates had substantial percentages of CD4(+) T cells with an activated, memory phenotype (effector CD4(+) T cells) in the lamina propria of the intestine compared to peripheral lymphoid tissues, even when examined on the day of birth. Moreover, profound and selective depletion of jejunum lamina propria CD4(+) T cells occurred in neonatal macaques within 21 days of infection, which was preceded by large numbers of SIV-infected cells in this compartment. Furthermore, neonates with less CD4(+) T-cell depletion in tissues tended to have higher viral loads. The persistence of intestinal lamina propria CD4(+) T cells in some neonates with high viral loads suggests that increased turnover and/or resistance to CD4(+) T-cell loss may contribute to the higher viral loads and increased severity of disease in neonatal hosts.     

Antiviral therapy during primary simian immunodeficiency virus infection fails to prevent acute loss of CD4+ T cells in gut mucosa but enhances their rapid restoration through central memory T cells

Gut-associated lymphoid tissue (GALT) is an early target of human immunodeficiency virus (HIV) and simian immunodeficiency virus (SIV) and a site for severe CD4+ T-cell depletion. Although antiretroviral therapy (ART) is effective in suppressing HIV replication and restoring CD4+ T cells in peripheral blood, restoration in GALT is delayed. The role of restored CD4+ T-cell help in GALT during ART and its impact on antiviral CD8+ T-cell responses have not been investigated. Using the SIV model, we investigated gut CD4+ T-cell restoration in infected macaques, initiating ART during either the primary stage (1 week postinfection), prior to acute CD4+ cell loss (PSI), or during the chronic stage at 10 weeks postinfection (CSI). ART led to viral suppression in GALT and peripheral blood mononuclear cells of PSI and CSI animals at comparable levels. CSI animals had incomplete CD4+ T-cell restoration in GALT. In PSI animals, ART did not prevent acute CD4+ T-cell loss by 2 weeks postinfection in GALT but supported rapid and complete CD4+ T-cell restoration thereafter. This correlated with an accumulation of central memory CD4+ T cells and better suppression of inflammation. Restoration of CD4+ T cells in GALT correlated with qualitative changes in SIV gag-specific CD8+ T-cell responses, with a dominance of interleukin-2-producing responses in PSI animals, while both CSI macaques and untreated SIV-infected controls were dominated by gamma interferon responses. Thus, central memory CD4+ T-cell levels and qualitative antiviral CD8+ T-cell responses, independent of viral suppression, were the immune correlates of gut mucosal immune restoration during ART.     

Memory CD4+ T Lymphocytes in the Gastrointestinal Tract Are a Major Source of Cell-Associated Simian Immunodeficiency Virus in Chronic Nonpathogenic Infection of African Green Monkeys

Simian immunodeficiency virus (SIV) infection of natural hosts is characterized by nonpathogenic chronic viremia, maintenance of gastrointestinal epithelial barrier integrity, and low numbers of target cells. Assessment of cell-associated virus load in T cell subsets in multiple anatomic compartments of chronically SIV-infected sabeus African green monkeys (AGMs) revealed that gastrointestinal memory CD4⁺ T lymphocytes are a major source of cell-associated virus and a significant contributor to SIV viremia in AGMs.     

Control of viremia and prevention of simian-human immunodeficiency virus-induced disease in rhesus macaques immunized with recombinant vaccinia viruses plus inactivated simian immunodeficiency virus and human immunodeficiency virus type 1 particles

An effective vaccine against the human immunodeficiency virus type 1 (HIV-1) will very likely have to elicit both cellular and humoral immune responses to control HIV-1 strains of diverse geographic and genetic origins. We have utilized a pathogenic chimeric simian-human immunodeficiency virus (SHIV) rhesus macaque animal model system to evaluate the protective efficacy of a vaccine regimen that uses recombinant vaccinia viruses expressing simian immunodeficiency virus (SIV) and HIV-1 structural proteins in combination with intact inactivated SIV and HIV-1 particles. Following virus challenge, control animals experienced a rapid and complete loss of CD4(+) T cells, sustained high viral loads, and developed clinical disease by 17 to 21 weeks. Although all of the vaccinated monkeys became infected, they displayed reduced postpeak viremia, had no significant loss of CD4(+) T cells, and have remained healthy for more than 15 months postinfection. CD8(+) T-cell and neutralizing antibody responses in vaccinated animals following challenge were demonstrable. Despite the control of disease, virus was readily isolated from the circulating peripheral blood mononuclear cells of all vaccinees at 22 weeks postchallenge, indicating that immunologic control was incomplete. Virus recovered from the animal with the lowest postchallenge viremia generated high virus loads and an irreversible loss of CD4(+) T-cell loss following its inoculation into a na?ve animal. These results indicate that despite the protection from SHIV-induced disease, the vaccinated animals still harbored replication-competent and pathogenic virus.     

Increased loss of CCR5+ CD45RA- CD4+ T cells in CD8+ lymphocyte-depleted Simian immunodeficiency virus-infected rhesus monkeys

Previously we have shown that CD8(+) T cells are critical for containment of simian immunodeficiency virus (SIV) viremia and that rapid and profound depletion of CD4(+) T cells occurs in the intestinal tract of acutely infected macaques. To determine the impact of SIV-specific CD8(+) T-cell responses on the magnitude of the CD4(+) T-cell depletion, we investigated the effect of CD8(+) lymphocyte depletion during primary SIV infection on CD4(+) T-cell subsets and function in peripheral blood, lymph nodes, and intestinal tissues. In peripheral blood, CD8(+) lymphocyte-depletion changed the dynamics of CD4(+) T-cell loss, resulting in a more pronounced loss 2 weeks after infection, followed by a temporal rebound approximately 2 months after infection, when absolute numbers of CD4(+) T cells were restored to baseline levels. These CD4(+) T cells showed a markedly skewed phenotype, however, as there were decreased levels of memory cells in CD8(+) lymphocyte-depleted macaques compared to controls. In intestinal tissues and lymph nodes, we observed a significantly higher loss of CCR5(+) CD45RA(-) CD4(+) T cells in CD8(+) lymphocyte-depleted macaques than in controls, suggesting that these SIV-targeted CD4(+) T cells were eliminated more efficiently in CD8(+) lymphocyte-depleted animals. Also, CD8(+) lymphocyte depletion significantly affected the ability to generate SIV Gag-specific CD4(+) T-cell responses and neutralizing antibodies. These results reemphasize that SIV-specific CD8(+) T-cell responses are absolutely critical to initiate at least partial control of SIV infection.     

Intrinsic susceptibility of rhesus macaque peripheral CD4(+) T cells to simian immunodeficiency virus in vitro is predictive of in vivo viral replication

Previous studies with simian immunodeficiency virus (SIV) infection of rhesus macaques suggested that the intrinsic susceptibility of peripheral blood mononuclear cells (PBMC) to infection with SIV in vitro was predictive of relative viremia after SIV challenge. The present study was conducted to evaluate this parameter in a well-characterized cohort of six rhesus macaques selected for marked differences in susceptibility to SIV infection in vitro. Rank order relative susceptibility of PBMC to SIVsmE543-3-infection in vitro was maintained over a 1-year period of evaluation. Differential susceptibility of different donors was maintained in CD8(+) T-cell-depleted PBMC, macrophages, and CD4(+) T-cell lines derived by transformation of PBMC with herpesvirus saimiri, suggesting that this phenomenon is an intrinsic property of CD4(+) target cells. Following intravenous infection of these macaques with SIVsmE543-3, we observed a wide range in plasma viremia which followed the same rank order as the relative susceptibility established by in vitro studies. A significant correlation was observed between plasma viremia at 2 and 8 weeks postinoculation and in vitro susceptibility (P < 0.05). The observation that the two most susceptible macaques were seropositive for simian T-lymphotropic virus type 1 may suggests a role for this viral infection in enhancing susceptibility to SIV infection in vitro and in vivo. In summary, intrinsic susceptibility of CD4(+) target cells appears to be an important factor influencing early virus replication patterns in vivo that should be considered in the design and interpretation of vaccine studies using the SIV/macaque model.     

Impairment of Gag-Specific CD8+ T-Cell Function in Mucosal and Systemic Compartments of Simian Immunodeficiency Virus mac251- and Simian-Human Immunodeficiency Virus KU2-Infected Macaques

The identification of several simian immunodeficiency virus mac251 (SIV(mac251)) cytotoxic T-lymphocyte epitopes recognized by CD8(+) T cells of infected rhesus macaques carrying the Mamu-A*01 molecule and the use of peptide-major histocompatibility complex tetrameric complexes enable the study of the frequency, breadth, functionality, and distribution of virus-specific CD8(+) T cells in the body. To begin to address these issues, we have performed a pilot study to measure the virus-specific CD8(+) and CD4(+) T-cell response in the blood, lymph nodes, spleen, and gastrointestinal lymphoid tissues of eight Mamu-A*01-positive macaques, six of those infected with SIV(mac251) and two infected with the pathogenic simian-human immunodeficiency virus KU2. We focused on the analysis of the response to peptide p11C, C-M (Gag 181), since it was predominant in most tissues of all macaques. Five macaques restricted viral replication effectively, whereas the remaining three failed to control viremia and experienced a progressive loss of CD4(+) T cells. The frequency of the Gag 181 (p11C, C-->M) immunodominant response varied among different tissues of the same animal and in the same tissues from different animals. We found that the functionality of this virus-specific CD8(+) T-cell population could not be assumed based on the ability to specifically bind to the Gag 181 tetramer, particularly in the mucosal tissues of some of the macaques infected by SIV(mac251) that were progressing to disease. Overall, the functionality of CD8(+) tetramer-binding T cells in tissues assessed by either measurement of cytolytic activity or the ability of these cells to produce gamma interferon or tumor necrosis factor alpha was low and was even lower in the mucosal tissue than in blood or spleen of some SIV(mac251)-infected animals that failed to control viremia. The data obtained in this pilot study lead to the hypothesis that disease progression may be associated with loss of virus-specific CD8(+) T-cell function.     

Estimating the effectiveness of simian immunodeficiency virus-specific CD8+ T cells from the dynamics of viral immune escape

Antiviral CD8(+) T cells are thought to play a significant role in limiting the viremia of human and simian immunodeficiency virus (HIV and SIV, respectively) infections. However, it has not been possible to measure the in vivo effectiveness of cytotoxic T cells (CTLs), and hence their contribution to the death rate of CD4(+) T cells is unknown. Here, we estimated the ability of a prototypic antigen-specific CTL response against a well-characterized epitope to recognize and kill infected target cells by monitoring the immunodominant Mamu-A*01-restricted Tat SL8 epitope for escape from Tat-specific CTLs in SIVmac239-infected macaques. Fitting a mathematical model that incorporates the temporal kinetics of specific CTLs to the frequency of Tat SL8 escape mutants during acute SIV infection allowed us to estimate the in vivo killing rate constant per Tat SL8-specific CTL. Using this unique data set, we show that at least during acute SIV infection, certain antiviral CD8(+) T cells can have a significant impact on shortening the longevity of infected CD4(+) T cells and hence on suppressing virus replication. Unfortunately, due to viral escape from immune pressure and a dependency of the effectiveness of antiviral CD8(+) T-cell responses on the availability of sufficient CD4(+) T cells, the impressive early potency of the CTL response may wane in the transition to the chronic stage of the infection.     

Patterns of CD8+ immunodominance may influence the ability of Mamu-B*08-positive macaques to naturally control simian immunodeficiency virus SIVmac239 replication

Certain major histocompatibility complex (MHC) class I alleles are strongly associated with control of human immunodeficiency virus and simian immunodeficiency virus (SIV). CD8(+) T cells specific for epitopes restricted by these molecules may be particularly effective. Understanding how CD8(+) T cells contribute to control of viral replication should yield important insights for vaccine design. We have recently identified an Indian rhesus macaque MHC class I allele, Mamu-B*08, associated with elite control and low plasma viremia after infection with the pathogenic isolate SIVmac239. Here, we infected four Mamu-B*08-positive macaques with SIVmac239 to investigate why some of these macaques control viral replication. Three of the four macaques controlled SIVmac239 replication with plasma virus concentrations below 20,000 viral RNA copies/ml at 20 weeks postinfection; two of four macaques were elite controllers (ECs). Interestingly, two of the four macaques preserved their CD4(+) memory T lymphocytes during peak viremia, and all four recovered their CD4(+) memory T lymphocytes in the chronic phase of infection. Mamu-B*08-restricted CD8(+) T-cell responses dominated the acute phase and accounted for 23.3% to 59.6% of the total SIV-specific immune responses. Additionally, the ECs mounted strong and broad CD8(+) T-cell responses against several epitopes in Vif and Nef. Mamu-B*08-specific CD8(+) T cells accounted for the majority of mutations in the virus at 18 weeks postinfection. Interestingly, patterns of viral variation in Nef differed between the ECs and the other two macaques. Natural containment of AIDS virus replication in Mamu-B*08-positive macaques may, therefore, be related to a combination of immunodominance and viral escape from CD8(+) T-cell responses.     

Small intestine CD4+ T cells are profoundly depleted during acute simian-human immunodeficiency virus infection, regardless of viral pathogenicity

To analyze the relationship between acute virus-induced injury and the subsequent disease phenotype, we compared the virus replication and CD4(+) T-cell profiles for monkeys infected with isogenic highly pathogenic (KS661) and moderately pathogenic (#64) simian-human immunodeficiency viruses (SHIVs). Intrarectal infusion of SHIV-KS661 resulted in rapid, systemic, and massive virus replication, while SHIV-#64 replicated more slowly and reached lower titers. Whereas KS661 systemically depleted CD4(+) T cells, #64 caused significant CD4(+) T-cell depletion only in the small intestine. We conclude that SHIV, regardless of pathogenicity, can cause injury to the small intestine and leads to CD4(+) T-cell depletion in infected animals during acute infection.     

Novel pathway for induction of latent virus from resting CD4(+) T cells in the simian immunodeficiency virus/macaque model of human immunodeficiency virus type 1 latency

Although combination therapy allows the suppression of human immunodeficiency virus type 1 (HIV-1) viremia to undetectable levels, eradication has not been achieved because the virus persists in cellular reservoirs, particularly the latent reservoir in resting CD4(+) T lymphocytes. We previously established a simian immunodeficiency virus (SIV)/macaque model to study latency. We describe here a novel mechanism for the induction of SIV from latently infected resting CD4(+) T cells. Several human cell lines including CEMx174 and Epstein-Barr virus-transformed human B-lymphoblastoid cell lines mediated contact-dependent activation of resting macaque T cells and induction of latent SIV. Antibody-blocking assays showed that interactions between the costimulatory molecule CD2 and its ligand CD58 were involved, whereas soluble factors and interactions between T-cell receptors and major histocompatibility complex class II were not. Combinations of specific antibodies to CD2 also induced T-cell activation and virus induction in human resting CD4(+) T cells carrying latent HIV-1. This is the first demonstration that costimulatory signals can induce latent virus without the coengagement of the T-cell receptor, and this study might provide insights into potential pathways to target latent HIV-1.     

Simian immunodeficiency viruses replication dynamics in African non-human primate hosts: common patterns and species-specific differences

METHODS: To define potential common features of simian immunodeficiency virus (SIV) infections in different naturally infected host species, we compared the dynamics of viral replication in 31 African green monkeys (10 sabeus, 15 vervets and seven Caribbean AGMs), 14 mandrills and three sooty mangabeys (SMs) that were experimentally infected with their species-specific viruses. RESULTS: After infection, these SIVs replicated rapidly reaching viral loads (VLs) of 10(5)-10(9) copies/ml of plasma between days 9-14 post-infection (p.i). Set point viremia was established between days 42 and 60 p.i., with levels of approximately 10(5)-10(6) copies/ml in SM and mandrills, and lower levels (10(3)-10(5) copies/ml) in AGMs. VL during the chronic phase did not correlate with viral genome structure: SIVmnd-2 (a vpx-containing virus) and SIVmnd-1 (which does not contain vpu or vpx) replicated to similar levels in mandrills. VL was dependent on virus strain: vervets infected with three different viral strains showed different patterns of viral replication. The pattern of viral replication of SIVagm.sab, which uses both CCR5 and CXCR4 co-receptors was similar to those of the other viruses. CONCLUSIONS: Our results show a common pattern of SIV replication in naturally and experimentally infected hosts. This is similar overall to that observed in pathogenic SIV infection of macaques. This result indicates that differences in clinical outcome between pathogenic and non-pathogenic infections rely on host responses rather than the characteristics of the virus itself.     

Prolonged dominance of clonally restricted CD4(+) T cells in macaques infected with simian immunodeficiency viruses

The repertoire of functional CD4(+) T lymphocytes in human immunodeficiency virus type 1-infected individuals remains poorly understood. To explore this issue, we have examined the clonality of CD4(+) T cells in simian immunodeficiency virus (SIV)-infected macaques by assessing T-cell receptor complementarity-determining region 3 (CDR3) profiles and sequences. A dominance of CD4(+) T cells expressing particular CDR3 sequences was identified within certain Vbeta-expressing peripheral blood lymphocyte subpopulations in the infected monkeys. Studies were then done to explore whether these dominant CD4(+) T cells represented expanded antigen-specific cell subpopulations or residual cells remaining in the course of virus-induced CD4(+) T-cell depletion. Sequence analysis revealed that these selected CDR3-bearing CD4(+) T-cell clones emerged soon after infection and dominated the CD4(+) T-cell repertoire for up to 14 months. Moreover, inoculation of chronically infected macaques with autologous SIV-infected cell lines to transiently increase plasma viral loads in the monkeys resulted in the dominance of these selected CDR3-bearing CD4(+) T cells. Both the temporal association of the detection of these clonal cell populations with infection and the dominance of these cell populations following superinfection with SIV suggest that these cells may be SIV specific. Finally, the inoculation of staphylococcal enterotoxin B superantigen into SIV-infected macaques uncovered a polyclonal background underlying the few dominant CDR3-bearing CD4(+) T cells, demonstrating that expandable polyclonal CD4(+) T-cell subpopulations persist in these animals. These results support the notions that a chronic AIDS virus infection can induce clonal expansion, in addition to depletion of CD4(+) T cells, and that some of these clones may be SIV specific.