Dysregulation of the polo-like kinase pathway in CD4+ T cells is characteristic of pathogenic simian immunodeficiency virus infection

CD4(+) T-cell dysfunction highlighted by defects within the intracellular signaling cascade and cell cycle has long been characterized as a direct and/or indirect consequence of human immunodeficiency virus (HIV) infection in humans and simian immunodeficiency virus (SIV) infection in rhesus macaques (RM). Dysregulation of the M phase of the cell cycle is a well-documented effect of HIV or SIV infection both in vivo and in vitro. In this study the effect of SIV infection on the modulation of two important regulators of the M phase-polo-like kinases Plk3 and Plk1-was investigated. We have previously shown that Plk3 is markedly downregulated in CD4(+) T cells from SIV-infected disease-susceptible RM but not SIV-infected disease-resistant sooty mangabeys (SM), denoting an association of downregulation with disease progression. Here we show that, in addition to the downregulation, Plk3 exhibits aberrant activation patterns in the CD4(+) T cells from SIV-infected RM following T-cell receptor stimulation. Interestingly, in vitro SIV infection of CD4(+) T cells leads to the upregulation, rather than downregulation, of Plk3, suggesting that different mechanisms operate in vitro and in vivo. In addition, CD4(+) T cells from RM with high viral loads exhibited consistent and significant upregulation of Plk1, concurrent with an aberrant activation-induced Plk1 response, suggesting complex mechanisms of SIV-induced M-phase abnormalities in vivo. Altogether this study presents a novel mechanism underlying M-phase defects observed in CD4(+) T cells from HIV or SIV-infected disease-susceptible humans and RM which may contribute to aberrant T-cell responses and disease pathogenesis.     

Simian immunodeficiency virus (SIV) infection influences the level and function of regulatory T cells in SIV-infected rhesus macaques but not SIV-infected sooty mangabeys

Differences in clinical outcome of simian immunodeficiency virus (SIV) infection in disease-resistant African sooty mangabeys (SM) and disease-susceptible Asian rhesus macaques (RM) prompted us to examine the role of regulatory T cells (Tregs) in these two animal models. Results from a cross-sectional study revealed maintenance of the frequency and absolute number of peripheral Tregs in chronically SIV-infected SM while a significant loss occurred in chronically SIV-infected RM compared to uninfected animals. A longitudinal study of experimentally SIV-infected animals revealed a transient increase in the frequency of Tregs from baseline values following acute infection in RM, but no change in the frequency of Tregs occurred in SM during this period. Further examination revealed a strong correlation between plasma viral load (VL) and the level of Tregs in SIV-infected RM but not SM. A correlation was also noted in SIV-infected RM that control VL spontaneously or in response to antiretroviral chemotherapy. In addition, immunofluorescent cell count assays showed that while Treg-depleted peripheral blood mononuclear cells from RM led to a significant enhancement of CD4+ and CD8+ T-cell responses to select pools of SIV peptides, there was no detectable T-cell response to the same pool of SIV peptides in Treg-depleted cells from SIV-infected SM. Our data collectively suggest that while Tregs do appear to play a role in the control of viremia and the magnitude of the SIV-specific immune response in RM, their role in disease resistance in SM remains unclear.     

Human and simian immunodeficiency virus-mediated upregulation of the apoptotic factor TRAIL occurs in antigen-presenting cells from AIDS-susceptible but not from AIDS-resistant species

Human immunodeficiency virus (HIV) and simian immunodeficiency virus (SIV) infections lead to AIDS in humans and rhesus macaques (RM), while they are asymptomatic in species naturally infected with SIV, such as chimpanzees, sooty mangabeys (SM), and African green monkeys (AGM). Differential CD4(+) T-cell apoptosis may be responsible for these species-specific differences in susceptibility to disease. To identify factors that influence the different apoptotic responses of these species, we analyzed virus-infected human and nonhuman primate peripheral blood mononuclear cells (PBMC). We found that the apoptotic factor TRAIL was present at higher levels in human and RM PBMC cultures and was mediating, at least in part, CD4(+) T-cell apoptosis in these cultures. The species-specific increase in TRAIL and death receptor expression observed with cultures also occurred in vivo in SIV-infected RM but not in SIV-infected SM. In human and RM myeloid immature dendritic cells and macrophages, the virus-induced expression of TRAIL and other interferon-inducible genes, which did not occur in the same cells from chimpanzee, SM, and AGM, was Tat dependent. Our results link the differential induction of TRAIL in human and nonhuman primate cells to species-specific differences in disease susceptibility.     

Simian immunodeficiency virus (SIV)-specific CD8+ T-cell responses in vervet African green monkeys chronically infected with SIVagm

African green monkeys (AGM) do not develop overt signs of disease following simian immunodeficiency virus (SIV) infection. While it is still unknown how natural hosts like AGM can cope with this lentivirus infection, a large number of investigations have shown that CD8(+) T-cell responses are critical for the containment of AIDS viruses in humans and Asian nonhuman primates. Here we have compared the phenotypes of T-cell subsets and magnitudes of SIV-specific CD8(+) T-cell responses in vervet AGM chronically infected with SIVagm and rhesus monkeys (RM) infected with SIVmac. In comparison to RM, vervet AGM exhibited weaker signs of immune activation and associated proliferation of CD8(+) T cells as detected by granzyme B, Ki-67, and programmed death 1 staining. By gamma interferon enzyme-linked immunospot assay and intracellular cytokine staining, SIV Gag- and Env-specific immune responses were detectable at variable but lower levels in vervet AGM than in RM. These observations demonstrate that natural hosts like SIV-infected vervet AGM develop SIV-specific T-cell responses, but the disease-free course of infection does not depend on the generation of robust CD8(+) T-cell responses.     

Relative resistance in the development of T cell anergy in CD4+ T cells from simian immunodeficiency virus disease-resistant sooty mangabeys

Despite high viral loads, T cells from sooty mangabey (SM) monkeys that are naturally infected with SIV but remain clinically asymptomatic, proliferate and demonstrate normal Ag-specific memory recall CD4(+) T cell responses. In contrast, CD4(+) T cells from rhesus macaques (RM) experimentally infected with SIV lose Ag-specific memory recall responses and develop immunological anergy. To elucidate the mechanisms for these distinct outcomes of lentiviral infection, highly enriched alloreactive CD4(+) T cells from humans, RM, and SM were anergized by TCR-only stimulation (signal 1 alone) and subsequently challenged with anti-CD3/anti-CD28 Abs (signals 1 + 2). Whereas alloreactive CD4(+)T cells from humans and RM became anergized, surprisingly, CD4(+) T cells from SM showed marked proliferation and IL-2 synthesis after restimulation. This resistance to undergo anergy was not secondary to a global deficiency in anergy induction of CD4(+) T cells from SM since incubation of CD4(+) T cells with anti-CD3 alone in the presence of rapamycin readily induced anergy in these cells. The resistance to undergo anergy was reasoned to be due to the ability of CD4(+) T cells from SM to synthesize IL-2 when incubated with anti-CD3 alone. Analysis of phosphorylated kinases involved in T cell activation showed that the activation of CD4(+) T cells by signal 1 in SM elicited a pattern of response that required both signals 1 + 2 in humans and RM. This function of CD4(+) T cells from SM may contribute to the resistance of this species to SIV-induced disease.     

Early induction of polyfunctional simian immunodeficiency virus (SIV)-specific T lymphocytes and rapid disappearance of SIV from lymph nodes of sooty mangabeys during primary infection

Although the cellular immune response is essential for controlling SIV replication in Asian macaques, its role in maintaining nonpathogenic SIV infection in natural hosts such as sooty mangabeys (SM) remains to be defined. We have previously shown that similar to rhesus macaques (RM), SM are able to mount a T lymphocyte response against SIV infection. To investigate early control of SIV replication in natural hosts, we performed a detailed characterization of SIV-specific cellular immunity and viral control in the first 6 mo following SIV infection in SM. Detection of the initial SIV-specific IFN-γ ELISPOT response in SIVsmE041-infected SM coincided temporally with a decline in peak plasma viremia and was similar in magnitude, specificity, and breadth to SIVsmE041-infected and SIVmac239-infected RM. Despite these similarities, SM showed a greater reduction in postpeak plasma viremia and a more rapid disappearance of productively SIV-infected cells from the lymph node compared with SIVmac239-infected RM. The early Gag-specific CD8(+) T lymphocyte response was significantly more polyfunctional in SM compared with RM, and granzyme B-positive CD8(+) T lymphocytes were present at significantly higher frequencies in SM even prior to SIV infection. These findings suggest that the early SIV-specific T cell response may be an important determinant of lymphoid tissue viral clearance and absence of lymph node immunopathology in natural hosts of SIV infection.     

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.     

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.     

Simian immunodeficiency virus-induced alterations in monocyte production of tumor necrosis factor alpha contribute to reduced immune activation in sooty mangabeys

Human immunodeficiency virus type 1 (HIV-1) infection is characterized by persistent viral replication in the context of CD4(+) T cell depletion and elevated immune activation associated with disease progression. In contrast, simian immunodeficiency virus (SIV) infection of African-origin sooty mangabeys (SM) generally does not result in simian AIDS despite high viral loads and therefore affords a unique model in which to study the immunologic contributions to a nonpathogenic lentiviral disease outcome. A key feature of these natural SIV infections is the maintenance of low levels of immune activation during chronic infection. Our goal was to delineate the contribution of monocytes to maintaining low levels of immune activation in SIV-infected SM. Utilizing an ex vivo whole-blood assay, proinflammatory cytokine production was quantified in monocytes in response to multiple Toll-like receptor (TLR) ligands and a specific, significant reduction in the tumor necrosis factor alpha (TNF-α) response to lipopolysaccharide (LPS) was observed in SIV-infected SM. In contrast, monocytes from hosts of pathogenic infections (HIV-infected humans and SIV-infected Asian macaques) maintained a robust TNF-α response. In SIV-infected SM, monocyte TNF-α responses to low levels of LPS could be augmented by the presence of plasma from uninfected control animals. The impact of LPS-induced TNF-α production on immune activation was demonstrated in vitro, as TNF-α blocking antibodies inhibited downstream CD8(+) T cell activation in a dose-dependent manner. These data demonstrate an association between nonpathogenic SIV infection of SM and a reduced monocyte TNF-α response to LPS, and they identify a role for monocytes in contributing to the suppressed chronic immune activation observed in these natural hosts.     

nef gene is required for robust productive infection by simian immunodeficiency virus of T-cell-rich paracortex in lymph nodes

The pathogenesis of AIDS virus infection in a nonhuman primate AIDS model was studied by comparing plasma viral loads, CD4(+) T-cell subpopulations in peripheral blood mononuclear cells, and simian immunodeficiency virus (SIV) infection in lymph nodes for rhesus macaques infected with a pathogenic molecularly cloned SIVmac239 strain and those infected with its nef deletion mutant (Deltanef). In agreement with many reports, whereas SIVmac239 infection induced AIDS and depletion of memory CD4(+) T cells in 2 to 3 years postinfection (p.i.), Deltanef infection did not induce any manifestation associated with AIDS up to 6.5 years p.i. To explore the difference in SIV infection in lymphoid tissues, we biopsied lymph nodes at 2, 8, 72, and 82 weeks p.i. and analyzed them by pathological techniques. Maximal numbers of SIV-infected cells (SIV Gag(+), Env(+), and RNA(+)) were detected at 2 weeks p.i. in both the SIVmac239-infected animals and the Deltanef-infected animals. In the SIVmac239-infected animals, most of the infected cells were localized in the T-cell-rich paracortex, whereas in the Deltanef-infected animals, most were localized in B-cell-rich follicles and in the border region between the paracortex and the follicles. Analyses by double staining of CD68(+) macrophages and SIV Gag(+) cells and by double staining of CD3(+) T cells and SIV Env(+) cells revealed that SIV-infected cells were identified as CD4(+) T cells in either the SIVmac239 or the Deltanef infection. Whereas the many functions of Nef protein were reported from in vitro studies, our finding of SIVmac239 replication in the T-cell-rich paracortex in the lymph nodes supports the reported roles of Nef protein in T-cell activation and enhancement of viral infectivity. Furthermore, the abundance of SIVmac239 infection and the paucity of Deltanef infection in the T-cell-rich paracortex accounted for the differences in viral replication and pathogenicity between SIVmac239 and the Deltanef mutant. Thus, our in vivo study indicated that the nef gene enhances SIV replication by robust productive infection in memory CD4(+) T cells in the T-cell-rich region in lymphoid tissues.     

Differential CD4+ T-lymphocyte apoptosis and bystander T-cell activation in rhesus macaques and sooty mangabeys during acute simian immunodeficiency virus infection

In contrast to pathogenic lentiviral infections, chronic simian immunodeficiency virus (SIV) infection in its natural host is characterized by a lack of increased immune activation and apoptosis. To determine whether these differences are species specific and predicted by the early host response to SIV in primary infection, we longitudinally examined T-lymphocyte apoptosis, immune activation, and the SIV-specific cellular immune response in experimentally infected rhesus macaques (RM) and sooty mangabeys (SM) with controlled or uncontrolled SIV infection. SIVsmE041, a primary SIVsm isolate, reproduced set-point viremia levels of natural SIV infection in SM but was controlled in RM, while SIVmac239 replicated to high levels in RM. Following SIV infection, increased CD8⁺ T-lymphocyte apoptosis, temporally coinciding with onset of SIV-specific cellular immunity, and elevated plasma Th1 cytokine and gamma interferon-induced chemokine levels were common to both SM and RM. Different from SM, SIV-infected RM showed a significantly higher frequency of peripheral blood activated CD8⁺ T lymphocytes despite comparable magnitude of the SIV-specific gamma interferon enzyme-linked immunospot response. Furthermore, an increase in CD4⁺ and CD4⁻CD8⁻ T-lymphocyte apoptosis and plasma tumor necrosis factor-related apoptosis-inducing ligand were observed only in RM and occurred in both controlled SIVsmE041 and uncontrolled SIVmac239 infection. These data suggest that the “excess” activated T lymphocytes in RM soon after SIV infection are predominantly of non-virus-specific bystander origin. Thus, species-specific differences in the early innate immune response appear to be an important factor contributing to differential immune activation in natural and nonnatural hosts of SIV infection.     

Decreased levels of recent thymic emigrants in peripheral blood of simian immunodeficiency virus-infected macaques correlate with alterations within the thymus

The thymus is responsible for de novo production of CD4(+) and CD8(+) T cells and therefore is essential for T-cell renewal. The goal of this study was to assess the impact of simian immunodeficiency virus (SIV) infection on the production of T cells by the thymus. Levels of recent thymic emigrants within the peripheral blood were assessed through quantification of macaque T-cell receptor excision circles (TREC). Comparison of SIV-infected macaques (n = 15) to uninfected macaques (n = 23) revealed stable or increased TREC levels at 20 to 34 weeks postinfection. Further assessment of SIV-infected macaques (n = 4) determined that TREC levels decreased between 24 and 48 weeks postinfection. Through the assessment of longitudinal time points in three additional SIVmac239-infected macaques, the SIV infection was divided into two distinct phases. During phase 1 (16 to 30 weeks), TREC levels remained stable or increased within both the CD4 and CD8 T-cell populations. During phase 2 (after 16 to 30 weeks), TREC levels declined in both T-cell populations. As has been described for human immunodeficiency virus (HIV)-infected patients, this decline in TREC levels did at times correlate with an increased level of T-cell proliferation (Ki67(+) cells). However, not all TREC decreases could be attributed to increased T-cell proliferation. Further evidence for thymic dysfunction was observed directly in a SIVmac239-infected macaque that succumbed to simian AIDS at 65 weeks postinfection. The thymus of this macaque contained an increased number of memory/effector CD8(+) T cells and an increased level of apoptotic cells. In summary, reduced levels of TREC can be observed beginning at 16 to 30 weeks post-SIV infection and correlate with changes indicative of dysfunction within the thymic tissue. SIV infection of macaques will be a useful model system to elucidate the mechanisms responsible for the thymic dysfunction observed in HIV-infected patients.     

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.     

Normal T-cell turnover in sooty mangabeys harboring active simian immunodeficiency virus infection

Sooty mangabeys naturally infected with simian immunodeficiency virus (SIV) remain healthy though they harbor viral loads comparable to those in rhesus macaques that progress to AIDS. To assess the immunologic basis of disease resistance in mangabeys, we compared the effect of SIV infection on T-cell regeneration in both monkey species. Measurement of the proliferation marker Ki-67 by flow cytometry showed that mangabeys harbored proliferating T cells at a level of 3 to 4% in peripheral blood irrespective of their infection status. In contrast, rhesus macaques demonstrated a naturally high fraction of proliferating T cells (7%) that increased two- to threefold following SIV infection. Ki-67(+) T cells were predominantly CD45RA(-), indicating increased proliferation of memory cells in macaques. Quantitation of an episomal DNA product of T-cell receptor alpha rearrangement (termed alpha1 circle) showed that the concentration of recent thymic emigrants in blood decreased with age over a 2-log unit range in both monkey species, consistent with age-related thymic involution. SIV infection caused a limited decrease of alpha1 circle numbers in mangabeys as well as in macaques. Dilution of alpha1 circles by T-cell proliferation likely contributed to this decrease, since alpha1 circle numbers and Ki-67(+) fractions correlated negatively. These findings are compatible with immune exhaustion mediated by abnormal T-cell proliferation, rather than with early thymic failure, in SIV-infected macaques. Normal T-cell turnover in SIV-infected mangabeys provides an explanation for the long-term maintenance of a functional immune system in these hosts.     

Correlates of preserved CD4(+) T cell homeostasis during natural, nonpathogenic simian immunodeficiency virus infection of sooty mangabeys: implications for AIDS pathogenesis

In contrast to HIV-infected humans, naturally SIV-infected sooty mangabeys (SMs) very rarely progress to AIDS. Although the mechanisms underlying this disease resistance are unknown, a consistent feature of natural SIV infection is the absence of the generalized immune activation associated with HIV infection. To define the correlates of preserved CD4(+) T cell counts in SMs, we conducted a cross-sectional immunological study of 110 naturally SIV-infected SMs. The nonpathogenic nature of the infection was confirmed by an average CD4(+) T cell count of 1,076 +/- 589/mm(3) despite chronic infection with a highly replicating virus. No correlation was found between CD4(+) T cell counts and either age (used as a surrogate marker for length of infection) or viremia. The strongest correlates of preserved CD4(+) T cell counts were a low percentage of circulating effector T cells (CD28(-)CD95(+) and/or IL-7R/CD127(-)) and a high percentage of CD4(+)CD25(+) T cells. These findings support the hypothesis that the level of immune activation is a key determinant of CD4(+) T cell counts in SIV-infected SMs. Interestingly, we identified 14 animals with CD4(+) T cell counts of <500/mm(3), of which two show severe and persistent CD4(+) T cell depletion (<50/mm(3)). Thus, significant CD4(+) T cell depletion does occasionally follow SIV infection of SMs even in the context of generally low levels of immune activation, lending support to the hypothesis of multifactorial control of CD4(+) T cell homeostasis in this model of infection. The absence of AIDS in these "CD4(low)" naturally SIV-infected SMs defines a protective role of the reduced immune activation even in the context of a significant CD4(+) T cell depletion.     

Increased B7-H1 expression on dendritic cells correlates with programmed death 1 expression on T cells in simian immunodeficiency virus-infected macaques and may contribute to T cell dysfunction and disease progression

Suppression of dendritic cell (DC) function in HIV-1 infection is thought to contribute to inhibition of immune responses and disease progression, but the mechanism of this suppression remains undetermined. Using the rhesus macaque model, we show B7-H1 (programmed death [PD]-L1) is expressed on lymphoid and mucosal DCs (both myeloid DCs and plasmacytoid DCs), and its expression significantly increases after SIV infection. Meanwhile, its receptor, PD-1, is upregulated on T cells in both peripheral and mucosal tissues and maintained at high levels on SIV-specific CD8(+) T cell clones in chronic infection. However, both B7-H1 and PD-1 expression in SIV controllers was similar to that of controls. Expression of B7-H1 on both peripheral myeloid DCs and plasmacytoid DCs positively correlated with levels of PD-1 on circulating CD4(+) and CD8(+) T cells, viremia, and declining peripheral CD4(+) T cell levels in SIV-infected macaques. Importantly, blocking DC B7-H1 interaction with PD-1(+) T cells could restore SIV-specific CD4(+) and CD8(+) T cell function as evidenced by increased cytokine secretion and proliferative capacity. Combined, the results indicate that interaction of B7-H1-PD-1 between APCs and T cells correlates with impairment of CD4(+) Th cells and CTL responses in vivo, and all are associated with disease progression in SIV infection. Blockade of this pathway may have therapeutic implications for HIV-infected patients.     

Gastrointestinal epithelium is an early extrathymic site for increased prevalence of CD34(+) progenitor cells in contrast to the thymus during primary simian immunodeficiency virus infection

The objective of this study was to determine the effects of primary simian immunodeficiency virus (SIV) infection on the prevalence and phenotype of progenitor cells present in the gastrointestinal epithelia of SIV-infected rhesus macaques, a primate model for human immunodeficiency virus pathogenesis. The gastrointestinal epithelium was residence to progenitor cells expressing CD34 antigen, a subset of which also coexpressed Thy-1 and c-kit receptors, suggesting that the CD34(+) population in the intestine comprised a subpopulation of primitive precursors. Following experimental SIVmac251 infection, an early increase in the proportions of CD34(+) Thy-1(+) and CD34(+) c-kit+ progenitor cells was observed in the gastrointestinal epithelium. In contrast, the proportion of CD34(+) cells in the thymus declined during primary SIV infection, which was characterized by a decrease in the frequency of CD34(+) Thy-1(+) progenitor cells. A severe depletion in the frequency of CD4-committed CD34(+) progenitors was observed in the gastrointestinal epithelium 2 weeks after SIV infection which persisted even 4 weeks after infection. A coincident increase in the frequency of CD8- committed CD34(+) progenitor cells was observed during primary SIV infection. These results indicate that in contrast to the primary lymphoid organs such as the thymus, the gastrointestinal epithelium may be an early extrathymic site for the increased prevalence of both primitive and committed CD34(+) progenitor cells. The gastrointestinal epithelium may potentially play an important role in maintaining T-cell homeostasis in the intestinal mucosa during primary SIV infection.