CD4 T-cell Depletion Research Articles

Biological Signature Characteristics of Primary Isolates from Human Immunodeficiency Virus Type 1 Group O in Ex Vivo Human Tonsil Histocultures

Human immunodeficiency virus type 1 (HIV-1) group M viruses have achieved a global distribution, while HIV-1 group O viruses are endemic only in particular regions of Africa. Here, we evaluated biological characteristics of group O and group M viruses in ex vivo models of HIV-1 infection. The replicative capacity and ability to induce CD4 T-cell depletion of eight group O and seven group M primary isolates were monitored in cultures of human peripheral blood mononuclear cells and tonsil explants. Comparative and longitudinal infection studies revealed HIV-1 group-specific activity patterns: CCR5-using (R5) viruses from group M varied considerably in their replicative capacity but showed similar levels of cytopathicity. In contrast, R5 isolates from group O were relatively uniform in their replicative fitness but displayed a high and unprecedented variability in their potential to deplete CD4 T cells. Two R5 group O isolates were identified that cause massive depletion of CD4 T cells, to an extent comparable to CXCR4-using viruses and not documented for any R5 isolate from group M. Intergroup comparisons found a five- to eightfold lower replicative fitness of isolates from group O than for isolates from group M yet a similar overall intrinsic pathogenicity in tonsil cultures. This study establishes biological ex vivo characteristics of HIV-1 group O primary isolates. The current findings challenge the belief that a grossly reduced replicative fitness or inherently impaired cytopathicity of viruses from this group underlies their low global prevalence.

The Size of the Viral Inoculum Contributes to the Outcome of Hepatitis B Virus Infection

The impact of virus dose on the outcome of infection is poorly understood. In this study we show that, for hepatitis B virus (HBV), the size of the inoculum contributes to the kinetics of viral spread and immunological priming, which then determine the outcome of infection. Adult chimpanzees were infected with a serially diluted monoclonal HBV inoculum. Unexpectedly, despite vastly different viral kinetics, both high-dose inocula (10(10) genome equivalents [GE] per animal) and low-dose inocula (10 degrees GE per animal) primed the CD4 T-cell response after logarithmic spread was detectable, allowing infection of 100% of hepatocytes and requiring prolonged immunopathology before clearance occurred. In contrast, intermediate (10(7) and 10(4) GE) inocula primed the T-cell response before detectable logarithmic spread and were abruptly terminated with minimal immunopathology before 0.1% of hepatocytes were infected. Surprisingly, a dosage of 10(1) GE primed the T-cell response after all hepatocytes were infected and caused either prolonged or persistent infection with severe immunopathology. Finally, CD4 T-cell depletion before inoculation of a normally rapidly controlled inoculum precluded T-cell priming and caused persistent infection with minimal immunopathology. These results suggest that the relationship between the kinetics of viral spread and CD4 T-cell priming determines the outcome of HBV infection.

Increased mortality and AIDS-like immunopathology in wild chimpanzees infected with SIVcpz

African primates are naturally infected with over 40 different simian immunodeficiency viruses (SIVs), two of which have crossed the species barrier and generated human immunodeficiency virus types 1 and 2 (HIV-1 and HIV-2). Unlike the human viruses, however, SIVs do not generally cause acquired immunodeficiency syndrome (AIDS) in their natural hosts. Here we show that SIVcpz, the immediate precursor of HIV-1, is pathogenic in free-ranging chimpanzees. By following 94 members of two habituated chimpanzee communities in Gombe National Park, Tanzania, for over 9 years, we found a 10- to 16-fold higher age-corrected death hazard for SIVcpz-infected (n = 17) compared to uninfected (n = 77) chimpanzees. We also found that SIVcpz-infected females were less likely to give birth and had a higher infant mortality rate than uninfected females. Immunohistochemistry and in situ hybridization of post-mortem spleen and lymph node samples from three infected and two uninfected chimpanzees revealed significant CD4(+) T-cell depletion in all infected individuals, with evidence of high viral replication and extensive follicular dendritic cell virus trapping in one of them. One female, who died within 3 years of acquiring SIVcpz, had histopathological findings consistent with end-stage AIDS. These results indicate that SIVcpz, like HIV-1, is associated with progressive CD4(+) T-cell loss, lymphatic tissue destruction and premature death. These findings challenge the prevailing view that all natural SIV infections are non-pathogenic and suggest that SIVcpz has a substantial negative impact on the health, reproduction and lifespan of chimpanzees in the wild.

CD4 + T lymphocytes mediate acute pulmonary ischemia–reperfusion injury

Postischemic reperfusion of the lung triggers proinflammatory responses that stimulate injurious neutrophil chemotaxis. We hypothesized that T lymphocytes are recruited and activated during reperfusion and mediate subsequent neutrophil-induced lung ischemia-reperfusion injury. An in vivo mouse model of lung ischemia-reperfusion injury was used. C57BL/6 mice were assigned to either the sham group (left thoracotomy) or 7 study groups that underwent 1-hour left hilar occlusion followed by 1 to 24 hours of reperfusion. After in vivo reperfusion, the lungs were perfused ex vivo with buffer whereby pulmonary function was assessed. Lung vascular permeability, edema, neutrophil accumulation, and cytokine/chemokine production (tumor necrosis factor alpha, interleukin 17, CCL3, and CXCL1) were assessed based on Evans blue dye leak, wet/dry weight ratio, myeloperoxidase level, and enzyme-linked immunosorbent assay, respectively. A preliminary study showed that 2 hours of reperfusion resulted in greater pulmonary dysfunction than 1 or 24 hours of reperfusion. The 2-hour reperfusion period was thus used for the remaining experiments. Comparable and significant protection from ischemia-reperfusion injury-induced lung dysfunction and injury occurred after antibody depletion of neutrophils or CD4(+) T cells but not CD8(+) T cells (P < .05 vs immunoglobulin G control). Lung ischemia-reperfusion injury was proportional to the infiltration of neutrophils but not T cells. Moreover, pulmonary neutrophil infiltration and the production of CXCL1 (KC) were significantly diminished by CD4(+) T-cell depletion but not vice versa. Both CD4(+) T lymphocytes and neutrophils accumulate during reperfusion and contribute sequentially to lung ischemia-reperfusion injury. The data suggest that neutrophils mediate ischemia-reperfusion injury; however, CD4(+) T cells play a critical role in stimulating chemokine production and neutrophil chemotaxis during ischemia-reperfusion injury.

The Gastrointestinal Tract and AIDS Pathogenesis

Gastrointestinal disease has been recognized as a major manifestation of human immunodeficiency virus infection since the earliest recognition of acquired immunodeficiency syndrome (AIDS). Originally, these disease manifestations were considered to be sequelae of the immune destruction that characterizes AIDS rather than being central to the pathogenesis of AIDS. Over time, it has become clear that the mucosal immune system in general and the intestinal immune system in particular are central to the pathogenesis of AIDS, with most of the critical events (eg, transmission, viral amplification, CD4+ T-cell destruction) occurring in the gastrointestinal tract. Compared with peripheral blood, these tissues are not easily accessible for analysis and have only begun to be examined in detail recently. In addition, although the resulting disease can progress over years, many critical events happen within the first few weeks of infection, when most patients are unaware that they are infected. Moreover, breakdown of the mucosal barrier and resulting microbial translocation are believed to be major drivers of AIDS progression. In this review, we focus on the interaction between primate lentiviruses and the gastrointestinal tract and discuss how this interaction promotes the pathogenesis of AIDS and drives immune dysfunction and progression to AIDS. This article draws extensively on work done in the nonhuman primate model of AIDS to fill gaps in our understanding of AIDS in humans.

Novel humanized murine models for HIV research

There are few models in which HIV pathogenesis, particularly gut-associated lymphoid tissue CD4(+) T-cell depletion, can be studied and in which potential clinical interventions against HIV disease can be evaluated. HIV cannot be studied in normal mice due to the limited species tropism of the virus. Through the pioneering efforts of many investigators, humanized mice are now routinely used to rapidly advance HIV research. It is important to recognize that not all humanized murine models are equal, and their strengths and weaknesses must be taken into consideration to obtain information that is most relevant to the human condition. This review distinguishes the major humanization protocols and highlights each model's recent contributions to HIV research, including mucosal transmission, gut-associated lymphoid tissue pathogenesis, and the evaluation of novel therapeutic and prevention approaches to potentially treat HIV disease and prevent the further spread of AIDS.

A Case for Innate Immune Effector Mechanisms as Contributors to Disease Resistance in SIV-Infected Sooty Mangabeys

Natural or experimental infection of the African sooty mangabey (SM) with the simian immunodeficiency virus (SIV) results in chronic high levels of virus replication but is associated with none of the debilitating immunopathology, including the marked CD4 T-cell depletion, persistent cell activation and acquired immunodeficiency, that afflicts non-natural hosts such as SIV-infected Asian rhesus macaques (RM) and HIV-infected humans. Although SIV-infected RM have served as important models of AIDS given their remarkably similar course of disease to HIV-infected humans, deciphering the immune mechanisms that enable SIV-infected SM to resist disease development despite high viremia has yet to be defined. Intense studies for the past two decades using these nonhuman primate models have been conducted with the hope that this will yield better insight into the pathogenesis of AIDS, translating into the development of therapeutic strategies for HIV-infected individuals such as but not limited to identifying correlates of protective immunity that can be harnessed for the preparation of effective vaccines. Although much has been reported about SIV-specific adaptive immune responses in both the natural and unnatural hosts of SIV, we submit that innate immunity may play a larger than previously appreciated role in SIV pathogenesis, in particular during the period of acute infection. The purpose of this review is to therefore highlight the recent advances that have been made in understanding innate immune responses in SIV-infected SM and to discuss the role(s) of the major innate immune cell lineages that potentially contribute to disease resistance in this non-human primate species.

Close association of CD8+/CD38bright with HIV‐1 replication and complex relationship with CD4+ T‐cell count

Measuring lymphocyte activation provides information in addition to CD4(+) T-cell count for immune monitoring of HIV-1 infected patients. CD38 is a well-established activation marker that is generally analyzed on the whole population of CD8(+) T-cells. Focusing specifically on CD38 high expression (CD8(+)/CD38(bright)) may be an interesting surrogate gating strategy because CD38(bright) characterizes principally activated memory cells. CD8(+)/CD38(bright) was investigated in 1,353 HIV-1 infected patients over a one-year period to establish relevant cutoff values and clarify the relationships of this marker with HIV-1 RNA viral load (VL) and CD4(+) T-cell count. The CD8(+)/CD38(bright) (>8,500 CD38 binding site per cells) is well correlated with HIV-1 VL (r = 0.87, P < 0.001) in this longitudinal follow-up of nonimmunodepressed patients that initiated antiviral therapy (ART). In aviremic patients on ART, the marker was highly predictive of VL rebound (sensitivity 93%, specificity 64% for a VL level of detection >200 copies/ml). While the CD8(+)/CD38(bright) moderately correlated with CD4(+) T-cell count independently of the VL (r = -0.37, P < 0.001), it increased dramatically in aviremic patient groups that exhibited profound CD4(+) T-cell depletion (median 39% for CD4(+) T-cell counts <50/mm(3)). This result indicates that other additional immunological and/or viral factors than readily detectable HIV-1 replication appears to be involved in T-cell activation of immunodepressed individuals. CD8(+)/CD38(bright) is an effective marker for monitoring T-cell activation, which is a central factor of HIV-1 pathogenesis. This gating strategy requires only a single additional staining in conventional four color CD4 protocols.

CD8+ T-Cell Depletion and Rapamycin Synergize with Combined Coreceptor/Stimulation Blockade to Induce Robust Limb Allograft Tolerance in Mice

The growing development of composite tissue allografts (CTA) highlights the need for tolerance induction protocols. Herein, we developed a mouse model of heterotopic limb allograft in a stringent strain combination in which potentially tolerogenic strategies were tested taking advantage of donor stem cells in the grafted limb. BALB/c allografts were transplanted into C57BL/6 mice treated with anti-CD154 mAb, nondepleting anti-CD4 combined to either depleting or nondepleting anti-CD8 mAbs. Some groups received additional rapamycin. Both depleting and nondepleting mAb combinations without rapamycin only delayed limb allograft rejection, whereas the addition of rapamycin induced long-term allograft survival in both combinations. Nevertheless, robust donor-specific tolerance, defined by the acceptance of a fresh donor-type skin allograft and simultaneous rejection of third-party grafts, required initial CD8(+) T-cell depletion. Mixed donor-recipient chimerism was observed in lymphoid organs and recipient bone marrow of tolerant but not rejecting animals. Tolerance specificity was confirmed by the inability to produce IL-2, IFN-gamma and TNF-alpha in MLC with donor antigen while significant alloreactivity persisted against third- party alloantigens. Collectively, these results show that robust CTA tolerance and mixed donor-recipient chimerism can be achieved in response to the synergizing combination of rapamycin, transient CD8(+) T-cell depletion and costimulation/coreceptor blockade.

Idiopathic CD4 lymphocytopenia and opportunistic infection — an update: Table 1

A severe CD4 T-cell depletion predisposes humans to opportunistic infections. In recent years, reports of cases of opportunistic infections caused by CD4 T-cell depletion without HIV infection have been accumulating. Such cases, termed idiopathic CD4 T lymphocytopenia (ICL), are very rare. The epidemiologic data do not suggest that the condition is caused by a transmissible agent. Unlike HIV infection, the decrease in the CD4 cell counts of patients with ICL is often slow. The clinical spectrum of ICL ranges from an asymptomatic laboratory abnormality to life-threatening opportunistic infections. However, the pathogens, clinical significance and treatment of ICL patients still await systematic research. This review summarizes the current knowledge of the poorly understood syndrome of idiopathic CD4 lymphocytopenia, providing key insights into the pathogenesis and immunologic characteristics, and suggesting approaches to enhance CD4 T-cell counts.

Differential pathogenicity of SHIVSF162 P4 infection in pig‐tailed and rhesus macaques

Differential pathogenicity has been observed in cynomolgus and rhesus macaques following primate lentivirus infection. However, little is known about the comparative susceptibility of pig-tailed macaques to lentivirus infection and diseases. We compared the in vivo infectivity and pathogenicity of a CCR5-tropic SHIV(SF162 P4) after intravenous, intravaginal or intrarectal inoculation in rhesus and pig-tailed macaques. Plasma viral load, peripheral blood CD4(+) T cell counts and clinical signs were monitored. Both rhesus and pig-tailed macaques are similarly susceptible to SHIV(SF162 P4) infection by intravenous and mucosal routes. However, infection was significantly more robust in pig-tailed macaques than in rhesus, resulting in persistent viremia in 9/21 pig-tails vs. 2/24 rhesus (P < 0.013) and severe CD4(+) T-cell depletion in 2/21 pig-tails (vs. none in rhesus). Together with earlier observations, our findings underscore the importance of considering host genetic and immunological factors when comparing vaccine efficacy in different macaque species.

IddLoci Synergize to Prolong Islet Allograft Survival Induced by Costimulation Blockade in NOD Mice

OBJECTIVE—NOD mice model human type 1 diabetes and are used to investigate tolerance induction protocols for islet transplantation in a setting of autoimmunity. However, costimulation blockade–based tolerance protocols have failed in prolonging islet allograft survival in NOD mice.RESEARCH DESIGN AND METHODS—To investigate the underlying mechanisms, we studied the ability of costimulation blockade to prolong islet allograft survival in congenic NOD mice bearing insulin-dependent diabetes (Idd) loci that reduce the frequency of diabetes.RESULTS—The frequency of diabetes is reduced in NOD.B6 Idd3 mice and is virtually absent in NOD.B6/B10 Idd3 Idd5 mice. Islet allograft survival in NOD.B6 Idd3 mice treated with costimulation blockade is prolonged compared with NOD mice, and in NOD.B6/B10 Idd3 Idd5, mice islet allograft survival is similar to that achieved in C57BL/6 mice. Conversely, some Idd loci were not beneficial for the induction of transplantation tolerance. Alloreactive CD8 T-cell depletion in (NOD × CBA)F1 mice treated with costimulation blockade was impaired compared with similarly treated (C57BL/6.H2g7 × CBA)F1 mice. Injection of exogenous interleukin (IL)-2 into NOD mice treated with costimulation prolonged islet allograft survival. NOD.B6 Idd3 mice treated with costimulation blockade deleted alloreactive CD8 T-cells and exhibited prolonged islet allograft survival.CONCLUSIONS—Il2 is the Idd3 diabetes susceptibility gene and can influence the outcome of T-cell deletion and islet allograft survival in mice treated with costimulation blockade. These data suggest that Idd loci can facilitate induction of transplantation tolerance by costimulation blockade and that IL-2/Idd3 is a critical component in this process.

Differential Th17 CD4 T-cell depletion in pathogenic and nonpathogenic lentiviral infections

AbstractAcute HIV infection is characterized by massive loss of CD4 T cells from the gastrointestinal (GI) tract. Th17 cells are critical in the defense against microbes, particularly at mucosal surfaces. Here we analyzed Th17 cells in the blood, GI tract, and broncheoalveolar lavage of HIV-infected and uninfected humans, and SIV-infected and uninfected sooty mangabeys. We found that (1) human Th17 cells are specific for extracellular bacterial and fungal antigens, but not common viral antigens; (2) Th17 cells are infected by HIV in vivo, but not preferentially so; (3) CD4 T cells in blood of HIV-infected patients are skewed away from a Th17 phenotype toward a Th1 phenotype with cellular maturation; (4) there is significant loss of Th17 cells in the GI tract of HIV-infected patients; (5) Th17 cells are not preferentially lost from the broncheoalveolar lavage of HIV-infected patients; and (6) SIV-infected sooty mangabeys maintain healthy frequencies of Th17 cells in the blood and GI tract. These observations further elucidate the immunodeficiency of HIV disease and may provide a mechanistic basis for the mucosal barrier breakdown that characterizes HIV infection. Finally, these data may help account for the nonprogressive nature of nonpathogenic SIV infection in sooty mangabeys.

Antiretroviral Therapy prior to Acute Viral Replication Preserves CD4 T Cells in the Periphery but Not in Rectal Mucosa during Acute Simian Immunodeficiency Virus Infection

The rectal mucosa is a major site for human immunodeficiency virus entry and CD4 T-cell depletion. The early and near-total loss of these cells from the rectal mucosa severely compromises the ability of the mucosal immune system to control various opportunistic infections. Protecting these cells from infection and destruction can delay disease progression, leading to a better long-term outcome. Here we show that effective suppression of viral infection in memory CD4 T cells from the rectal mucosa and peripheral blood to a very low level with antiretroviral therapy (ART) initiated prior to the peak of infection is associated with opposite outcomes in these tissues. A near-total loss of CD4 T cells in the rectal mucosa contrasted with preservation of most memory CD4 T cells in peripheral blood during the course of treatment. Interestingly, ART significantly reduced viral infection in memory CD4 T cells from both rectal mucosa and peripheral blood. Although early ART was of limited value in protecting the CD4 T cells in the rectal mucosa, the significant preservation of peripheral CD4 T cells could contribute to maintaining immune competence, leading to a better long-term outcome.

Regulatory T cells in HIV infection: pathogenic or protective participants in the immune response?

Regulatory T cells in HIV infection: pathogenic or protective participants in the immune response?

Human Immunodeficiency Virus-Related Microbial Translocation and Progression of Hepatitis C

Human immunodeficiency virus (HIV)-1 infection has been associated with enhanced microbial translocation, and microbial translocation is a mechanism through which alcohol and some enteric conditions cause liver disease. We hypothesized that HIV promotes liver disease by enhancing microbial translocation. We studied human cohorts in which hepatitis C virus (HCV) and HIV outcomes were carefully characterized. HIV-related CD4(+) lymphocyte depletion was strongly associated with microbial translocation as indicated by elevated levels of circulating lipopolysaccharide (LPS), LPS-binding protein, soluble CD14, and fucose-binding lectin (AAL) reactive to immunoglobulin G specific for the alpha-galactose epitope and suppressed levels of endotoxin core antibodies (EndoCAb IgM) in HIV-infected subjects compared with the same persons before they had HIV infection and compared with HIV-uninfected subjects. The same measures of microbial translocation were strongly associated with HCV-related liver disease progression (cirrhosis), eg, LPS, odds ratio, 19.0 (P = .002); AAL, odds ratio, 27.8 (P < .0001); in addition, levels of LPS were elevated prior to recognition of cirrhosis. Microbial translocation may be a fundamental mechanism through which HIV accelerates progression of chronic liver disease.

Tissue-specific reduction in DC-SIGN expression correlates with progression of pathogenic simian immunodeficiency virus infection

Studies were undertaken to determine whether previously described reductions in splenic DC-SIGN expression in simian acquired immune deficiency syndrome (AIDS) are limited to pathogenic simian immunodeficiency virus (SIV) infection. DC-SIGN expression was evaluated by immunohistochemistry in lymphoid tissues from AIDS-susceptible Asian macaque monkeys as compared with AIDS-resistant sooty mangabey monkeys in the presence and absence of SIV infection. The phenotype of DC-SIGN+ cells in susceptible and resistant species was identical and most consistent with macrophage identity. Significantly lower levels of DC-SIGN expression were identified in spleen, mesenteric lymph node, and bone marrow of macaques with AIDS (P<0.05). Reduced levels of splenic DC-SIGN correlated significantly with CD4T cell depletion in long-term pathogenic infection of macaques (P<0.01), whereas SIV-infected mangabeys retained high levels of DC-SIGN expression in spleen despite persistent infection. Reduced expression of DC-SIGN in spleen specifically characterizes pathogenic forms of SIV infection, correlates with disease progression, and may contribute to SIV pathogenesis.

High frequencies of polyfunctional HIV-specific T cells are associated with preservation of mucosal CD4 T cells in bronchoalveolar lavage

The mechanisms underlying the massive gastrointestinal tract CD4 T-cell depletion in human immunodeficiency virus (HIV) infection are not well understood nor is it clear whether similar depletion is manifest at other mucosal surfaces. Studies of T-cell and virus dynamics in different anatomical sites have begun to illuminate the pathogenesis of HIV-associated disease. Here, we studied depletion and HIV infection frequencies of CD4 T cells from the gastrointestinal tract, bronchoalveolar lavage (BAL), and blood with the frequencies and functional profiles of HIV-specific T cells in these anatomically distinct sites in HIV-infected individuals. The major findings to emerge were as follows: (i) depletion of gastrointestinal CD4 T cells is associated with high frequencies of infected CD4 T cells; (ii) HIV-specific T cells are present at low frequencies in the gastrointestinal tract compared to blood; (iii) BAL CD4 T cells are not massively depleted during the chronic phase; (iv) infection frequencies of BAL CD4 T cells are similar to those in blood; (v) significantly higher frequencies and increased functionality of HIV-specific T cells were observed in BAL compared to blood. Taken together, these data suggest mechanisms for mucosal CD4 T-cell depletion and interventions that might circumvent global depletion of mucosal CD4 T cells.

Chronic CD4+ T-cell activation and depletion in human immunodeficiency virus type 1 infection: type I interferon-mediated disruption of T-cell dynamics.

The mechanism of CD4(+) T-cell depletion during chronic human immunodeficiency virus type 1 (HIV-1) infection remains unknown. Many studies suggest a significant role for chronic CD4(+) T-cell activation. We assumed that the pathogenic process of excessive CD4(+) T-cell activation would be reflected in the transcriptional profiles of activated CD4(+) T cells. Here we demonstrate that the transcriptional programs of in vivo-activated CD4(+) T cells from untreated HIV-positive (HIV(+)) individuals are clearly different from those of activated CD4(+) T cells from HIV-negative (HIV(-)) individuals. We observed a dramatic up-regulation of cell cycle-associated and interferon-stimulated transcripts in activated CD4(+) T cells of untreated HIV(+) individuals. Furthermore, we find an enrichment of proliferative and type I interferon-responsive transcription factor binding sites in the promoters of genes that are differentially expressed in activated CD4(+) T cells of untreated HIV(+) individuals compared to those of HIV(-) individuals. We confirm these findings by examination of in vivo-activated CD4(+) T cells. Taken together, these results suggest that activated CD4(+) T cells from untreated HIV(+) individuals are in a hyperproliferative state that is modulated by type I interferons. From these results, we propose a new model for CD4(+) T-cell depletion during chronic HIV-1 infection.

Gastrointestinal Disease in Simian Immunodeficiency Virus-Infected Rhesus Macaques Is Characterized by Proinflammatory Dysregulation of the Interleukin-6-Janus Kinase/Signal Transducer and Activator of Transcription3 Pathway

Gastrointestinal disease and inflammation are common sequelae of human and simian immunodeficiency virus (SIV) infection. Nevertheless, the molecular mechanisms that lead to gastrointestinal dysfunction remain unclear. We investigated regulation of the interleukin (IL)-6-JAK-STAT3 pathway in jejunum and colon, collected at necropsy, from 10 SIV-infected macaques with diarrhea (group 1), 10 non-SIV-infected macaques with diarrhea (group 2), and 7 control uninfected macaques (group 3). All group 1 and 2 macaques had chronic diarrhea, wasting, and colitis, but group 1 animals had more frequent and severe lesions in the jejunum. A significant increase in IL-6 and SOCS-3 gene expression along with constitutive STAT3 activation was observed in the colon of all group 1 and 2 macaques and in the jejunum of only group 1 macaques compared to controls. Further, in colon, histopathology severity scores correlated significantly with IL-6 (groups 1 and 2) and SOCS-3 (group 2) gene expression. In jejunum, a similar correlation was observed only in group 1 animals. Phosphorylated STAT3 (p-STAT3) was localized to lymphocytes (CD3+) and macrophages (CD68+), with fewer CD3+ lymphocytes expressing p-STAT3 in group 1 macaques. Despite high SOCS-3 expression, STAT3 remained constitutively active, providing a possible explanation for persistent intestinal inflammation and immune activation that may favor viral replication and disease pro-gression.