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The enteropathic manifestations of the human immunodeficiency virus (HIV) and the simian immunodeficiency virus (SIV) in late infection are usually due to infection by other microbes, but in early infection the viruses themselves cause an enteropathy by heretofore undetermined mechanisms. Here we report that SIV induces massive apoptosis of intestinal epithelial cells lining the small and large bowel, thus identifying apoptosis as the driving force behind the regenerative pathology of early infection. We found that apoptosis of gut epithelium paralleled the previously documented apoptosis and massive depletion of CD4 T cells in gut lamina propria, triggered by established mechanisms of gut epithelial cell apoptosis and, at peak, possibly by virus interactions with GPR15/Bob, an intestinal epithelial cell-associated alternative coreceptor for SIV and HIV-1. Apoptosis in early SIV infection is thus the common theme of the pathological processes that quickly afflict the innate as well as adaptive arms of the gut immune system. [ABSTRACT FROM AUTHOR]

In human immunodeficiency virus (HIV) infection, collagen deposition and fibrosis within the T cell zone disrupt the lymphatic tissue architecture, contributing to depletion of CD4+ T cells and limiting immune reconstitution. We used relevant animal and in vitro models to investigate the kinetics and possible underlying mechanism(s) of this process. In the lymphatic tissue of simian immunodeficiency virus (SIV)-infected rhesus macaques, we observed parallel increases in immune activation, transforming growth factor (TGF) β1-positive regulatory T (Treg) cells, and collagen type I deposition by 7 days after inoculation, consistent with the hypothesis that early immune activation elicits a countering Treg cell response associated with TGFβ1 expression and collagen deposition. In support of this hypothesis and the possible role of fibrosis in viral pathogenesis, we show (1) spatial colocalization and temporal concordance in levels of TGFβ1+ Treg cells and collagen deposition; (2) TGFβ1+ inducible Treg cell stimulation of primary lymphatic tissue fibroblasts to produce collagen type I in vitro; and (3) high levels of immune activation, TGFβ1+ Treg cells, and collagen deposition in pathogenic SIV infection of macaques, in contrast to apathogenic SIV infection in sooty mangabeys in which levels of immune activation, TGFβ1+ Treg cells, and collagen deposition were low. We thus conclude that the response of TGFβ1+ Treg cells to immune activation in early SIV/HIV infection is a double-edged sword: TGFβ1+ Treg cells normally have a positive effect by limiting immunopathological and autoreactive immune responses, but they also have a negative effect by dampening the antiviral immune response and, as we show here, causing deleterious effects on CD4+ T cell homeostasis by inducing collagen deposition in lymphatic tissues. [ABSTRACT FROM AUTHOR]

In human immunodeficiency virus (HIV) infection, collagen deposition and fibrosis within the T cell zone disrupt the lymphatic tissue architecture, contributing to depletion of CD4(+) T cells and limiting immune reconstitution. We used relevant animal and in vitro models to investigate the kinetics and possible underlying mechanism(s) of this process. In the lymphatic tissue of simian immunodeficiency virus (SIV)-infected rhesus macaques, we observed parallel increases in immune activation, transforming growth factor (TGF) beta 1-positive regulatory T (T(reg)) cells, and collagen type I deposition by 7 days after inoculation, consistent with the hypothesis that early immune activation elicits a countering T(reg) cell response associated with TGF beta 1 expression and collagen deposition. In support of this hypothesis and the possible role of fibrosis in viral pathogenesis, we show (1) spatial colocalization and temporal concordance in levels of TGF beta 1(+) T(reg) cells and collagen deposition; (2) TGF beta 1(+) inducible T(reg) cell stimulation of primary lymphatic tissue fibroblasts to produce collagen type I in vitro; and (3) high levels of immune activation, TGF beta 1(+) T(reg) cells, and collagen deposition in pathogenic SIV infection of macaques, in contrast to apathogenic SIV infection in sooty mangabeys in which levels of immune activation, TGF beta 1(+) T(reg) cells, and collagen deposition were low. We thus conclude that the response of TGF beta 1(+) T(reg) cells to immune activation in early SIV/HIV infection is a double-edged sword: TGF beta 1(+) T(reg) cells normally have a positive effect by limiting immunopathological and autoreactive immune responses, but they also have a negative effect by dampening the antiviral immune response and, as we show here, causing deleterious effects on CD4(+) T cell homeostasis by inducing collagen deposition in lymphatic tissues. [ABSTRACT FROM AUTHOR]

Here we report the results of an investigation into the possibility that one mechanism responsible for the establishment of persistent human immunodeficiency virus infection is an early regulatory T (Treg) cell response that blunts virus-specific responses. Using the simian immunodeficiency virus (SIV)-infected rhesus macaque model, we show that, indeed, viral replication and immune activation in lymphatic tissue drive a premature immunosuppressive response, with dramatic increases in the frequencies of CD4+CD25+FOXP3+ Treg cells, transforming growth factor-β1+ cells, interleukin-10+ cells, and indoleamine 2,3-dioxygenase+CD3+ cells. When we compared SIV infection with rhesus cytomegalovirus (RhCMV) infection, we found that the frequency of Treg cells paralleled the magnitude of immune activation during both infections but that the magnitude of immune activation and of the Treg cell response were lower and peaked much later during RhCMV infection. Importantly, the frequency of Treg cells inversely correlated with the magnitude of the SIV-specific cytotoxic T lymphocyte response. We conclude that an early Treg cell response during acute SIV infection may contribute to viral persistence by prematurely limiting the antiviral immune response before infection is cleared. [ABSTRACT FROM AUTHOR]