Numerous studies have demonstrated that CD8؉ T lymphocytes suppress virus replication during human immunodeficiency virus (HIV)/simian immunodeficiency virus (SIV) infection. However, the mechanisms underlying this activity of T cells remain incompletely understood. Here, we conducted CD8 ؉ T lymphocyte depletion in 15 rhesus macaques (RMs) infected intravenously (i.v.) with SIV mac239 . At day 70 postinfection, the animals (10 progressors with high viremia and 5 controllers with low viremia) were CD8 depleted by i.v. administration of the antibody M-T807R1. As expected, CD8 depletion resulted in increased virus replication, more prominently in controllers than progressors, which correlated inversely with predepletion viremia. Of note, the feature of CD8 ؉ T lymphocyte predepletion that correlated best with the increase in viremia postdepletion was the level of CD8؉ T-bet ؉ lymphocytes. We next found that CD8 depletion resulted in a homogenous increase of SIV RNA in superficial and mesenteric lymph nodes, spleen, and the gastrointestinal tract of both controllers and progressors. Interestingly, the level of SIV DNA increased postdepletion in both CD4؉ central memory T lymphocytes (T CM ) and CD4 ؉ effector memory T lymphocytes (T EM ) in progressor RMs but decreased in the CD4؉ T CM of 4 out of 5 controllers. Finally, we found that CD8 depletion is associated with a greater increase in CD4 ؉ T lymphocyte activation (measured by Ki-67 expression) in controllers than in progressors. Overall, these data reveal a differential impact of CD8 ؉ T lymphocyte depletion between controller and progressor SIV-infected RMs, emphasizing the complexity of the in vivo antiviral role of CD8 ؉ T lymphocytes. IMPORTANCEIn this study, we further dissect the impact of CD8 ؉ T lymphocytes on HIV/SIV replication during SIV infection. CD8 ؉ T lymphocyte depletion leads to a relatively homogenous increase in viral replication in peripheral blood and tissues. CD8؉ T lymphocyte depletion resulted in a more prominent increase in viral loads and CD4 ؉ T lymphocyte activation in controllers than in progressors. Interestingly, we found T-bet expression on CD8 ؉ T lymphocytes to be the best predictor of viral load increase following depletion. The levels of SIV DNA increase postdepletion in both CD4؉ T CM and T EM in progressor RMs but decrease in the CD4 ؉ T CM of controllers. The findings described in this study provide key insights into the differential functions of CD8 ؉ T lymphocytes in controller and progressor RMs. S everal lines of evidence indicate that CD8ϩ T lymphocytes mediate control of virus replication during both human immunodeficiency virus (HIV) infection of humans and simian immunodeficiency virus (SIV) infection of rhesus macaques (RMs). First, the postpeak decline of viremia in acute HIV infection is coincident with the expansion of HIV-specific T cells (1, 2). Second, during both acute and chronic HIV/SIV infection, immune pressure mediated by HIV/SIV-specific CD8 ϩ T lymphocytes is manifested by viral escape mut...

T follicular helper cells (TFH) are critical for the development and maintenance of germinal centers (GC) and humoral immune responses. During chronic HIV/SIV infection TFH accumulate, possibly as a result of antigen persistence. The HIV/SIV-associated TFH expansion may also reflect lack of regulation by suppressive follicular regulatory CD4+ T-cells (TFR). TFR are natural regulatory T-cells (TREG) that migrate into the follicle and, similarly to TFH, up-regulate CXCR5, Bcl-6, and PD1. Here we identified TFR as CD4+CD25+FoxP3+CXCR5+PD1hiBcl-6+ within lymph nodes of rhesus macaques (RM) and confirmed their localization within the GC by immunohistochemistry. RNA sequencing showed that TFR exhibit a distinct transcriptional profile with shared features of both TFH and TREG, including intermediate expression of FoxP3, Bcl-6, PRDM1, IL-10, and IL-21. In healthy, SIV-uninfected RM, we observed a negative correlation between frequencies of TFR and both TFH and GC B-cells as well as levels of CD4+ T-cell proliferation. Following SIV infection, the TFR/TFH ratio was reduced with no change in the frequency of TREG or TFR within the total CD4+ T-cell pool. Finally, we examined whether higher levels of direct virus infection of TFR were responsible for their relative depletion post-SIV infection. We found that TFH, TFR and TREG sorted from SIV- infected RM harbor comparable levels of cell-associated viral DNA. Our data suggests that TFR may contribute to the regulation and proliferation of TFH and GC B-cells in vivo and that a decreased TFR/TFH ratio in chronic SIV infection may lead to unchecked expansion of both TFH and GC B-cells.

The host pathogen interaction is strikingly complex during HIV infection. While several immune effector mechanisms (i.e., cytotoxic T cells, neutralizing antibodies, NK cells, etc) can play a strong antiviral role in vivo, the virus is remarkably able to evade these responses. In addition, the virus preferentially infects and kills activated memory CD4+ T cells, thus exploiting the host antiviral immune response as a source of new cellular targets for infection. Recent advances in understanding (i) how HIV perturbs the host immune system, (ii) how the immune system fights HIV; and (iii) how HIV disease persists when virus replication is suppressed by antiretroviral drugs may hopefully lead to better prevention and treatment strategies for this deadly viral infection.

This information is current as Infection in Chronic FH to Accumulation of T Infected Rhesus Macaques May Contribute

The HIV reservoir is largely composed of latently infected memory CD4 + T cells that persist during antiretroviral therapy and constitute a major barrier toward HIV eradication. In particular, CD4 + T follicular helper cells have been demonstrated as key targets for viral replication and persistence under ART.