A hallmark of HIV infection is the recruitment of host factors involved in immune activation that help promote viral replication in various cellular compartments. HIV replication in CD4+ T cells, for example, is most efficient in the activated, memory subset. HIV antigen, in turn, activates HIV-specific cells and, indirectly, can activate non-specific T cells, thus creating a vicious cycle of immune activation and HIV replication. In addition, the chronic immune activation generated by persistent production of HIV antigen is thought to contribute to the immune dysfunction characteristic of HIV disease. This project is designed to further our understanding of the host factors and cellular subsets that influence HIV disease progression by modulating HIV-specific and non-specific immune activation. We are currently investigating the potential role of host-mediated immunosuppressive mechanisms, which are induced under conditions of persistent immune activation, in modulating HIV-specific immune responses. Our initial studies have focused on an immunosuppressive CD4+ T cell subset, CD25+ regulatory T cells (Treg) in the context of HIV infection. We have demonstrated that CD25+ Treg cells isolated from the blood of HIV+ subjects inhibit HIV-specific CD4+ and CD8+ T cell immune responses in vitro, particularly in individuals in the early stages of disease. HIV-specific immune responses suppressed by CD25+ Treg cells include proliferation, cytokine and chemokine secretion and the ability of CD8+ T cells to kill HIV expressing target cells. ? These detrimental effects of CD25+ Treg cells on virus-specific immune responses may be counter-balanced by the ability of these cells to suppress generalized, hyper-immune activation that may cause damage to the host and perpetuate HIV replication. In this regard, reduced CD25+ Treg function/frequency in the peripheral blood of HIV+ individuals with progressive disease has been proposed as a contributing factor to hyper immune activation associated with untreated progressive HIV infection. However, we have recently demonstrated that functional CD25+ Treg cells, capable of suppressing HIV-specific T cell responses, are present in the lymphoid tissue of HIV+ subjects, including those with advanced disease (high VL and low CD4+ T cell counts). These data support phenotypic studies suggesting that CD25+ Treg cells migrate out of blood and into HIV antigen expressing tissue. Treg-mediated immunosuppression in lymphoid tissue may be particularly relevant as this is the primary site of adaptive immune response priming as well as a major site of HIV replication. ? We are further investigating, in collaboration with others, the role of CD25+ Treg cells in the control of hyper immune activation/disease progression in the non-pathogenic SIV-infected sooty mangabey model. This model, which supports the concept that chronic immune activation is an important component of pathogenic HIV/SIV infection, is characterized by a very weak SIV-specific T cell immune response, no significant CD4+ T cell loss, generalized hyper immune activation or disease despite significant levels of viremia. ? Finally, in vivo studies designed to deplete CD25+ cells (the Treg-containing population) in rhesus macaques in the context of SIV infection proved unfruitful due to ineffectiveness of the anti-CD25 immunotoxin used. ? We have also initiated studies investigating the role of Programmed Death (PD)-1 and its ligands (PD-L1 and PD-L2) in the functional exhaustion of HIV-specific T cells. The interaction between PD-1 (primarily on activated T cells) and its ligands (on antigen presenting cells (APCs]) suppresses T cell activation; interference of this interaction has been shown to rescue exhausted CD8+ T cell responses in chronically LCMV-infected mice. Similar to chronic LCMV infection, chronic HIV infection is associated with anergy/exhaustion of virus-specific T cells, a phenomenon that occurs relatively early in disease and is progressive in untreated HIV infection. We found that chronic HIV infection is associated with increased frequencies of PD-1+ T cells and PD-L1+ monocytes in both blood and lymphoid tissue. Treatment of PBMCs from HIV+ subjects with blocking anti-PD-L1 Ab significantly enhances HIV-specific CD4+ and CD8+ T cell proliferative responses in vitro. This enhancing effect is most pronounced in cells from HIV+ individuals with high PD-1 expression and weak/negative baseline HIV-specific responses. These data suggest that HIV-specific immune responses, which are dramatically impaired in most chronically HIV-infected individuals, may be enhanced at least transiently by interfering with the interaction between PD-1 and its ligands in vivo.
