Differences in immune activation have been identified as the single most significant difference between AIDS- susceptible and resistant species. Immune activation can be induced by a variety of mechanisms, including stimulation of immune responses by viral antigens, production of a superantigen, and/or production of activating cytokines and chemokines. It is quite likely that more than one mechanism is occurring simultaneously during HIV infection. We have shown that HIV and SIV infections modulates primate APC and T-cell gene expression and that at least a subset of the IFN-stimulated genes (ISG), reprogrammed in infected human and RM iDC, are not affected by SIV infection in APC of AIDS resistant species. We postulated that induction and maintenance of immune activation could depend on the induction by HIV or SIV of cell pathways leading to the production of immunoactivating cytokines and chemokines and have shown that this is the case in vitro. p38 MAPK, which has been reported to be activated in HIV and SIV infection, is key in the pathway of induction of ISG and is associated in vivo with the some of the pathology produced by HIV and SIV infection in AIDS susceptible primates. As inhibitors of p38 MAPK are available and currently tested in human trials for other diseases, we intend to evaluate the effects of treating SIV-infected macaques with a p38 inhibitor that has been shown to reduce immune activation in trials for different human diseases in conjunction with ART. Our goals are: 1 to evaluate in vivo the impact that PH-797804 alone or added to ART has on immune activation in SIV- infected RM. As primary end points we will evaluate expression of surface and intracellular molecules linked to immune activation and gene expression profiles in RM PBMC, lymph node and rectal mononuclear cell (MNC) subpopulations, and plasma levels of inflammatory cytokines and chemokines; 2. to evaluate the effects that treatments have on viral loads, viral reservoirs, and preservation of central memory CD4+ T cells as secondary end points; 3. to evaluate the treatment impact on protein levels of selected IGS and on immune activation markers in lymph node, intestinal tissue and brain sections.
The hallmark of Human Immunodeficiency Virus and Simian Immunodeficiency Virus infection in disease-susceptible species is the progressive decline of the CD4+ T cell population and heightened immune activation, which can cause the death of CD4+ T cells and is present in HIV-infected humans and SIV infected macaques but not in other infected primate species. Immune activation can be induced by the cellular pathway regulated by p38 MAPK, which is activated in HIV and SIV infection. We intend to investigate whether a drug that has been shown to reduce in human the immune activation mediated by p38 MAPK can also reduce it in SIV infected macaques. When combined with antiretroviral therapy this drug could significantly impact the course of AIDS. This work could provide the rationale to test the same drug in clinical trials of HIV infected individuals and stimulate the discovery of inhibitors of the HIV protein critical to this activation that are currently not explored.