In vivo suppression of SIV-mediated immune activation

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DESCRIPTION (provided by applicant): Differences in levels of immunoactivation have been identified as the single more significant difference between AIDS susceptible and resistant species. Higher levels of immunoactivation correlate with HIV and SIV pathogenicity in certain species, possibly because increased CD4+ T cell immunoactivation would result in increased immunoactivation-mediated apoptosis, accompanied by CD4+ T cell depletion. Immunoactivation can be induced by a variety of mechanisms, including persistent stimulation of immune responses by viral antigens, and/or production of immunoactivating cytokines and chemokines. 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 had 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. We identified how the viral protein Tat directly modulates cellular proteins that lead to the activation of the p38 MAPK pathway. As no effective drugs that block Tat activity exist and 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. Our goal is to 1. To evaluate longitudinally the impact that in vivo PH-797804-mediated inhibition of p38 MAPK has on immune activation in four SIV-infected RM by evaluating as primary end points the gene expression profiles and expression of surface molecules linked to immune activation in RM PBMC, lymph node and rectal mucosa biopsies and the serum levels of inflammatory cytokines and chemokines; 2. to evaluate as secondary end points the effect that the treatment has on viral loads, preservation of central memory CD4+ T cells, and possibly on disease progression. This work could provide the rationale for testing p38 MAPK inhibitors in preclinical and clinical trials and for encouraging the development of effective Tat inhibitors.