Role of PD-1H mediated monocyte activation in HIV pathogenesis

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DESCRIPTION (provided by applicant): Abstract: Chronic immune activation, which can persist even with antiretroviral therapy, is the strongest predictor of disease progression in HIV infection. Understanding the mechanism of chronic immune activation may help identify novel targets for therapeutic interventions in HIV-infection. Extensive evidence from literature suggests that HIV disease directly or indirectly activates monocyte/macrophages to secrete proinflammatory cytokines which play a major role in this pathogenic immune activation. Monocytes from HIV infected individuals are known to secrete cytokines spontaneously, although the mechanism for this or the molecules involved are not known. PD-1H is a newly discovered member of the B7/CD28 family of costimulatory and coinhibitory receptors, which has not been characterized in humans so far. Data to date suggest that the molecule may be derived from a different precursor than all other B7 family members. Although, amongst the B7/CD28 family, the full length sequence of PD-1H has the highest similarity to the negative regulatory molecule PD-1, unlike PD-1, the cytoplasmic domain of PD-1H does not contain the immunoreceptor tyrosine-based inhibitory motif (ITIM) or the immunoreceptor tyrosine-based switch motif (ITSM). Our preliminary data shows that PD- 1H is broadly expressed on hematopoietic cells with higher levels of expression on monocytes. Enforced overexpression of PD-1H in human monocytes is sufficient to induce spontaneous secretion of multiple cytokines. Further, monocytes from HIV-infected individuals overexpress PD-1H which correlates with cytokine gene expression in monocytes and immune activation markers on T cells but not with viral load. Based on these data, we hypothesize that PD-1H acts as a monocyte activation molecule that plays a major role in HIV pathogenesis. In this proposal we will test this hypothesis and evaluate how ART influences this process using PBMCs from defined stages of HIV disease and humanized BLT model which recapitulates key features of HIV pathogenesis, including immune activation. Our specific aims are to: 1) To characterize the evolution of PD-1h over expression in relation to immune activation, plasma proinflammatory cytokine levels, CD4 T cell depletion and plasma viremia using defined groups of HIV infected individuals. 2) Characterize PD-1H expression at different time points during the course of HIV infection in humanized BLT mice vis-¿-vis viral load, CD4 T cell counts and immune activation defined by monocyte associated biomarkers/cytokines and activation markers on T cells. We will also test how PD-1H expression changes after ART, in relation to other parameters and 3) Test if silencing PD-1H or related molecules in humanized mice reverses immune activation or affects other parameters of HIV infection with or without ART.