Grant: New Investigator Award - PA: HIV/AIDS Biomedical/Clinical Research

Immature dendritic cells (iDCs) which reside in these mucosal tissues capture internalize and serve as hidden reservoirs for the virions. This helps the virus escape immune surveillance during the DCs migration to the secondary lymphoid organs where the virions are transmitted to CD4 cells. The virus can replicate in these T cells which are severely depleted in less than 10 days after primary infection. In fact, HIV infection is controlled by CD4 T cell responses and depletion of these cells during primary infection affects the initiation of the specific immune response, which could explain the long-term inability of the host immune response to control the infection. Based on preliminary data, we propose a mechanism by which exosomes released by HIV-1-iDCs can induce functional defects in CD4 T cells. We have observed that iDCs stimulated with HIV-1 release particles akin to HIV-1 and called exosomes, and these exosomes contain at their surface several molecules which are able to eliminate the CD4 T cells. It should be pointed out that the link between the surface molecules associated with exosomes and the effects of the latter on the activity of the various CD4 T cell sub-populations has not been studied in the context of HIV-1 infection. Filling this gap is a major aim of the present application. Two distinct but interlinked research objectives are proposed to test this hypothesis. AIM I: To further characterize exosomes and determine the mechanisms involved in their release from iDCs after HIV-1 capture. AIM II: To investigate the effects of HIV-1-iDC-derived exosomes on the functional responses of CD4 T cells. Altogether the proposed research project should contribute to our comprehension of the various mechanisms underlying the complex interplay occurring between iDCs-exosomes HIV-1 and CD4 T cells. This study is of utmost importance to elucidate the mechanisms of immune depletion in HIV-1 patients.