Nonhuman Primate Core

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A major barrier to HIV cure is the persistence of HIV-1 infected cells that constitute the viral reservoir which even after prolonged combined antiretroviral therapy (cART), fuels a consistent and rapid rebound if viral replication following cART interruption. This has unfortunately been true even for patients initiated on ART during acute infection. Thus, long-term persistent HIV reservoirs are seeded rapidly post infection, and our team and others have confirmed this finding in the nonhuman primate model of HIV. In addition, data from several groups and ours strongly suggest that residual viral replication is actually ongoing in various lymphoid tissues in spite of highly active cART, be it due to poor drug penetration, drug metabolization, or sanctuaries with limited antiviral immune contribution. Preliminary data from our ongoing reservoir investigations in the simian immunodeficiency infection of rhesus macaques with ART initiated less than 7 days post infection have led to unexpected findings: 1) we were able to see SIV expand and colonize the entire host for >1 week post cART initiation using immunoPET/CT monitoring, with signal decreasing thereafter; 2) Even after 6-8 months of cART, immunoPET/CT was sensitive enough to detect residual viral (protein) signal in tissues in spite of undetectable viremia in the blood; upon ART interruption, viral signals rebounded as early as 4 days post cART interruption (ATI) but also 2 weeks before detection of virus in plasma; analysis of the tissues and cells fueling this initial rebound surprisingly showed a paucity if not absence of T cells, but predominantly myeloid type cells, among which, many appeared positive for the mast cell specific tryptase biomarker. While our team had documented the ability of developing mast cells to be susceptible to HIV and SIV infection in vitro in the past, this was the first clear evidence that mast cells may contribute at the very least to the very early seeded SIV reservoir. In this application, we propose to quantify and map the reservoir formation in the context of cART initiation at 6 weeks post infection, as more representative of the human clinic, using a series of state of the art imaging guided collection techniques allowing for detailed cellular and viral analyses of the reservoirs obtained at various times of cART and early ATI. Next we propose to address the functional viral reservoir following prolonged cART with and without immune interventions designed to allow for transient viral replication, and finally, investigate the role of such interventions on the reservoir dynamic and composition upon ATI, in efforts to articulate novel strategies to silence viral reservoirs in the future