Unraveling the Mechanisms of HIV Persistence and Rebound

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PROJECT SUMMARY/ABSTRACT (Overall) The persistence of HIV infection despite long term suppression of viremia by cART constitutes the major obstacle to HIV cure. This is unfortunately true even for patients initiated on cART during acute infection. Thus, long-term persistent HIV reservoirs are seeded rapidly post infection, and this was confirmed in the nonhuman primate (NHP) model of HIV. In addition, data from several groups and ours strongly suggest that residual viral replication is ongoing despite in tissues despite full suppression of viremia by cART. Our on-going studies investigate the “eclipse phase” of viral rebound in the NHP model after cART interruption. This “eclipse phase” is key to understand the rebound process since the virus is spreading in tissues before viremia and it is influenced by adaptive and innate responses as well as the host microenvironment. In our studies of early (4 days post- infection) cART initiation, our innovative SIV-env ImmunoPET-CT guided analysis and sampling led to several important, sometimes unexpected findings: 1) we detected SIV expansion throughout the entire host for >1 week post cART initiation, 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; 3) 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; 4) analysis of the tissues collected at rebound through our PET-CT guided necropsy workflow surprisingly showed that the majority of infected cells were of myeloid cells. After extensive analysis, these cells revealed to be mast cells (MC), a predominantly tissue resident granulocytes that we demonstrate expresses CD4 and CCR5. By teaming up with a local MC expert, we were able to demonstrate that primary tissue MC are susceptible to HIV infection in vitro and their susceptibility and ability to support viral replication is heavily influenced by environmental stimuli. In this PPG, we will leverage several important insights and innovative techniques developed during our current PPG to investigate the hypothesis that MC contribute to HIV persistence in tissues during cART and/or contribute to viral rebound upon cART interruption. Moreover, we will clarify virus-host dynamics through phyloanatomical analysis of viral populations in tissues using tissues and cells isolated through our innovative PET-CT guided sampling workflow. These tissues will be identified also through the analysis of additional features of “rebound tissues” that we have recognized through our current studies. This PPG comprises of 3 independent, although highly interconnected projects, 1 scientific NHP core and 1 administrative core. The 3 projects will all use in different ways tissues from the NHP studies as well as resources unique to each project and will address different although complementary questions with the ultimate goal to dissect the mechanisms of HIV persistence and rebound.