This research project is focused on the role of gp120-mediated signal transduction in viral replication and immune dysfunction that leads to HIV pathogenesis. We have described in the past that gp120 engages integrin alpha4beta7, the gut-homing receptor, opening up many new and potentially important questions. Because alpha4beta7 mediates leukocyte homing to gut associated lymphoid tissue, which is a principal site of HIV replication during the acute phase of infection we have set out to explore the role of alpha4beta7 expressing CD4+ T cells in HIV transmission. We tested this hypothesis in a NHP model of HIV/SIV infection, and determined that an antibody specific for alpha4beta7 prevented transmission in a rhesus macaque model of mucosal transmission. Of note, this antibody is a primatized version of Vedolizumab, an FDA approved drug employed for the treatment of inflammatory bowel diseases (IBDs). We are now exploring the impact of such alpha4beta7 antagonist in an in vivo NHP study in the context of anti retroviral (ART) treatment. SIV-infected monkeys were treated with ART initiated at 5 weeks post infection followed by infusions of the primatized antibody alpha4beta7 integrin administered every 3 weeks until week 32. These animals subsequently maintained low to undetectable viral loads and normal CD4+ T-cell counts in plasma and gastro-intestinal tissues (GIT) for over 2 years even after all treatment was withdrawn.
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