Immunological and virological effects of targeting gut homing integrin alpha4beta7 in HIV-1 infected humans

Icahn School Of Medicine At Mount Sinai, New York NY

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Abstract

Project summary Although combination antiretroviral therapy (cART) has dramatically improved the therapeutic landscape of HIV-1 infection, a cure remains elusive. As a result, HIV-1 infected patients are often confined to long-term therapy, which is associated with significant cost and morbidity. Gastrointestinal (GI) immune cells are preferred targets for HIV-1 infection during all stages of the infection. Additionally, we and others have reported that GI CD4+ T cells do not reconstitute well despite years of apparently suppressive cART. Integrin ?4?7 is identified as one of the major molecules that is associated with the homing of circulating immune cells to the GI tract. Multiple lines of evidence demonstrate that ?4?7 expressing CD4+ T cells play a critical role in the acquisition and pathogenesis of HIV-1 (SIV) infection and the administration of anti-?4?7 monoclonal antibody (mAb) prevents and/or delays transmission of SIV upon repeated challenges and preserves CD4+ T cells in rhesus macaques (RM). Furthermore, it has been demonstrated that administration of anti-?4?7 mAb in SIV-infected RM receiving cART suppresses plasma viremia for extended periods following discontinuation of cART. Together, these results support our hypothesis that targeting ?4?7 integrin in combination with cART will significantly lower the frequency of infection of intestinal lymphocytes over time. This, in turn will deplete the latent reservoir and enhance immune reconstitution within the GI tract. The proposed research will be carried out through a collaborative effort between three laboratories with distinct and complementary expertise uniquely suited to address the central hypothesis of this application. The PI of this application, Dr. Saurabh Mehandru is a trained gastroenterologist with more than 15 years of experience in the study of intestinal lymphocytes. In addition to making several key contributions to our understanding of the effect of HIV-1 infection on the GI immune system, Dr. Mehandru is intimately involved in the administration of Vedolizumab to patients. Co-I, Dr. Lishomwa Ndhlovu, is an NIH funded leader in studies of HIV-1 latency and strategies to effect its eradication. Co-I, Dr. Schacker, an internationally recognized expert on HIV-associated inflammatory damage of lymphoid tissues, has pioneered the use of a novel assay to examine latently infected cells in the GI tissue. In addition, the research will be done in close collaboration with Dr. Gabriella Rodriguez, Director of the Jack Martin Foundation Clinic at Mount Sinai and Dr. Jean-Frederic Colombel, Director of the IBD center, with considerable experience with clinical trials involving Vedolizumab. This proposal will allow us to determine the effect of VDZ on immunological parameters in the peripheral blood and GI tissue (Aim 1) and, to determine its impact on the HIV-1 levels within circulation and in tissue (aim 2).