HIV infection is still a major global health problem. Since the majority of HIV infections occur by sexual exposure, designing a preventive vaccine requires a clear understanding of HIV transmission and local mucosal immune responses. Studies in macaques have shown that a small founder population of SIV-infected CD4+ T cells is established at the site of mucosal transmission. This population expands locally over the first few days with the recruitment of CD4+ CCR5+ target T cells into the cervico-vaginal tissue (CVT). Infection then spreads to the draining lymph nodes (dLNs) where it is fueled by the ready availability of target CD4+ T cells. From there, HIV spreads to other lymphoid and non-lymphoid tissues to establish a systemic infection. These initial events are very inefficient, suggesting that the best opportunity to prevent HIV infection is at the site of mucosal entry and before dissemination. Exploiting this early virus vulnerability requires understanding the cellular and molecular requirements for HIV vaginal transmission and dissemination. Further, how the adaptive immune response in the vaginal mucosa influences HIV transmission is not known and is of critical importance for HIV vaccine design. Recent data have demonstrated a role for tissue resident memory CD4+ and CD8+ T cells for protective immunity at mucosal surfaces;however, the role of these T cell responses in HIV transmission and immunity is not known. Detailed studies of HIV transmission and mucosal immune responses are not possible in humans. We have found that a model of HIV infection, where immunodeficient mice are reconstituted with human bone marrow, liver, and thymus (BLT mice), recapitulates these early events following HIV vaginal transmission. Using HIV infection of humanized BLT mice, we will test the novel hypothesis that blocking chemokine-mediated CD4+ T cell trafficking will interfere with HIV transmission and dissemination. Further, we will also determine the extent by which the local immune response in the CVT influences HIV transmission. In preliminary studies, we have found that pertussis toxin, an inhibitor of all chemokine-mediated cell trafficking, inhibits HIV dissemination in vaginally challenged BLT mice. Chemokines direct T cell trafficking, and we hypothesize that specific chemokine function controls several aspects of T cell migration required for HIV infection and local immunity. Thus, the major goal of this project is to determine the role of chemokines in the migration of T cells required for HIV transmission and local CVT immune responses. Specifically, we will: (1) Identify the chemokines required for CD4+ and CD8+ T cell recruitment into and migration within the CVT following genital HIV exposure;(2) Determine the role of chemokines in the spread of HIV from CVT to dLNs and the effect of chemokines on migratory behavior of infected T cells once in the LN; (3) Determine the role of chemokines in spread of infection beyond the dLN. This Project is also tightly interconnected with Projects 1 and 2 by studying CD8+ T cell differentiation in HIV infection and the role of PD- 1 in this process with the goal of developing novel strategies to achieve better control of viral replication.
Understanding how HIV is sexually transmitted and the effect of the immune response at the site of HIV exposure will allow the design of more effective vaccines. This understanding has been hampered by the lack of an animal model suitable to study HIV transmission. We will use a humanized mouse model of HIV infection to decipher the early critical events in establishing infection following vaginal transmission. This model will allow us to test new strategies to inhibit HIV transmission, such as specific inhibitors of T cell migration to prevent local HIV amplification and its spread from genital tissue into lymphoid tissue and beyond by infected cells.
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