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Date Submitted

Spring 4-21-2013

Research Mentor and Department

Andrew D. Luster

Restricted/Unrestricted

Dissertation/Thesis

Abstract

HIV-1 was first isolated and described by Françoise Barré-Sinoussi and Luc Montagnier in 1984, leading to the identification of the causative agent for an enigmatic AIDS disease. Since its discovery, HIV-1 transmission has led to a global AIDS epidemic, and although antiretroviral therapies have helped alleviate the threat, drug efficacies are limited both by the logistics of drug administration in developing countries and by the biology of HIV-1, which mutates rapidly due to high error-prone reverse transcriptase and selective pressures in hosts. Understanding mechanisms of HIV-1 transmission is crucial for developing effective treatments. Within the infected population, more than 80% of adults acquired HIV-1 through sexual exposure of mucosal barriers to the virus. Of interest, studies in rhesus macaques using SIV infection revealed potential vulnerabilities of founder virus populations at the mucosal barrier during earliest stages of infection. This novel paradigm has led to new approaches in vaccine-oriented research, bolstered by developments in humanized mouse models of HIV-1 infection. The recent renaissance in humanized mice research has allowed investigators to study pathogenesis of a strictly human pathogen using in vivo animal models. While the immune response against acute HIV-1 infection has been appreciably described, the role of immune cell trafficking in mediating HIV-1 dissemination remains poorly defined. Mechanistically, the role of chemokines in cell-associated viral dissemination remains underappreciated and largely unknown. The current study aims to address these questions in the cervicovaginal infection model, which recapitulates sexual transmission of HIV-1 through mucosal barriers. We report that HIV-1 dissemination is mediated by infected CD4 T cells that circulate in the lymphatic system, likely in response to chemokine gradients.