The effects of HIV gp120 on CTL migration and efficacy

Massachusetts General Hospital, Boston MA

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Abstract

DESCRIPTION (provided by applicant): The candidate is currently enrolled in her third year of clinical and research fellowship training in Infectious Diseases at the Massachusetts General Hospital. She plans a career as a basic science researcher at an academic medical center with a dominant research focus complimented by clinical responsibilities. The environment in which the proposed research training program will be accomplished will provide a supportive atmosphere with ample opportunity for formal learning and collaboration, and will prepare the candidate for an independent investigative career. Most HIV-infected individuals worldwide do not have access to highly active anti-retroviral therapy (HAART) and therefore ultimately develop uncontrolled viremia and progressive disease. HIV exploits various mechanisms in order to evade the immune system including the infection and lysis of HIV-specific helper T-cells, the generation of escape mutations, and direct effects of viral proteins. This proposal aims to demonstrate that the HIV protein, gp120, interferes with immune cell migration via its interaction with the chemokine receptors CXCR4 and CCR5, thus allowing HIV-infected cells to escape challenge by host immune effector cells. The functional efficacy of H1V-specific cytotoxic T lymphocytes (CTL) will be assessed using standard transmigration assays as well as cytotoxicity assays modified to account for the effects of cell migration on killing efficacy. The signal transduction pathways, activated by gp120 binding CXCR4 or CCR5, that lead to dysregulation of CTL localization will be defined. Additionally, a murine model will be designed in order to examine the effects of HIV gp120---chemokine receptor interaction on CTL migration in an in vivo setting. Data generated will expand the understanding of why the human immune system fails to contain HIV infection, and ideally facilitate the design of novel therapies that will assist in the eradication of the virus in HIV-infected individuals.