Chemokine receptors as HIV coreceptors / Benjamin J. Doranz.

Format:

Book

Manuscript

Microformat

Thesis/Dissertation

Author/Creator:

Doranz, Benjamin J.

Contributor:

Doms, Robert W., advisor.

University of Pennsylvania.

Language:

English

Subjects (All):

Penn dissertations--Cell and molecular biology.

Cell and molecular biology--Penn dissertations.

Cell and Molecular Biology.

Academic Dissertations as Topic.

Medical Subjects:

Cell and Molecular Biology.

Academic Dissertations as Topic.

Local Subjects:

Penn dissertations--Cell and molecular biology.

Cell and molecular biology--Penn dissertations.

Physical Description:

ix, 131 pages : illustrations ; 29 cm

Production:

1998.

Summary:

The mechanism by which human immunodeficiency virus (HIV) enters cells has been investigated for over a decade. While CD4 was quickly identified as the primary binding receptor for HIV type 1 (HIV-1), other cellular molecules, so-called "coreceptors", were thought to be involved in viral fusion. In 1996, we and others identified the chemokine receptors CCR5 and CXCR4 as the primary fusion coreceptors for HIV. The identification of chemokine receptors as HIV fusion coreceptors has had a major impact on our understanding of HIV biology and AIDS. The use of CCR5 and CXCR4 helps explain viral tropism, the inability of HIV-1 to infect most non-primate cells, and the contribution of host factors to AIDS pathogenesis. Our discovery that a subpopulation of people harbor a non-functional polymorphism of CCR5 (CCR5$\Delta$32) that renders homozygotes nearly completely resistant to HIV-1 transmission also helps explain the existence of a subset of exposed-uninfected and long-term non-progressing infected individuals. By examining the structural requirements for coreceptor function and ligand binding, we identified regions of the coreceptors necessary and sufficient for function. This structural information has allowed us to propose models for the evolution of HIV-1 in vivo, hypothesize mechanisms of fusion, and identify rational targets for anti-viral therapy. These studies also provide a basis for structural modeling of this poorly understood class of molecules. Since CCR5 is required for nearly all HIV transmission events and since CCR5 is completely dispensable for normal human health, CCR5 is ideal for pharmaceutical targeting. Our identification of a small-molecule inhibitor of the chemokine receptor CXCR4, ALX40-4C, demonstrated that HIV-1 can be stopped by pharmaceutical intervention from using coreceptors and entering cells. We are now using many of the techniques developed and employed in our lab for biochemical analysis of HIV fusion, such as high efficiency cell-cell fusion assays, virus infection assays, and Envelope binding assays, to identify novel chemokine receptor drug candidates that target CCR5 in a high-throughput large-scale drug screen.

Notes:

Supervisor: Robert W. Doms.

Thesis (Ph.D. in Cell and Molecular Biology) -- University of Pennsylvania, 1998.

Includes bibliographical references.

Local Notes:

University Microfilms order no.: 98-40182.

OCLC:

187472874