DOI

10.17077/etd.c4n5-okpp

Document Type

Dissertation

Date of Degree

Summer 2019

Degree Name

PhD (Doctor of Philosophy)

Degree In

Microbiology

First Advisor

Haim, Hillel

First Committee Member

Klingelhutz, Aloysius

Second Committee Member

Fuentes, Ernesto

Third Committee Member

Perlman, Stanley

Fourth Committee Member

Stapleton, Jack

Abstract

Human immunodeficiency virus type 1 (HIV-1) establishes a persistent infection that leads to acquired immunodeficiency syndrome (AIDS). Approximately 36 million people worldwide are living with HIV-1, which is commonly acquired through sexual contact. Antiviral therapies control disease progression, but do not eliminate this virus from the host. Thus, global efforts are focused on developing vaccines that prevent HIV-1 transmission. Such vaccines are based on eliciting the production of protective antibodies that target the envelope glycoproteins (Envs) of this virus. Unfortunately, HIV-1 immunization trials have shown limited efficacy. A better understanding of the antibody-mediated inactivation process is needed to improve vaccine strategies. In this work we describe two novel factors that contribute to HIV-1 inactivation. First, we show that structural stability of the Env protein determines its sensitivity to vaccine-elicited antibodies. Different interactions within Env contribute to its stability. Perturbation of the Env-stabilizing interactions by physical and chemical treatments enhances sensitivity of HIV-1 to antibodies. Second, we found that the chemical composition of the transmission medium affects Env inhibition by antibodies and other inhibitory agents. Semen is the most common vehicle for HIV-1 transmission. This medium contains high concentrations of the sugar fructose. We found that semen fructose competitively blocks binding of antiviral agents that target sugar residues on Env. Together, this work advances our understanding of the mechanism that underlies HIV-1 inactivation by vaccine-elicited antibodies and provides novel strategies to enhance their potency.

Keywords

Antibody neutralization, Envelope Glycoprotein, Human Immunodeficiency Virus (HIV), Protein stability

Pages

xv, 190 pages

Bibliography

Includes bibliographical references (pages 168-190).

Copyright

Copyright © 2019 Jacklyn Johnson

Included in

Microbiology Commons

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