Antibody Targeting of HIV-1 Env: a Structural Perspective

Author: Abernathy, Morgan Elizabeth

Year: 2022

Degree: Dissertation (Ph.D.)

Advisor: Bjorkman, Pamela J.

Committee Members: Rees, Douglas C.; Tirrell, David A.; Clemons, William M.; Bjorkman, Pamela J.

Option: Chemistry

DOI: 10.7907/0p2b-aa45

Abstract

A key component of contemporary efforts toward a human immunodeficiency virus 1 (HIV-1) vaccine is the use of structural biology to understand the structural characteristics of antibodies elicited both from human patients and animals immunized with engineered 'immunogens,' or early vaccine candidates. This thesis will report on projects characterizing both types of antibodies against HIV-1. Chapter 1 will introduce relevant topics, including the reasons HIV-1 is particularly capable of evading the immune system in natural infection and after vaccination, the 20+ year history of unsuccessful HIV-1 vaccine large-scale efficacy trials, an introduction to broadly neutralizing antibodies (bNAbs), and a review of common strategies utilized in HIV-1 immunogen design today. Chapter 2 describes the isolation, high-resolution structural characterization, and in vitro resistance profile of a new bNAb, 1-18, that is both very broad and potent, as well as able to restrict HIV-1 escape in vivo. Chapter 3 reports the results of an epitope-focusing immunogen design and immunization experiment carried out in wild type mice, rabbits, and non-human primates where it was shown that B cells targeting the desired epitope were expanded after a single prime immunization with immunogen RC1 or a variant, RC1-4fill. Chapter 4 describes Ab1245, an off-target non-neutralizing monoclonal antibody isolated in a macaque that had been immunized with a series of sequential immunogens after the prime immunization reported in Chapter 3. The antibody structure describes a specific type of distracting response as it binds in a way that causes a large structural change in Env, resulting in the destruction of the neutralizing fusion peptide epitope. Chapter 5 is adapted from a review about how antibodies differentially recognize the viruses HIV-1, SARS-CoV-2, and Zika virus. This review serves as an introduction to the virus SARS-CoV-2, which is the topic of the final chapter, Chapter 6. In this chapter, structures of many neutralizing antibodies isolated from SARS-CoV-2 patients were used to define potentially therapeutic classes of neutralizing receptor-binding domain (RBD) antibodies based on their epitopes and binding profiles.

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