Maturation of Autologous and Heterologous Neutralization Breadth in Subtypes A and B HIV-1 Infection Open Access

Murphy, Megan Katherine (2013)

Permanent URL: https://etd.library.emory.edu/concern/etds/b2773v812?locale=en
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Abstract

Precise routes of viral escape from autologous neutralizing antibodies have been inadequately deciphered in human immunodeficiency virus (HIV-1) infection, especially as they extend from their points of origin along lineages that may influence or direct the expansion of heterologous neutralization potential. Only one quarter of HIV-1 infected people will generate neutralizing antibodies with potent, cross-clade recognition profiles, but we do not understand what distinguishes these individuals or their infections from others.

What follows is an investigation into the roots of neutralization breadth. We first determined, in a cohort of sixteen subtype B-infected viremic patients in the United States, the status of the B cell compartment during chronic infection and subsequent effects on neutralization potential. Then, in one Rwandan subtype A-infected seroconverter (R880F), we pinpointed the primary neutralizing antibody target and the successive pathways of immune evasion using envelope glycoproteins from the transmitted/founder virus and longitudinal escape variants.

In the chronically infected subjects, plasma from three of sixteen (19%) individuals showcased broad heterologous neutralization, which partnered with high levels of total IgG production. Measures of immune activation, dysregulation, CD4 T cell count, and plasma viral load, however, did not differentiate them from the thirteen patients with lower neutralizing activity. In subject R880F, a single mutation at one of three clustered residues proximal to gp120's third hypervariable loop conferred early viral escape. This putative epitope subsequently elicited at least two somatically related monoclonal antibodies, which bound and neutralized viral envelopes containing a subset of the established escape mutations. Resistance to this secondary wave of immune pressure then arose in later viral envelopes through introduction of two N-linked glycosylation motifs that presumably obscured this consistently targeted space. At 16-months post-infection, what had been a narrow, regional response evolved to force recognition/neutralization of distinct envelope portions, which resulted in moderate cross-clade neutralization breadth.

Our data suggest that B cell dysregulation does not directly forestall the observed scope of neutralization. Instead, unveiling a certain chain of envelope mutations could drive B cells toward the production of broadly neutralizing antibodies. Appreciating this knowledge during immunogen construction could positively impact HIV-1 vaccine design.

Table of Contents

Abstract

Dedication

Acknowledgements

Introduction-pg. 1

Chapter 1, Viral Escape From Neutralizing Antibodies in Early Subtype A HIV-1 Infection Drives An Increase in Autologous Neutralization Breadth-pg. 13

Chapter 2, B-lymphocyte Dysfunction in Chronic HIV-1 Infection Does Not Prevent Cross-clade Neutralization Breadth-pg. 90

Discussion-pg. 127

Literature Cited in the Introduction and Discussion-pg. 135

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