Date of Award

2021

Degree Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

Graduate Group

Cell & Molecular Biology

First Advisor

George M. Shaw

Abstract

The development of an effective HIV-1 vaccine remains a scientific and global health priority despite nearly four decades of intensive investigation. A major roadblock to rational HIV-1 vaccine design is the lack of a primate model in which broadly neutralizing antibodies (bNAbs) can be commonly induced, thereby enabling the molecular and immunological mechanisms responsible for such responses to be studied reproducibly and iteratively. We hypothesized that one means to elicit such antibodies in primates might be by infecting rhesus macaques (RMs) with simian-human immunodeficiency viruses (SHIVs) that bear primary HIV-1 envelope glycoproteins (Envs). Here, we chose to investigate rhesus bNAbs targeting the V2 apex epitope of Env, as human V2 apex bNAbs share several defining characteristics that make them attractive vaccine candidates. We constructed 17 novel SHIVs bearing genetically diverse HIV-1 Envs and used these viruses to infect 127 RMs. Approximately 20% of RMs developed bNAbs that exhibited a wide range of breadth and potency after four months to three years of SHIV infection, half of which recognized the V2 apex. We isolated nine rhesus monoclonal V2 apex bNAb lineages, the characterization of which revealed conserved immunogenetic, chemical, and phenotypic solutions to epitope recognition that recapitulated key features of human V2 apex bNAbs. This included atypically long and anionic heavy chain complementarity-determining region 3s (HCDR3s) derived from an identical IGHD gene that are tyrosine-sulfated and make critical contacts with cationic residues in the C-strand, a key component of the V2 apex epitope. CryoEM structures of two rhesus bNAbs revealed structural mimicry of two distinct HCDR3 topologies that define the PGT145 and VRC26-classes of human V2 apex bNAbs. In eight donor macaques, SHIV Env evolution within or proximal to the C-strand was temporally associated with the development of V2 apex-mediated neutralization breadth and exhibited patterns like that of Env evolution in HIV-1 infected humans with V2 apex bNAbs. The molecular Env-Ab coevolutionary pathway of one rhesus lineage reveals striking similarities of V2 apex bNAb ontogeny in RMs and humans. Overall, SHIV-induced rhesus V2 apex bNAbs can recapitulate developmental features of human bNAbs, thereby guiding HIV-1 V2 apex vaccine design.

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