Date of Award

Spring 1-1-2025

Document Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

Department

Molecular Biophysics and Biochemistry

First Advisor

Xiong, Yong

Abstract

Several million people live with infection by human immunodeficiency virus type 2 (HIV-2). Like its pandemic-causing relative, HIV-1, infection with HIV-2 can progress to AIDS, is largely incurable, and is similarly mutation-prone, presenting a challenge for treatment. Despite this, detailed study of HIV-2 is widely lacking while most of the understanding of the virus and its proteins is borne out of comparison with HIV-1. The two are sufficiently similar that this is generally effective, but differences in infection outcomes of the two viruses must be explicable by molecular determinants. One domain of viral biology particularly worth attention in this regard is the capsid. The HIV-1 capsid is well-studied and a novel therapeutic target, but the system for researching the HIV-2 capsid is not similarly established. My thesis work focuses on resolving this by leveraging approaches from the study of HIV-1 to establish methods for investigating HIV-2 and to elucidate the structure and assembly properties of the HIV-2 capsid. By determining high-resolution structures of the capsid lattice with cryo-electron microscopy, I identify both convergent and divergent features of the capsid, implicated in determinants of its assembly and the evolutionary pressures upon the retroviruses. I begin to uncover details of capsid-host protein interactions through biochemical and structural investigation of proviral factors including Nup153, CPSF6, and CypA as well as a differential restriction factor, NONO. I describe a series of approaches and ongoing work to establish a wider array of assembly systems, providing insight into HIV-2 capsid protein assembly characteristics as well as a biochemical toolkit for future study of the capsid. Inclusive in this is contribution to the study of small pharmaceutical molecule interaction with its target interface. This work provides a foundation for expanded study of HIV-2, improving understanding and potential treatment of the disease, but also giving better context to the broader family of retroviruses.

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