Structure-Guided Exploration of the Divergence of HIV-1 and SRLV Lentiviral Pathways

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

My thesis work focuses on understanding how viral pathways have diverged between different lentiviruses to infect their respective hosts. I focus on two critical viral proteins that actively interact with host proteins to ensure infection, the capsid protein (CA) and the virion infectivity factor (Vif). I determined the cryo-EM CA structures of the two main types of small ruminant lentiviruses (SRLVs), maedi-visna virus (MVV) and caprine arthritis encephalitis virus (CAEV), which infect sheep and goats respectively. Analyzing the SRLV CA proteins in their assembled capsomeric forms and comparing them against HIV-1 revealed key divergences and conserved features. These features include a novel class of IP6-independent capsids with hydrophobic central pores, a likely distinct mechanism for deoxynucleotide triphosphate (dNTP) import into the capsid, a unique pentameric conformation, and the absence of Cyclophilin A (CypA) binding sites. A small portion of my thesis is dedicated to the optimization of the HIV-1 and MVV Vif host/pathogen complexes with their respective APOBEC3 (A3) host restriction factor targets. Lentiviruses use Vif to highjack the host E3-ubiquitin ligase to poly-ubiquitinate and degrade the A3 proteins. The HIV-1 and SRLV Vif/host E3-ligase complexes require the non-canonical host cofactors CBFβ and CypA, respectively, to stabilize the host/pathogen complexes. CBFβ and CypA are unrelated in sequence and structure, yet both are repurposed specifically by each virus to stabilize their Vif/E3 ligase complex. Through comparative analysis of two different critical pathways in the lentiviral lifecycle of HIV-1 and the SRLVs, I have expanded our understanding of lentivirus biology.

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