Variations in protein processing lead to variations in structure and function of the HIV-1 envelope protein
Embargo until
2020-05-01
Date
2019-01-22
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Publisher
Johns Hopkins University
Abstract
Mucosal transmission of HIV is a complex, inefficient event that leads to the seeding, and eventual disruption, of the gut-associated lymphoid tissue. The basis for the gut-tropic nature of acute HIV infection is unknown. The HIV envelope protein (Env) of early-replicating viruses encode several distinct transmission signatures believed to impart increased transmission fitness on these isolates. One such signature involves a reduced number of potential N-linked glycosylation sites underscoring the importance of glycosylation on the fitness of early-replicating isolates. Our group has previously shown that Env glycosylation plays a role in the interaction between the V2 domain of Env gp120 (V2) and the gut homing receptor, integrin α4β7, expressed on HIV target CD4+ T-cells. The α4β7 binding epitope on the V2 overlaps with the RV144 Thailand HIV vaccine trial sieve residues associated with vaccine-elicited immune pressure. In this thesis, we present data showing that a second signature of transmission located in the signal peptide (SP) of Env can modulate the antigenicity of gp120 and influence viral neutralization sensitivity through altered glycan processing. Additionally, we show that deglycosylation of gp120 can increase the functional capacity of α4β7 adhesion to the V2. We also show that mAbs from vaccination and natural infection targeting an alternate, helical conformation of the V2 that is absent from the SOSIP stabilized trimer inhibit the adhesion of α4β7 expressing cells to V2 peptides. This conformation of the V2 is present on incompletely-processed Env that is expressed on the surface of infected cells and is incorporated into virions. This data suggests that incompletely-processed Env presents the V2 in an unconstrained, helical conformation that is capable of binding α4β7. Taken together, the data presented in this thesis suggests a mechanism by which the virus can modulate glycosylation of the Env protein without changing the primary amino acid sequence of the functional protein, and that relevant, incompletely-processed Env exposes the α4β7 binding site on V2. This data supports the connection between Env glycosylation, the gut homing integrin α4β7 and the transmission and pathogenesis of HIV. We believe this data is useful for HIV vaccine and therapy design.
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Keywords
HIV, Transmission, Envelope Protein, Signal Peptide, Integrin alpha-4beta-7