Dissecting How Interactions at the Apex of HIV-1 Env Modulate Epitope Exposure at the Distant Base of the Glycoprotein

Hannah M Schapiro, Thomas Jefferson University


The envelope glycoprotein, Env, of human immunodeficiency virus type 1 (HIV-1) mediates viral entry through membrane fusion. Env is a structurally dynamic trimer consisting of three protomers; each protomer consists of a surface gp120 and a transmembrane gp41 subunit. Being the sole virally encoded protein accessible on the virion, vaccine strategies target Env. However, structural plasticity limits the exposure of immunodominant epitopes. We assessed how inter- and intraprotomer interactions between specific apical segments in Env, labeled V1V2 and V3 loops, result in structural and functional changes. Swapping the V3 loop from the EnvSF162 strain into the background of EnvHXB2 altered global epitope exposure as determined by antibody neutralization assays. The chimeric Env was more stable, as determined by a reduced sensitivity to cold inactivation and soluble CD4-induced gp120 shedding, and the binding stoichiometry of target cell CD4 receptors to mediate viral entry increased when compared to EnvHXB2. Cumulatively, these data suggest alterations in the prefusogenic structural and energetic landscape of the chimeric Env. We further identified residue 306 within the V3 loop as a key modulator of EnvHXB2 intraprotomer interaction with direct implications on structure and function. Specifically, our data suggest a novel conformation along the activation pathway in which the V1V2 and V3 loops disengage from the trimer core (loss of interprotomer interaction) but remain associated through intraprotomer interactions. Subsequent loss of V1V2 and V3 intraprotomer interaction results in splaying of the loops, enabling exposure of the membrane proximal external region (MPER) at the distant base of the glycoprotein. To assess the relationship between apical splaying and MPER exposure, protomers that differed in their propensity to undergo splaying were combined to produce heterotrimers. Through analysis of anti-MPER antibody potency, we determined that apical splaying and resultant MPER exposure follows a cooperative mechanism. The R306S substitution in other Env strains produced variable results to MPER exposure, leading us to hypothesize that other residues outside the V3 loop play a modulatory role in apex-to-base communication. We compared the primary sequences of EnvHXB2 and EnvNL4-3 to elucidate a putative allosteric network that appears to be modulated via a complex mechanism. The work herein provides greater insight into Env structure and function and can be utilized in the development of clinical approaches that target HIV-1.

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Recommended Citation

Schapiro, Hannah M, "Dissecting How Interactions at the Apex of HIV-1 Env Modulate Epitope Exposure at the Distant Base of the Glycoprotein" (2022). ETD Collection for Thomas Jefferson University. AAI29258111.