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Receptor Activation of HIV-1 Env Leads to Asymmetric Exposure of the gp41 Trimer.

ABSTRACT: Structural rearrangements of HIV-1 glycoprotein Env promote viral entry through membrane fusion. Env is a symmetric homotrimer with each protomer composed of surface subunit gp120 and transmembrane subunit gp41. Cellular CD4- and chemokine receptor-binding to gp120 coordinate conformational changes in gp41, first to an extended prehairpin intermediate (PHI) and, ultimately, into a fusogenic trimer-of-hairpins (TOH). HIV-1 fusion inhibitors target gp41 in the PHI and block TOH formation. To characterize structural transformations into and through the PHI, we employed asymmetric Env trimers containing both high and low affinity binding sites for individual fusion inhibitors. Asymmetry was achieved using engineered Env heterotrimers composed of protomers deficient in either CD4- or chemokine receptor-binding. Linking receptor engagement to inhibitor affinity allowed us to assess conformational changes of individual Env protomers in the context of a functioning trimer. We found that the transition into the PHI could occur symmetrically or asymmetrically depending on the stoichiometry of CD4 binding. Sequential engagement of multiple CD4s promoted progressive exposure of individual fusion inhibitor binding sites in a CD4-dependent fashion. By contrast, engagement of only a single CD4 molecule led to a delayed, but symmetric, exposure of the gp41 trimer. This complex coupling between Env-CD4 interaction and gp41 exposure explained the multiphasic fusion-inhibitor titration observed for a mutant Env homotrimer with a naturally asymmetric gp41. Our results suggest that the spatial and temporal exposure of gp41 can proceed in a nonconcerted, asymmetric manner depending on the number of CD4s that engage the Env trimer. The findings have important implications for the mechanism of viral membrane fusion and the development of vaccine candidates designed to elicit neutralizing antibodies targeting gp41 in the PHI.

SUBMITTER: Khasnis MD

PROVIDER: S-EPMC5222517 | biostudies-literature | 2016 Dec

REPOSITORIES: biostudies-literature

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Receptor Activation of HIV-1 Env Leads to Asymmetric Exposure of the gp41 Trimer.

Khasnis Mukta D MD Halkidis Konstantine K Bhardwaj Anshul A Root Michael J MJ

PLoS pathogens 20161219 12

Structural rearrangements of HIV-1 glycoprotein Env promote viral entry through membrane fusion. Env is a symmetric homotrimer with each protomer composed of surface subunit gp120 and transmembrane subunit gp41. Cellular CD4- and chemokine receptor-binding to gp120 coordinate conformational changes in gp41, first to an extended prehairpin intermediate (PHI) and, ultimately, into a fusogenic trimer-of-hairpins (TOH). HIV-1 fusion inhibitors target gp41 in the PHI and block TOH formation. To chara ...[more]

PMID: 27992602

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Project description:The antibody response against the HIV-1 envelope glycoproteins (Envs) guides evolution of this protein within each host. Whether antibodies with similar target specificities are elicited in different individuals and affect the population-level evolution of Env is poorly understood. To address this question, we analyzed properties of emerging variants in the gp41 fusion peptide-proximal region (FPPR) that exhibit distinct evolutionary patterns in HIV-1 clade B. For positions 534, 536, and 539 in the FPPR, alanine was the major emerging variant. However, 534A and 536A show a constant frequency in the population between 1979 and 2016, whereas 539A is gradually increasing. To understand the basis for these differences, we introduced alanine substitutions in the FPPR of primary HIV-1 strains and examined their functional and antigenic properties. Evolutionary patterns could not be explained by fusion competence or structural stability of the emerging variants. Instead, 534A and 536A exhibited modest but significant increases in sensitivity to antibodies against the membrane-proximal external region (MPER) and gp120-gp41 interface. These Envs were also more sensitive to poorly neutralizing sera from HIV-1-infected individuals than the clade ancestral form or 539A variant. Competition binding assays confirmed for all sera tested the presence of antibodies against the base of the Env trimer that compete with monoclonal antibodies targeting the MPER and gp120-gp41 interface. Our findings suggest that weakly neutralizing antibodies against the trimer base are commonly elicited; they do not exert catastrophic population size reduction effects on emerging variants but, instead, determine their set point frequencies in the population and historical patterns of change. IMPORTANCE Infection by HIV-1 elicits formation of antibodies that target the viral Env proteins and can inactivate the virus. The specific targets of these antibodies vary among infected individuals. It is unclear whether some target specificities are shared among the antibody responses of different individuals. We observed that antibodies against the base of the Env protein are commonly elicited during infection. The selective pressure applied by such antibodies is weak. As a result, they do not completely eliminate the sensitive forms of the virus from the population, but maintain their frequency at a low level that has not increased since the beginning of the AIDS pandemic. Interestingly, the changes in Env do not occur at the sites targeted by the antibodies, but at a distinct region of Env, the fusion peptide-proximal region, which regulates their exposure.

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Dataset Information

Receptor Activation of HIV-1 Env Leads to Asymmetric Exposure of the gp41 Trimer.

Publications

Receptor Activation of HIV-1 Env Leads to Asymmetric Exposure of the gp41 Trimer.

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