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Gp41-targeted antibodies restore infectivity of a fusion-deficient HIV-1 envelope glycoprotein.

ABSTRACT: The HIV-1 envelope glycoprotein (Env) mediates viral entry via conformational changes associated with binding the cell surface receptor (CD4) and coreceptor (CCR5/CXCR4), resulting in subsequent fusion of the viral and cellular membranes. While the gp120 Env surface subunit has been extensively studied for its role in viral entry and evasion of the host immune response, the gp41 transmembrane glycoprotein and its role in natural infection are less well characterized. Here, we identified a primary HIV-1 Env variant that consistently supports >300% increased viral infectivity in the presence of autologous or heterologous HIV-positive plasma. However, in the absence of HIV-positive plasma, viruses with this Env exhibited reduced infectivity that was not due to decreased CD4 binding. Using Env chimeras and sequence analysis, we mapped this phenotype to a change Q563R, in the gp41 heptad repeat 1 (HR1) region. We demonstrate that Q563R reduces viral infection by disrupting formation of the gp41 six-helix bundle required for virus-cell membrane fusion. Intriguingly, antibodies that bind cluster I epitopes on gp41 overcome this inhibitory effect, restoring infectivity to wild-type levels. We further demonstrate that the Q563R change increases HIV-1 sensitivity to broadly neutralizing antibodies (bNAbs) targeting the gp41 membrane-proximal external region (MPER). In summary, we identify an HIV-1 Env variant with impaired infectivity whose Env functionality is restored through the binding of host antibodies. These data contribute to our understanding of gp41 residues involved in membrane fusion and identify a mechanism by which host factors can alleviate a viral defect.

SUBMITTER: Joshi VR

PROVIDER: S-EPMC7241850 | biostudies-literature | 2020 May

REPOSITORIES: biostudies-literature

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Gp41-targeted antibodies restore infectivity of a fusion-deficient HIV-1 envelope glycoprotein.

Joshi Vinita R VR Newman Ruchi M RM Pack Melissa L ML Power Karen A KA Munro James B JB Okawa Ken K Madani Navid N Sodroski Joseph G JG Schmidt Aaron G AG Allen Todd M TM

PLoS pathogens 20200511 5

The HIV-1 envelope glycoprotein (Env) mediates viral entry via conformational changes associated with binding the cell surface receptor (CD4) and coreceptor (CCR5/CXCR4), resulting in subsequent fusion of the viral and cellular membranes. While the gp120 Env surface subunit has been extensively studied for its role in viral entry and evasion of the host immune response, the gp41 transmembrane glycoprotein and its role in natural infection are less well characterized. Here, we identified a primar ...[more]

PMID: 32392227

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Project description:HIV-1 enters cells through binding between viral envelope glycoprotein (Env) and cellular receptors to initiate virus and cell fusion. HIV-1 Env precursor (gp160) is cleaved into two units noncovalently bound to form a trimer on virions, including a surface unit (gp120) and a transmembrane unit (gp41) responsible for virus binding and membrane fusion, respectively. The polar region (PR) at the N terminus of gp41 comprises 17 residues, including 7 polar amino acids. Previous studies suggested that the PR contributes to HIV-1 membrane fusion and infectivity; however, the precise role of the PR in Env-mediated viral entry and the underlying mechanisms remain unknown. Here, we show that the PR is critical for HIV-1 fusion and infectivity by stabilizing Env trimers. Through analyzing the PR sequences of 57,645 HIV-1 isolates, we performed targeted mutagenesis and functional studies of three highly conserved polar residues in the PR (S532P, T534A, and T536A) which have not been characterized previously. We found that single or combined mutations of these three residues abolished or significantly decreased HIV-1 infectivity without affecting viral production. These PR mutations abolished or significantly reduced HIV-1 fusion with target cells and also Env-mediated cell-cell fusion. Three PR mutations containing S532P substantially reduced gp120 and gp41 association, Env trimer stability, and increased gp120 shedding. Furthermore, S532A mutation significantly reduced HIV-1 infectivity and fusogenicity but not Env expression and cleavage. Our findings suggest that the PR of gp41, particularly the key residue S532, is structurally essential for maintaining HIV-1 Env trimer, viral fusogenicity, and infectivity.IMPORTANCE Although extensive studies of the transmembrane unit (gp41) of HIV-1 Env have led to a fusion inhibitor clinically used to block viral entry, the functions of different domains of gp41 in HIV-1 fusion and infectivity are not fully elucidated. The polar region (PR) of gp41 has been proposed to participate in HIV-1 membrane fusion in biochemical analyses, but its role in viral entry and infectivity remain unclear. In our effort to characterize three nucleotide mutations of an HIV-1 RNA element that partially overlaps the PR coding sequence, we identified a novel function of the PR that determines viral fusion and infectivity. We further demonstrated the structural and functional impact of six PR mutations on HIV-1 Env stability, viral fusion, and infectivity. Our findings reveal the previously unappreciated function of the PR and the underlying mechanisms, highlighting the important role of the PR in regulating HIV-1 fusion and infectivity.

Dataset Information

Gp41-targeted antibodies restore infectivity of a fusion-deficient HIV-1 envelope glycoprotein.

Publications

Gp41-targeted antibodies restore infectivity of a fusion-deficient HIV-1 envelope glycoprotein.

Similar Datasets

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