The Polar Region of the HIV-1 Envelope Protein Determines Viral Fusion and Infectivity by Stabilizing the gp120-gp41 Association

Wuxun Lu; Shuliang Chen; Jingyou Yu; Ryan Behrens; Joshua Wiggins; Nathan Sherer; Shan-Lu Liu; Yong Xiong; Shi-Hua Xiang; Li Wu

doi:10.1128/jvi.02128-18

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The Polar Region of the HIV-1 Envelope Protein Determines Viral Fusion and Infectivity by Stabilizing the gp120-gp41 Association

Journal article

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Peer reviewed

The Polar Region of the HIV-1 Envelope Protein Determines Viral Fusion and Infectivity by Stabilizing the gp120-gp41 Association

Wuxun Lu, Shuliang Chen, Jingyou Yu, Ryan Behrens, Joshua Wiggins, Nathan Sherer, Shan-Lu Liu, Yong Xiong, Shi-Hua Xiang and Li Wu

Journal of virology, Vol.93(7), e02128-18

04/01/2019

DOI: 10.1128/jvi.02128-18

PMCID: PMC6430531

PMID: 30651369

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Abstract

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.

Cell Line

HIV-1 - metabolism

HIV Infections - virology

Humans

Virion - physiology

HIV Envelope Protein gp41 - metabolism

env Gene Products, Human Immunodeficiency Virus - metabolism

Virion - metabolism

HIV Envelope Protein gp120 - metabolism

Virus Internalization

HIV-1 - physiology

HEK293 Cells

Cell Line, Tumor

HeLa Cells

Details

Title: Subtitle: The Polar Region of the HIV-1 Envelope Protein Determines Viral Fusion and Infectivity by Stabilizing the gp120-gp41 Association
Creators: Wuxun Lu - Center for Retrovirus Research, Department of Veterinary Biosciences, The Ohio State University, Columbus, Ohio, USA
Shuliang Chen - Center for Retrovirus Research, Department of Veterinary Biosciences, The Ohio State University, Columbus, Ohio, USA
Jingyou Yu - Center for Retrovirus Research, Department of Veterinary Biosciences, The Ohio State University, Columbus, Ohio, USA
Ryan Behrens - McArdle Laboratory for Cancer Research and Institute for Molecular Virology, University of Wisconsin-Madison, Madison, Wisconsin, USA
Joshua Wiggins - School of Veterinary Medicine and Biomedical Sciences, Nebraska Center for Virology, University of Nebraska-Lincoln, Lincoln, Nebraska, USA
Nathan Sherer - McArdle Laboratory for Cancer Research and Institute for Molecular Virology, University of Wisconsin-Madison, Madison, Wisconsin, USA
Shan-Lu Liu - Department of Microbial Infection and Immunity, The Ohio State University, Columbus, Ohio, USA
Yong Xiong - Department of Molecular Biophysics and Biochemistry, Yale University, New Haven, Connecticut, USA
Shi-Hua Xiang - School of Veterinary Medicine and Biomedical Sciences, Nebraska Center for Virology, University of Nebraska-Lincoln, Lincoln, Nebraska, USA
Li Wu - Department of Microbial Infection and Immunity, The Ohio State University, Columbus, Ohio, USA
Resource Type: Journal article
Publication Details: Journal of virology, Vol.93(7), e02128-18
Publisher: United States
DOI: 10.1128/jvi.02128-18
PMID: 30651369
PMCID: PMC6430531
ISSN: 1098-5514
eISSN: 1098-5514
Grant note: R01 AI150343 / NIAID NIH HHS T32 AI078985 / NIAID NIH HHS R01 GM128212 / NIGMS NIH HHS T32 GM008688 / NIGMS NIH HHS R01 GM132069 / NIGMS NIH HHS R01 AI110221 / NIAID NIH HHS R01 AI120209 / NIAID NIH HHS R01 AI112381 / NIAID NIH HHS T32 NS105594 / NINDS NIH HHS
Language: English
Date published: 04/01/2019
Academic Unit: Microbiology and Immunology
Record Identifier: 9984001120402771

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