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Virus-Cell Interactions

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
Frank Kirchhoff, Editor
Wuxun Lu
aCenter for Retrovirus Research, Department of Veterinary Biosciences, The Ohio State University, Columbus, Ohio, USA
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Shuliang Chen
aCenter for Retrovirus Research, Department of Veterinary Biosciences, The Ohio State University, Columbus, Ohio, USA
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Jingyou Yu
aCenter for Retrovirus Research, Department of Veterinary Biosciences, The Ohio State University, Columbus, Ohio, USA
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Ryan Behrens
bMcArdle Laboratory for Cancer Research and Institute for Molecular Virology, University of Wisconsin—Madison, Madison, Wisconsin, USA
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Joshua Wiggins
cSchool of Veterinary Medicine and Biomedical Sciences, Nebraska Center for Virology, University of Nebraska—Lincoln, Lincoln, Nebraska, USA
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Nathan Sherer
bMcArdle Laboratory for Cancer Research and Institute for Molecular Virology, University of Wisconsin—Madison, Madison, Wisconsin, USA
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  • ORCID record for Nathan Sherer
Shan-Lu Liu
aCenter for Retrovirus Research, Department of Veterinary Biosciences, The Ohio State University, Columbus, Ohio, USA
eDepartment of Microbial Infection and Immunity, The Ohio State University, Columbus, Ohio, USA
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Yong Xiong
dDepartment of Molecular Biophysics and Biochemistry, Yale University, New Haven, Connecticut, USA
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Shi-Hua Xiang
cSchool of Veterinary Medicine and Biomedical Sciences, Nebraska Center for Virology, University of Nebraska—Lincoln, Lincoln, Nebraska, USA
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Li Wu
aCenter for Retrovirus Research, Department of Veterinary Biosciences, The Ohio State University, Columbus, Ohio, USA
eDepartment of Microbial Infection and Immunity, The Ohio State University, Columbus, Ohio, USA
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Frank Kirchhoff
Ulm University Medical Center
Roles: Editor
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DOI: 10.1128/JVI.02128-18
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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.

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.

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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
Journal of Virology Mar 2019, 93 (7) e02128-18; 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
Wuxun Lu, Shuliang Chen, Jingyou Yu, Ryan Behrens, Joshua Wiggins, Nathan Sherer, Shan-Lu Liu, Yong Xiong, Shi-Hua Xiang, Li Wu
Journal of Virology Mar 2019, 93 (7) e02128-18; DOI: 10.1128/JVI.02128-18
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KEYWORDS

HIV-1
entry
envelope glycoprotein
fusion
gp160
gp41
infectivity
polar region
trimer

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