Gp41-targeted antibodies restore infectivity of a fusion-deficient HIV-1 envelope glycoprotein
Authors
Joshi, Vinita R.Newman, Ruchi M.
Pack, Melissa L.
Power, Karen A.
Munro, James B.
Okawa, Ken
Madani, Navid
Sodroski, Joseph G.
Schmidt, Aaron G.
Allen, Todd M.
UMass Chan Affiliations
Department of Microbiology and Physiological SystemsDocument Type
Journal ArticlePublication Date
2020-05-11Keywords
AntibodiesHIV-1
Membrane fusion
Viral entry
Viral diseases
Enzyme-linked immunoassays
Arginine
Monoclonal antibodies
Amino Acids, Peptides, and Proteins
Immunology of Infectious Disease
Immunopathology
Pathogenic Microbiology
Virology
Virus Diseases
Viruses
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Show full item recordAbstract
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.Source
Joshi VR, Newman RM, Pack ML, Power KA, Munro JB, Okawa K, Madani N, Sodroski JG, Schmidt AG, Allen TM. Gp41-targeted antibodies restore infectivity of a fusion-deficient HIV-1 envelope glycoprotein. PLoS Pathog. 2020 May 11;16(5):e1008577. doi: 10.1371/journal.ppat.1008577. PMID: 32392227; PMCID: PMC7241850. Link to article on publisher's site
DOI
10.1371/journal.ppat.1008577Permanent Link to this Item
http://hdl.handle.net/20.500.14038/41483PubMed ID
32392227Related Resources
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Copyright: © 2020 Joshi et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.Distribution License
http://creativecommons.org/licenses/by/4.0/ae974a485f413a2113503eed53cd6c53
10.1371/journal.ppat.1008577
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Except where otherwise noted, this item's license is described as Copyright: © 2020 Joshi et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.