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dc.contributor.authorJoshi, Vinita R.
dc.contributor.authorNewman, Ruchi M.
dc.contributor.authorPack, Melissa L.
dc.contributor.authorPower, Karen A.
dc.contributor.authorMunro, James B.
dc.contributor.authorOkawa, Ken
dc.contributor.authorMadani, Navid
dc.contributor.authorSodroski, Joseph G.
dc.contributor.authorSchmidt, Aaron G.
dc.contributor.authorAllen, Todd M.
dc.date2022-08-11T08:09:56.000
dc.date.accessioned2022-08-23T16:49:32Z
dc.date.available2022-08-23T16:49:32Z
dc.date.issued2020-05-11
dc.date.submitted2020-06-23
dc.identifier.citation<p>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. <a href="https://doi.org/10.1371/journal.ppat.1008577">Link to article on publisher's site</a></p>
dc.identifier.issn1553-7366 (Linking)
dc.identifier.doi10.1371/journal.ppat.1008577
dc.identifier.pmid32392227
dc.identifier.urihttp://hdl.handle.net/20.500.14038/41483
dc.description.abstractThe 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.
dc.language.isoen_US
dc.relation<p><a href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&list_uids=32392227&dopt=Abstract">Link to Article in PubMed</a></p>
dc.rightsCopyright: © 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.
dc.rights.urihttp://creativecommons.org/licenses/by/4.0/
dc.subjectAntibodies
dc.subjectHIV-1
dc.subjectMembrane fusion
dc.subjectViral entry
dc.subjectViral diseases
dc.subjectEnzyme-linked immunoassays
dc.subjectArginine
dc.subjectMonoclonal antibodies
dc.subjectAmino Acids, Peptides, and Proteins
dc.subjectImmunology of Infectious Disease
dc.subjectImmunopathology
dc.subjectPathogenic Microbiology
dc.subjectVirology
dc.subjectVirus Diseases
dc.subjectViruses
dc.titleGp41-targeted antibodies restore infectivity of a fusion-deficient HIV-1 envelope glycoprotein
dc.typeJournal Article
dc.source.journaltitlePLoS pathogens
dc.source.volume16
dc.source.issue5
dc.identifier.legacyfulltexthttps://escholarship.umassmed.edu/cgi/viewcontent.cgi?article=5288&amp;context=oapubs&amp;unstamped=1
dc.identifier.legacycoverpagehttps://escholarship.umassmed.edu/oapubs/4262
dc.identifier.contextkey18226438
refterms.dateFOA2022-08-23T16:49:32Z
html.description.abstract<p>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.</p>
dc.identifier.submissionpathoapubs/4262
dc.contributor.departmentDepartment of Microbiology and Physiological Systems
dc.source.pagese1008577


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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.
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.