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dc.contributor.authorWeichseldorfer, Matthew
dc.contributor.authorTagaya, Yutaka
dc.contributor.authorReitz, Marvin
dc.contributor.authorDeVico, Anthony L
dc.contributor.authorLatinovic, Olga S
dc.date.accessioned2022-01-28T15:33:23Z
dc.date.available2022-01-28T15:33:23Z
dc.date.issued2022-01-24
dc.identifier.urihttp://hdl.handle.net/10713/17800
dc.description.abstractBackground: The chemokine receptor CCR5 is the major coreceptor for HIV-1 cell entry. We previously observed that not all CCR5 mAbs reduce HIV-1 infection, suggesting that only some CCR5 populations are permissive for HIV-1 entry. This study aims to better understand the relevant conformational states of the cellular coreceptor, CCR5, involved in HIV entry. We hypothesized that CCR5 assumes multiple configurations during normal cycling on the plasma membrane, but only particular forms facilitate HIV-1 infection. Methods: To this end, we quantified different CCR5 populations using six CCR5 monoclonal antibodies (mAbs) with different epitope specificities and visualized them with super-resolution microscopy. We quantified each surface CCR5 population before and after HIV-1 infection. Results: Based on CCR5 conformational changes, down-modulation, and trafficking rates (internalization and recycling kinetics), we were able to distinguish among heterogeneous CCR5 populations and thus which populations might best be targeted to inhibit HIV-1 entry. We assume that a decreased surface presence of a particular CCR5 subpopulation following infection means that it has been internalized due to HIV-1 entry, and that it therefore represents a highly relevant target for future antiviral therapy strategies. Strikingly, this was most true for antibody CTC8, which targets the N-terminal region of CCR5 and blocks viral entry more efficiently than it blocks chemokine binding. Conclusions: Defining the virus-host interactions responsible for HIV-1 transmission, including specific coreceptor populations capable of establishing de novo infections, is essential for the development of an HIV-1 vaccine. This study hopefully will facilitate further development of inhibitors to block CCR5 usage by HIV-1, as well as inform future HIV-1 vaccine design.en_US
dc.description.urihttps://doi.org/10.1186/s12967-022-03243-8en_US
dc.language.isoenen_US
dc.publisherSpringer Natureen_US
dc.relation.ispartofJournal of Translational Medicineen_US
dc.rights© 2022. The Author(s).en_US
dc.subjectAIDS pathogenesisen_US
dc.subjectCCR5 coreceptor populationsen_US
dc.subjectConformational changesen_US
dc.subjectHIVen_US
dc.titleIdentifying CCR5 coreceptor populations permissive for HIV-1 entry and productive infection: implications for in vivo studies.en_US
dc.typeArticleen_US
dc.identifier.doi10.1186/s12967-022-03243-8
dc.identifier.pmid35073923
dc.source.journaltitleJournal of translational medicine
dc.source.volume20
dc.source.issue1
dc.source.beginpage39
dc.source.endpage
dc.source.countryEngland


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