Affiliation:
1. From the Center for Drug Evaluation and Research (CDER) and the Center for Biologics Evaluation and Research, Food and Drug Administration (FDA), Bethesda, MD; F. Edward Hébert School of Medicine, Uniformed Services University of the Health Sciences, Bethesda, MD; and the National Institute of Child Health and Human Diseases and the National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD.
Abstract
Abstract
Attachment of gp120 to CD4 during HIV-1 entry triggers structural rearrangement in gp120 that enables binding to an appropriate coreceptor. Following coreceptor engagement, additional conformational changes occur in the envelope (Env), resulting in fusion of virion and cell membranes. Catalysts with redox-isomerase activity, such as protein disulfide isomerase (PDI), facilitate Env conversion from its inactive to its fusion-competent conformation. We report here that anti-PDI agents effectively block CXCR4 Env-mediated fusion and spread of virus infection. Exogenously added PDI, in turn, can rescue fusion from this blockade. We further find that PDI facilitates thiol/disulfide rearrangement in gp120 during conformational change, whereas inhibition of this redox shuffling prevents gp41 from assuming the fusogenic 6-helix bundle conformation. At the virus-cell contact site, gp120 induces assembly of PDI, CD4, and CXCR4 into a tetramolecular protein complex serving as a portal for viral entry. Our findings support the hypothesis that Env conformational change depends on a well-coordinated action of a tripartite system in which PDI works in concert with the receptor and the coreceptor to effectively lower the activation energy barrier required for Env conformational rearrangement.
Publisher
American Society of Hematology
Subject
Cell Biology,Hematology,Immunology,Biochemistry
Cited by
125 articles.
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