Thiol/disulfide exchange is a prerequisite for CXCR4-tropic HIV-1 envelope-mediated T-cell fusion during viral entry

Uniformed Services University of the Health Sciences, 베서스다, Maryland, United States
Blood (Impact Factor: 10.45). 04/2004; 103(5):1586-94. DOI: 10.1182/blood-2003-05-1390
Source: PubMed


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.

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Available from: Christopher Broder, Feb 03, 2015
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    • "virus, (CMV) they found the virus requires sulfhydryl groups to infect cells (Mirazmi, et. al., 1999). If the thiol groups were oxidized, CMV lost infectivity. When thiols were chemically rereduced (by dithiothreitol), the virus regained 65% infectivity. Reflecting on the reduction of " critical " disulfide bonds for vaccinia virus cellular entry, Markovic, et. al., (2004) found that protein disulfide isomerase inhibitors limited HIV-1 entry into T cells. Ozone inactivates many viruses including polio, Norwalk, coliophage MS2, hepatitis A and others (Kekez and Sattar, 1997; Shin and Sobsey, 2003; Herbold, et. al., 1989; Emerson, et. al., 1982). Ebola appears no different. Studies by Sanders et al. have be"
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    • "It is also found on the cell membrane and may be actively secreted by various cell types [32], [33]. Extracellular PDI has been shown to regulate numerous activities, including cellular adhesion [34], pathogen entry [35], [36], platelet aggregation and secretion [37], intracellular nitric oxide delivery [38], and insulin degradation [39], [40]. Lymphocytes (especially CD4+ T cells) increase the availability of cell surface thiols after immune activation [41]. "
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