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J. Biol. Chem., Vol. 277, Issue 52, 50579-50588, December 27, 2002
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From the We previously reported that monoclonal
antibodies to protein-disulfide isomerase (PDI) and other
membrane-impermeant PDI inhibitors prevented HIV-1 infection. PDI is
present at the surface of HIV-1 target cells and reduces disulfide
bonds in a model peptide attached to the cell membrane. Here we show
that soluble PDI cleaves disulfide bonds in recombinant envelope
glycoprotein gp120 and that gp120 bound to the surface receptor CD4
undergoes a disulfide reduction that is prevented by PDI inhibitors.
Concentrations of inhibitors that prevent this reduction and inhibit
the cleavage of surface-bound disulfide conjugate prevent infection at
the level of HIV-1 entry. The entry of HIV-1 strains differing in their
coreceptor specificities is similarly inhibited, and so is the
reduction of gp120 bound to CD4 of coreceptor-negative cells. PDI
inhibitors also prevent HIV envelope-mediated cell-cell fusion but have
no effect on the entry of HIV-1 pseudo-typed with murine leukemia virus
envelope. Importantly, PDI coprecipitates with both soluble and
cellular CD4. We propose that a PDI·CD4 association at the cell
surface enables PDI to reach CD4-bound virus and to reduce disulfide
bonds present in the domain of gp120 that binds to CD4. Conformational changes resulting from the opening of gp120-disulfide loops may drive
the processes of virus-cell and cell-cell fusion. The biochemical events described identify new potential targets for anti-HIV agents.
Inhibitors of Protein-Disulfide Isomerase Prevent
Cleavage of Disulfide Bonds in Receptor-bound Glycoprotein 120 and
Prevent HIV-1 Entry*
§,¶¶,,
,**
Department of Pathology and
¶¶ Microbiology, Boston University School of Medicine,
Boston, Massachusetts 02118, ¶ Montana Biotechnology Center, The
University of Montana, Missoula, Montana 59812, and the
Department of Microbiology & Immunology, Uniformed Services
University of the Health Sciences, Bethesda, Maryland 20814-4799
*
This work was supported by NCI, National Institutes of
Health Grant CA14551, National Institutes of Health Grant AI41758, and
Pediatric AIDS Foundation Grants 50623 and 50891 (to H. J.-P. R.) and
National Institutes of Health Grants AI44312, AI44669 (to M. T.), HLB
57882 (G. A. V.) and AI43885 (to C. C. B.).The costs of publication of this
article were defrayed in part by the
payment of page charges. The article
must therefore be hereby marked
"advertisement" in
accordance with 18 U.S.C. Section
1734 solely to indicate this fact.
Both authors contributed equally to this work.
Copyright © 2002 by The American Society for Biochemistry and Molecular Biology, Inc.
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