Received for publication October 14, 2004.
Revised December 9, 2004.
Accepted for publication January 10, 2005.

Glycosaminoglycans and Protein Disulfide Isomerase-Mediated Reduction of HIV Env

Abstract

Conformational changes within the HIV-1 surface glycoprotein gp120 result from binding to the lymphocyte surface receptors and trigger gp41-mediated virus/cell membrane fusion. The triggering of fusion requires cleavage of 2 of the 9 disulfide bonds of gp120 by a cell-surface protein disulfide-isomerase (PDI). Soluble glycosaminoglycans such as heparin and heparan sulfate bind gp120 via V3 and, possibly, a CD4-induced domain. They exert anti-HIV activity by interfering with Env/cell surface interaction. Env also binds cell surface glycosaminoglycans. Here, using surface plasmon resonance, we observed an inverse relationship between heparin binding by gp120 and its thiol content. In vitro, and in conditions where gp120 could bind CD4, heparin and heparan sulfate reduced PDI-mediated gp120 reduction by about 80%. Interaction of Env with the surface of lymphocytes treated using sodium chlorate, an inhibitor of glycosaminoglycan synthesis, led to gp120 reduction. We conclude that, besides their capacity to block Env/cell interaction, soluble glycosaminoglycans can effect anti-HIV activity via interference with PDI-mediated gp120 reduction. In contrast, their presence at the cell surface is dispensable for Env reduction during the course of interaction with the lymphocyte surface. This work suggests that the reduction of exofacial proteins in various diseases can be inhibited by compounds targeting the substrates, not PDI as is usually done, and that glycosaminoglycans which primarily protect proteins by preserving them from proteolysis, also have a role in preventing reduction.

Key words: Protein targets, Antiviral drugs

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