A Highly Conserved Arginine in gp120 Governs HIV-1 Binding to Both Syndecans and CCR5 via Sulfated Motifs

Aymeric De Parseval,Michael D Bobardt,Anju Chatterji,Udayan Chatterji,John H Elder,Guido David,Susan Zolla-Pazner,Michael Farzan,Tun-Hou Lee,Philippe A Gallay

doi:10.1074/jbc.m504233200

Aymeric De Parseval, Michael D Bobardt + Show 8 more

Open Access

https://doi.org/10.1074/jbc.m504233200

Copy DOI

Abstract

HIV-1 has maximized its utilization of syndecans. It uses them as in cis receptors to infect macrophages and as in trans receptors to infect T-lymphocytes. In this study, we investigated at a molecular level the mechanisms that control HIV-1-syndecan interactions. We found that a single conserved arginine (Arg-298) in the V3 region of gp120 governs HIV-1 binding to syndecans. We found that an amine group on the side chain of this residue is necessary for syndecan utilization by HIV-1. Furthermore, we showed that HIV-1 binds syndecans via a 6-O sulfation, demonstrating that this binding is not the result of random interactions between basic residues and negative charges, but the result of specific contacts between gp120 and a well defined sulfation in syndecans. Surprisingly, we found that Arg-298, which mediates HIV-1 binding to syndecans, also mediates HIV-1 binding to CCR5. We postulated that HIV-1 recognizes similar motifs on syndecans and CCR5. Supporting this hypothesis, we obtained several lines of evidence that suggest that the 6-O sulfation recognized by HIV-1 on syndecans mimics the sulfated tyrosines recognized by HIV-1 in the N terminus of CCR5. Our finding that CCR5 and syndecans are exploited by HIV-1 via a single determinant echoes the mechanisms by which chemokines utilize these two disparate receptors and suggests that the gp120/chemokine mimicry may represent a common strategy in microbial pathogenesis.

Highlights

The V3 Region of gp120 Contains the Syndecan-binding Site for HIV-1—We asked if gp120 serves as the main ligand for HIV-1 binding to syndecans
To more definitely demonstrate that V3, in the context of whole virus, is necessary for HIV-1 binding to syndecans, we examined the capacity of a virus deleted for V3 to bind syndecans
The Highly Conserved Arginine 298 Is Necessary for HIV-1 Binding to Both Syndecans and CCR5—To delineate the contribution of HIV-1syndecan interactions to HIV-1 infectivity, we examined the replication of the R298A virus in CD4ϩ T-lymphocytes and macrophages

Summary

Introduction

Previous work suggests that the requirement for syndecans and HSPGs in HIV-1 infection is accentuated when target cells express low levels of entry receptors (CD4 and CCR5/CXCR4) such as CD4ϩ HeLa cells and macrophages [1]. Endothelial syndecans enhance HIV-1 replication in T cells via a yet uncharacterized mechanism [2]. Syndecans and HSPGs on brain microvascular endothelial cells play a significant role in HIV-1 transmigration through the blood-brain barrier [3, 12]. These observations suggest that syndecans, by acting as in cis and in trans receptors on different cells and tissues, may profoundly impact HIV-1 pathogenesis. We examined at a molecular level the mechanisms that control HIV-1-syndecan interactions to subsequently delineate the function and relevance of these interactions in vivo

Methods

Results

Conclusion