Novel Peptides Based on HIV-1 gp120 Sequence with Homology to Chemokines Inhibit HIV Infection in Cell Culture

Oleg Chertov,Earl E Henderson,Thomas J Rogers,Xin Chen,Amber D Steele,Joost J Oppenheim,Ning Zhang,Anatoli Malyguine,Raymond C Sowder,Jacek Lubkowski,Michele A Kutzler,Connor Mcgrath,Bruce J Crise,Linqi Zhang

doi:10.1371/journal.pone.0014474

Abstract

The sequential interaction of the envelope glycoprotein of the human immunodeficiency virus type 1 (HIV-1) with CD4 and certain chemokine coreceptors initiates host cell entry of the virus. The appropriate chemokines have been shown to inhibit viral replication by blocking interaction of the gp120 envelope protein with the coreceptors. We considered the possibility that this interaction involves a motif of the gp120 that may be structurally homologous to the chemokines. In the amino acid sequences of most chemokines there is a Trp residue located at the beginning of the C-terminal α-helix, which is separated by six residues from the fourth Cys residue. The gp120 of all HIV-1 isolates have a similar motif, which includes the C-terminal part of a variable loop 3 (V3) and N-terminal part of a conserved region 3 (C3). Two synthetic peptides, derived from the relevant gp120 sequence inhibited HIV-1 replication in macrophages and T lymphocytes in sequence-dependent manner. The peptides also prevented binding of anti-CXCR4 antibodies to CXCR4, and inhibited the intracellular Ca2+ influx in response to CXCL12/SDF-1α. Thus these peptides can be used to dissect gp120 interactions with chemokine receptors and could serve as leads for the design of new inhibitors of HIV-1.

Highlights

The envelope glycoprotein of the human immunodeficiency virus type 1 (HIV-1) mediates the fusion of viral and host cell membranes necessary for virion entry [1]
In the amino acid sequences of most chemokines, there is a Trp residue located at the beginning of C-terminal a-helix that is separated by six residues from the fourth Cys residue
Amino acid homology between gp120 and chemokines We noticed that in the amino acid sequences of most CC and some CXC chemokines there is a Trp residue located at the beginning of C-terminal a-helix, and separated by six residues from the fourth Cys residue

Summary

Introduction

The envelope glycoprotein of the human immunodeficiency virus type 1 (HIV-1) mediates the fusion of viral and host cell membranes necessary for virion entry [1]. Several studies have identified the amino acid residues of gp120 that are responsible for the specific interaction with CD4, the primary receptor for HIV-1 [3–6]. Recent studies suggest that the association of the CD4-gp120 complex with the viral coreceptor leads to a rearrangement of gp120 that allows the interaction of the gp envelope protein subunit with the host cell membrane and viral entry [8,9]. The gp120 of all HIV-1 isolates have a very similar motif adjacent to the V3 loop. We hypothesized that this region of gp120 may directly interact with chemokine receptors. The synthesized peptides based on the relevant gp120 sequence were found to interfere with chemokine receptor function and inhibit HIV replication in susceptible cells

Methods

Results

Conclusion