CD4-dependent, antibody-sensitive interactions between HIV-1 and its co-receptor CCR-5

Abstract

The beta-chemokine receptor CCR-5 is an essential co-factor for fusion of HIV-1 strains of the non-syncytium-inducing (NSI) phenotype with CD4+ T-cells. The primary binding site for human immunodeficiency virus (HIV)-1 is the CD4 molecule, and the interaction is mediated by the viral surface glycoprotein gp120 (refs 6, 7). The mechanism of CCR-5 function during HIV-1 entry has not been defined, but we have shown previously that its beta-chemokine ligands prevent HIV-1 from fusing with the cell. We therefore investigated whether CCR-5 acts as a second binding site for HIV-1 simultaneously with or subsequent to the interaction between gp120 and CD4. We used a competition assay based on gp120 inhibition of the binding of the CCR-5 ligand, macrophage inflammatory protein (MIP)-1beta, to its receptor on activated CD4+ T cells or CCR-5-positive CD4- cells. We conclude that CD4 binding, although not absolutely necessary for the gp120-CCR-5 interaction, greatly increases its efficiency. Neutralizing monoclonal antibodies against several sites on gp120, including the V3 loop and CD4-induced epitopes, inhibited the interaction of gp120 with CCR-5, without affecting gp120-CD4 binding. Interference with HIV-1 binding to one or both of its receptors (CD4 and CCR-5) may be an important mechanism of virus neutralization.

HIV-1 Resistance to CCR5 Antagonists Associated with Highly Efficient Use of CCR5 and Altered Tropism on Primary CD4 + T Cells

“…Targeting stages of the HIV entry process with antiretroviral drugs is a productive method of inhibiting HIV replication, as demonstrated by the potent antiviral effects of small-molecule CCR5 antagonists and fusion inhibitors (23,35,49). As with other antiretroviral drugs, HIV can develop resistance to entry inhibitors, and a detailed understanding of viral and host determinants of resistance will be critical to the optimal clinical use of these agents.The coreceptor binding site that is induced by CD4 engagement consists of noncontiguous regions in the bridging sheet and V3 loop of gp120 (4,18,42,43,50). Interactions between gp120 and CCR5 occur in at least two distinct areas: (i) the bridging sheet and the stem of the V3 loop interact with sul-…”

“…The coreceptor binding site that is induced by CD4 engagement consists of noncontiguous regions in the bridging sheet and V3 loop of gp120 (4,18,42,43,50). Interactions between gp120 and CCR5 occur in at least two distinct areas: (i) the bridging sheet and the stem of the V3 loop interact with sulfated tyrosine residues in the NЈ terminus of CCR5, and (ii) the crown of the V3 loop is thought to engage the extracellular loops (ECLs), particularly ECL2, of CCR5 (10-12, 14, 18, 28).…”

Viral surface glycoproteins, gp120 and gp41, as potential drug targets against HIV-1: Brief overview one quarter of a century past the approval of zidovudine, the first anti-retroviral drug

“…Additional changes in gp120 occur with CD4 binding, including movement of the V1/V2 and V3 loop domains. As a result, CD4 binding not only induces the formation of the bridging sheet, as it likely also enhances exposure of this region and orients it and the V3 loop toward the target cell membrane, where they can engage the viral co-receptor [83,84]. The HIV-1 gp120 envelope protein is an essential component in the multi-tiered viral entry process.…”

The good and evil of complement activation in HIV-1 infection

“…34 The HIV-1-specific nAbs described to date interfere with viral attachment to the cellular receptor CD4, binding to the coreceptor (most commonly CCR5 or CXCR4), or postreceptor engagement in the actual fusion process. [35][36][37][38][39][40][41][42][43][44][45] When a host is infected with a virus, Abs are produced against many epitopes on multiple viral proteins. These Abs consist of a mixture of nAbs and non-nAbs, which can contribute to antiviral immunity in four ways: 34 (i) nAbs directly neutralize free virus particles; (ii) both nAbs and non-nAbs trigger complement-mediated lysis of free virus particles and infected cells via specific Ab-antigen binding events and complement activation; (iii) both nAbs and non-nAbs bind to and coat viruses to mediate opsonization and phagocytosis by macrophages and other cells; and (iv) both nAbs and non-nAbs trigger destruction of viruses by stimulating other immune responses such as Ab-dependent cellular cytotoxicity (ADCC).…”