HIV and the chemokine system: 10 years later

Abstract

The unexpected encounter, 10 years ago, between human immunodeficiency virus (HIV) and the chemokine system has dramatically advanced our understanding of the pathogenesis of AIDS, opening new perspectives for the development of effective prophylactic and therapeutic measures. To initiate infection, the HIV-1 external envelope glycoprotein, gp120, sequentially interacts with two cellular receptors, CD4 and a chemokine receptor (or coreceptor) like CCR5 or CXCR4. This peculiar two-stage receptor-interaction strategy allows gp120 to maintain the highly conserved coreceptor-binding site in a cryptic conformation, protected from neutralizing antibodies. The differential use of CCR5 and CXCR4 defines three HIV-1 biological variants (R5, R5X4, X4), which vary in their prevalence during the disease course. The evolutionary choice of HIV-1 to exploit chemokine receptors as cellular entry gateways has turned their chemokine ligands into endogenous antiviral factors that variably modulate viral transmission, disease progression and vaccine responses. Likewise, the natural history of HIV-1 infection is influenced by specific polymorphisms of chemokine and chemokine-receptor genes. The imminent clinical availability of coreceptor-targeted viral entry inhibitors raises new hope for bridging the gap towards a definitive cure of HIV infection.

Figure 1

Two-stage interaction of the HIV envelope with its cellular receptors. The native, unbound envelope homotrimer (left panel; structure derived from Chen et al, 2005) exposes the CD4-binding surface but maintains the coreceptor-binding surface in a cryptic conformation. After binding to CD4, gp120 undergoes dramatic conformational changes (right panel; structure derived from Huang et al, 2005) that lead to de novo formation and/or unshielding of the high-affinity coreceptor-binding site.

Figure 2

Structure of the putative CCR5-binding region of RANTES. Molecular surface representation (by GRASP) of the NMR solution structure of the RANTES dimer showing a large hydrophobic surface, lined by charged residues, where critical amino acids for CCR5 interaction and anti-HIV activity were mapped. Blue denotes positive electrical charge; red, negative charge; white, no charge (adapted from Nardese et al, 2001).