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.