C-C chemokine receptor type 5 and C-X-C chemokine receptor type 4 (CCR5/CXCR4)

The C-C chemokine receptor type 5 (CCR5) and C-X-C chemokine receptor type 4 (CXCR4) are G protein-coupled receptors that function as the essential co-receptors for HIV-1 entry into CD4+ cells (Alkhatib et al., 1996, Science; Feng et al., 1996, Science). Following the initial binding of the viral gp120 protein to CD4, a conformational change exposes a binding loop that interacts with either CCR5 or CXCR4 to trigger membrane fusion (Wilen et al., 2012, Cold Spring Harb Perspect Med). CCR5 is the predominant co-receptor for viral transmission and early-stage infection, whereas CXCR4-tropic viruses often appear in later stages and are linked to accelerated disease progression (Berger et al., 1999, Annu Rev Immunol). Pharmacological targeting of these receptors, such as with the CCR5 antagonist maraviroc, prevents the gp120-co-receptor interaction, effectively blocking viral entry (Dorr et al., 2005, Antimicrob Agents Chemother). While CCR5 is a viable long-term target due to the relative health of individuals with the CCR5-delta32 mutation, CXCR4 inhibition is more complex because the receptor is vital for hematopoietic stem cell trafficking and development (Broxmeyer, 2008, Expert Opin Ther Targets).

Other names

CCR5CXCR4CD195CD184FusinCKR5CMKBR5C-C CKR-5C-X-C CKR-4HIV-1 co-receptorHIV-1 co-receptor binding region

Antagonism of the co-receptor binding site to prevent HIV-1 gp120 interaction and subsequent viral entry (Dragic et al., 2000, PNAS; Wood and Armour, 2005, Prog Drug Res).