The biology of CCR5 and CXCR4

Abstract

Purpose of review: We discuss the current knowledge concerning the biology of CXCR4 and CCR5 and their roles in HIV-1 infection.

Recent findings: Important research findings reported in the last 2 years have advanced our knowledge in the field of HIV coreceptors and pathogenesis. Novel methods have been used to crystallize two new members of the G-protein coupled receptors. It has been demonstrated that expression and stability of the naturally occurring truncated CCR5 protein is critical for resistance to HIV-1. The first stem cell transplantation of donor cells with the CCR5 mutation provided proof of principle. The Food and Drug Administration approved the first CCR5-based entry inhibitor. New CXCL12 isoforms were discovered, one isoform is a potent X4 inhibitor with weak chemotaxis activity.

Summary: The coreceptor discoveries revealed new insights into host and viral factors influencing HIV transmission and disease. The HIV/coreceptor interaction has become a major target for the development of novel antiviral strategies to treat and prevent HIV infection. The first CCR5-based entry inhibitor has been recently approved. New drugs that promote CCR5 and CXCR4 internalization, independent of cellular signaling, might provide clinical benefits with minimum side effects.

Figure 1. Schematic ball diagram showing the amino acid sequence and membrane orientation of CXCR4 gr1

The shaded residues represent potential phosphorylation sites (total of 25). Potential N-linked glycosylation sites are marked. Asterisks indicate the cysteine residues involved in disulfide bonding.

Figure 2. Coreceptor usage and HIV-1 tropism gr2

X4-tropic strains are specific for CXCR4 and infect continuous CD4⁺ T cell lines and primary CD4⁺ T cells. R5-tropic strains are specific for CCR5 and can infect primary macrophages and CD4⁺ T cells. R5X4-tropic strains can utilize both CXCR4 and CCR5. Reproduced with permission from [1•].

Figure 3. Mechanism of HIV-1 entry gr3

(a) Diagram of the major players involved in HIV-1 entry. Upon binding of CD4 cell (b), gp120 undergoes a conformational change that exposes a hidden coreceptor-binding site (c). Binding of gp120 to the coreceptor brings the envelope into close proximity to the cell surface and induces gp120 to undergo a second conformational change (d) that allows the gp41 protein to penetrate the cell membrane and form a six helices bundle. Through processes that are unknown, fusion occurs between the cell and viral membranes allowing entry of the viral capsid and proteins.

Figure 4. CXCR4 trafficking within the endosomal–lysosomal system gr4

CXCL12-activated CXCR4 is ubiquitinated at the cell membrane by the E3 ubiquitin ligase AIP4. CISK inhibits endosomal sorting of CXCR4 and favors receptor recycling. Under conditions of high PI-3-kinase signaling (i.e during the development or cancer progression), the degradation of CXCR4 is strongly inhibited. AIP4, atrophin-interacting protein 4; CISK, cytokine independent survival kinase; ESCRT, endosomal-sorting complex required for transport; MVB, multivesicular bodies; Ub, ubiquitin; Vps4, vacuolar protein sorting. Adapted with permission from [11••].