Abstract
Chemokine receptors CCR5 and CXCR4 are considered the main coreceptors for initial HIV infection, replication and transmission, and subsequent AIDS progression. Over the years, other chemokine receptors, belonging to the family of G protein-coupled receptors, have also been identified as candidate coreceptors for HIV entry into human host cells. Amongst them, CXCR7, also known as atypical chemokine receptor 3 (ACKR3), was suggested as a coreceptor candidate capable of facilitating both HIV-1 and HIV-2 entry in vitro. In this study, a cellular infection model was established to further decipher the role of CXCR7 as an HIV coreceptor. Using this model, CXCR7-mediated viral entry was demonstrated for several clinical HIV isolates as well as laboratory strains. Of interest, the X4-tropic HIV-1 HE strain showed rapid adaptation towards CXCR7-mediated infection after continuous passaging on CD4- and CXCR7-expressing cells. Furthermore, we uncovered anti-CXCR7 monoclonal antibodies, small molecule CXCR7 inhibitors and the natural CXCR7 chemokine ligands as potent inhibitors of CXCR7 receptor-mediated HIV entry and replication. Even though the clinical relevance of CXCR7-mediated HIV infection remains poorly understood, our data suggest that divergent HIV-1 and HIV-2 strains can quickly adapt their coreceptor usage depending on the cellular environment, which warrants further investigation.
Highlights
Human immunodeficiency virus (HIV) is the causal agent of the disease known as acquired immune deficiency syndrome (AIDS)
HIV strains that infect host cells using the Chemokine Receptor 5 (CCR5) coreceptor are known as M-tropic, non-syncytium-inducing, CCR5tropic (R5) viruses, while infections via the CXC Chemokine Receptor 4 (CXCR4) coreceptor occur with T-tropic, syncytium-inducing, CXCR4-tropic (X4) HIV strains
Both U87.CD4 and U87-MG cells were stably transfected with CXCR7 cDNA contained in the pTEJ-8 mammalian expression vector
Summary
Human immunodeficiency virus (HIV) is the causal agent of the disease known as acquired immune deficiency syndrome (AIDS). The viral entry of HIV-1 and HIV-2 occurs via the initial attachment of the HIV envelope glycoprotein (gp120) subunits to CD4 molecules on the host cell surface, thereby exposing the coreceptor binding site. HIV strains that infect host cells using the CCR5 coreceptor are known as M-tropic, non-syncytium-inducing, CCR5tropic (R5) viruses, while infections via the CXCR4 coreceptor occur with T-tropic, syncytium-inducing, CXCR4-tropic (X4) HIV strains. There are HIV strains that can bind both CCR5 and CXCR4, the so-called dual-tropic strains. Several reports have indicated an increase of HIV-1 strains that predominantly use CXCR4 as a coreceptor for virus attachment and entry. These X4 HIV-1 strains are associated with rapid disease progression towards AIDS in infected individuals. A faster clinical course is well-documented for individuals infected with dual-tropic (most likely X4) HIV-1 strains [8, 9, 10]
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