The second extracellular loop of CXCR4 is involved in CD4-independent entry of human immunodeficiency virus type 2

This study investigates how HIV-2 infects cells without CD4, focusing on the CXCR4 chemokine receptor. Researchers used HIV-2 ROD strains that naturally undergo CD4-independent infection and tested them against rat and human CXCR4 receptors, as well as chimeric receptors containing mixed rat-human sequences. Rat CXCR4 alone could not support CD4-independent HIV-2 entry, while human CXCR4 functioned efficiently. By systematically swapping extracellular domains between rat and human CXCR4, the researchers identified the second extracellular loop (E2) as critical for CD4-independent HIV-2 infection. A chimeric receptor containing only human E2 in a rat CXCR4 background restored infection capability. The E2 domain was also shown to be important for CD4-dependent HIV-1 infection, indicating conserved mechanisms between the two viruses. Antibody inhibition studies confirmed that E2 contributes to the CXCR4 epitope recognized by neutralizing antibodies, though other receptor regions also influence recognition and inhibition patterns.

Key findings

• The second extracellular loop (E2) of human CXCR4 is essential for CD4-independent entry of HIV-2, as demonstrated using rat-human chimeric receptors
• The rat homologue of CXCR4 cannot support HIV-2 entry despite high sequence similarity to human CXCR4, highlighting species-specific differences in viral receptor function
• The role of E2 in HIV entry is conserved between HIV-1 and HIV-2 and functions in both CD4-dependent and CD4-independent infection pathways
• The natural ligand SDF-1α blocks HIV-2 entry equally on human and chimeric E2-containing receptors, while antibody inhibition varies depending on receptor composition outside E2