Pairwise comparison of isogenic HIV-1 viruses: R5 phenotype replicates more efficiently than X4 phenotype in primary CD4+ T cells expressing physiological levels of CXCR4.

CCR5-using (R5) HIV-1 strains are present during the whole course of the infection in all subjects, whereas CXCR4-using (X4) HIV-1 strains appear only in the late stages of the infection in some subjects. In this study, we tested the hypothesis that this phenomenon might be the result of a replicative advantage of R5 over X4 strains. We compared the infectivity of an R5 and an X4 strain that differ only in their env gene in peripheral blood mononuclear cells. CD4 T cells in culture, where the CXCR4 ligand SDF-1 is absent, overexpress CXCR4 at their surface. Therefore, a cell line producing the chemokine SDF-1, that binds to and induces the internalization of CXCR4, was established by transfer of the SDF-1 gene. We cocultured peripheral blood mononuclear cells with this SDF-1-producing cell line to obtain SDF-1 concentrations that maintained the CD4 T cell surface CXCR4 densities observed in vivo. Under these conditions, the R5 strain appeared to replicate more efficiently than the X4 strain. Thus, in vitro, when CD4 T cells express physiological levels of CXCR4 coreceptors, R5 virions are more fit for replication than X4 virions and in vivo that limited surface expression of CXCR4 on cell targets could contribute to the preponderance of R5 viruses.