Inhibition of R5X4 dualtropic HIV-1 primary isolates by single chemokine co-receptor ligands

The susceptibility of HIV-1 to chemokine-mediated inhibition may be lost as a consequence of the expanded usage of chemokine co-receptors frequently o ccurring in clade B isolates obtained from individuals with advanced diseas e. Since chemokine-based immune intervention is under intense investigation , it is crucial to determine its potential effect on primary dualtropic HIV isolates characterized by simultaneous utilization of CCR5 and CXCR4 chemo kine co-receptors (R5X4 viruses). In the present study, the CCR5 binding ch emokine regulated upon activation normal T cell expressed and secreted (RAN TES) strongly inhibited the replication of two of eight primary R5X4 viruse s in mitogen-activated primary peripheral blood mononuclear cells (PBMC). T he CXCR4 antagonist AMD3100 efficiently suppressed the replication of other two HIV isolates, whereas the remaining four viruses were partially inhibi ted by treatment with either RANTES or AMD3100. The potency of chemokine-me diated inhibition was influenced by PBMC donor variability, but it was usua lly independent from the levels of expression of CCR5 or CXCR4. Dual co-rec eptor usage was maintained by the viruses after two serial passages on U87. CD4 astrocytic cell lines expressing exclusively either CCR5 or CXCR4. The gp120 env variable domains were sequenced before and after passages on U87. CD4 cells Virus replication into U87.CD4-CXCR4 cells did not result in chan ges in the V3 region but perturbed the dominant env V4 sequence. Interestin gly, double passage onto U87.CD4-CXCR4 cells determined the loss of suscept ibility to RANTES inhibition. In conclusion, interference with CCR5 may eff iciently inhibit the replication of at least some dualtropic HIV-1 strains, whereas forced CXCR4 usage may result in viral escape from CCR5-dependent inhibitory effects. (C) 2001 Academic Press.