Sensitivity of primary R5 HTV-1 to inhibition by RANTES correlates with sensitivity to small-molecule R5 inhibitors.

In approximately 50% of HIV-1 subtype B-infected individuals, progression to AIDS is preceded by the emergence of CXCR4-using (X4) variants, whereas the rest progress to AIDS in the presence of CCR5-using (R5) variants only. In a previous study, we showed that during disease progression in the presence of R5 variants only, HIV-1 variants emerge with a decreased sensitivity to inhibition by RANTES, a natural ligand of CCR5 that inhibits cellular entry of R5 variants. This observation was of potential clinical relevance as HIV-1 small-molecule R5 entry inhibitors are a new class of drugs that, in analogy to RANTES, target the binding and subsequent entry of HIV into the target cell. Here we show that R5 HIV-1 sensitivity to RANTES correlates with sensitivity to the R5 small-molecule inhibitor AD101. HIV-1 small-molecule entry inhibitors are a new class of drugs that target the binding and subsequent entry of HIV into the target cell. Furthermore, we found that R5 variants obtained from individuals who later developed X4 variants were less sensitive to AD101 inhibition compared with R5 variants obtained from individuals who never developed X4 variants. These results may have implications for the evaluation of R5 inhibitors in future clinical trials.