Entry coreceptor use and fusion inhibitor T20 sensitivity of dual-tropic R5X4 HIV-1 in primary macrophage infection

摘要

Macrophages are important targets for HIV-1 and R5X4 strains play a central role in pathogenesis, especially in late-stage patients who may receive the fusion inhibitor T20. Sensitivity to T20 varies markedly among HIV-1 strains and is influenced by both viral and cellular factors that affect Env/CD4/coreceptor interactions. We addressed the relationship between T20 inhibition and pathway by which R5X4 HIV-1 infect primary macrophages, which express both coreceptors. In U87/CD4/coreceptor cells T20 sensitivity for entry through CCR5 and CXCR4 were correlated. In macrophages, the proportion of total entry mediated by each coreceptor differed among isolates. However, neither pathway was uniformly more or less sensitive to T20, nor did the proportion of entry mediated by each coreceptor predict T20 sensitivity. T20 sensitivity for macrophage infection overall correlated modestly with that for entry through CCR5 but not CXCR4, but unlike U87 cells, sensitivity of entry through CCR5 and CXCR4 were not correlated. These results suggest that strain-specific factors influence R5X4 T20 sensitivity regardless of coreceptor used; an absence of systematic differences in efficiency by which R5X4 strains use the two coreceptors; and that efficiency/kinetics of interactions with CCR5 are a central determinant of macrophage entry even when both pathways are utilized.