Molecular basis for cell tropism of CXCR4-dependent human immunodeficiencyvirus type 1 isolates

Laboratory isolates of human immunodeficiency virus type 1 (HIV-1) that uti lize CXCR4 as a coreceptor infect primary human macrophages inefficiently e ven though these express a low but detectable level of cell surface CXCR4. In contrast, infection of primary macrophages by primary CXCR4-tropic HIV-1 isolates is readily detectable, Here, we provide evidence suggesting that this difference in cell tropism results from a higher requirement for cell surface CXCR4 for infection by Laboratory HIV-1 isolates. Transfected COS7 cells that express a high level of CD4 but a low level of CXCR4 were infect ed significantly more efficiently by two primary CXCR4-tropic HIV-1 isolate s compared to the prototypic laboratory HIV-1 isolate IIIB. More importantl y, overexpression of either wild-type or signaling-defective CXCR4 on prima ry macrophages dramatically enhanced the efficiency of infection by the lab oratory HIV-1 isolate yet only modestly enhanced infection by either primar y CXCR4-tropic virus. Overexpression of CD4 had, in contrast, only a limite d effect on macrophage infection by the laboratory HIV-1, although infectio n by the primary isolates was markedly enhanced. We therefore conclude that the laboratory CXCR4-tropic HIV-1 isolate exhibits a significantly higher CXCR4 requirement for efficient infection than do the primary CXCR4-tropic isolates and that this difference can explain the poor ability of the labor atory HIV-1 isolate to replicate in primary macrophages. More generally, we propose that the cell tropisms displayed by different strains of HIV-1 in culture can largely be explained on the basis of differential requirements for cell surface CD4 and/or coreceptor expression levels.