DIFFERENCES IN CD4 DEPENDENCE FOR INFECTIVITY OF LABORATORY-ADAPTED AND PRIMARY PATIENT ISOLATES OF HUMAN-IMMUNODEFICIENCY-VIRUS TYPE-1

CD4 is known to be an important receptor for human immunodeficiency vi rus type 1 (HIV-1) infection of T lymphocytes and macrophages. However , the limiting steps in CD4-dependent HIV-1 infections in vivo and in vitro are poorly understood. To address this issue, we produced a pane l of HeLa-CD4 cell clones that express widely different amounts of CD4 and quantitatively analyzed their infection by laboratory-adapted and primary patient HIV-1 isolates. For all HIV-1 isolates, adsorption fr om the medium onto HeLa-CD4 cells was inefficient and appeared to be l imiting for infection in the conditions of our assays. Adsorption of H IV-1 onto CD4-positive peripheral blood mononuclear cells was also ine fficient. Moreover, there was a striking difference between laboratory -adapted and primary T-cell-tropic HIV-1 isolates in the infectivity t iters detected on different HeLa-CD4 cells. Laboratory-adapted HIV-1 i solates infected all HeLa-CD4 cell clones with equal efficiencies rega rdless of the levels of CD4, whereas primary HIV-1 isolates infected t hese clones in direct proportion to cellular CD4 expression. Our inter pretation is that for laboratory-adapted isolates, a barrier step that preceeds CD4 encounter was limiting and the subsequent CD4-dependent virus capture process was highly efficient, even at very low cell surf ace concentrations. In contrast, for primary HIV-1 isolates, the CD4-d ependent steps appeared to be much less efficient. We conclude that pr imary isolates of HIV-1 infect inefficiently following contact with su rfaces of CD4-positive cells, and we propose that this confers a selec tive disadvantage during passage in rapidly dividing leukemia cell lin es. Conversely, in vivo selective pressure appears to favor HIV-1 stra ins that require large amounts of CD4 for infection.