Role of CD4 and CCR5 levels in the susceptibility of primary macrophages to infection by CCR5-dependent HIV type 1 isolates

Macrophages are a preferred target for sexually transmitted human immunodef iciency virus type 1 (HIV-1) isolates that use CCR5 as a coreceptor in comb ination with CD4, To assess whether the susceptibility of MDMs to infection by an R5 isolate was influenced by CD4 and/or CCR5 expression, levels of m embrane CD4 or CCR5 transcripts at the time of infection and ID50 values 15 days postinfection were measured in cultures of primary macrophages infect ed with HIV-1(10005). To analyze the data, subjects were divided so as to m aximize differences in the levels of CD4 or CCR5 expression between groups. Indeed, the difference in CD4 expression between the CD4(high) (MFI, 16.7 +/- 2.2) and CD4(low) (MFI, 6.7 +/- 0.7) groups attained high significance (p < 0.005). Of note, susceptibility to infection of MDMs isolated from CD4 (high) donors was strikingly enhanced as compared with CD4(low) subjects, a s shown by a fourfold increase in ID50 titers at day 15 postinfection (p < 0.002). In contrast, no significant difference in ID50 was apparent when th e subjects were grouped according to the levels of CCR5 transcripts, even t hough CCR5 expression in the two groups differed significantly (p = 0.01). These results suggest that, regardless of variations among individuals, the intensity of CD4 expression in macrophages is such that CCR5 levels are ab ove the threshold required for efficient HIV-1 infection. Consistent with t his hypothesis, macrophages from three additional donors selected for high CD4 expression and low CCR5 transcripts were found to be highly susceptible to HIV-1 infection.