Role of CD4 and CCR5 Levels in the Susceptibility of Primary Macrophages to Infection by CCR5-Dependent HIV Type 1 Isolates

Abstract

Macrophages are a preferred target for sexually transmitted human immunodeficiency virus type 1 (HIV-1) isolates that use CCR5 as a coreceptor in combination 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 membrane CD4 or CCR5 transcripts at the time of infection and ID50 values 15 days postinfection were measured in cultures of 50 primary macrophages infected with HIV-110005. To analyze the data, subjects were divided so as to maximize differences in the levels of CD4 or CCR5 expression between groups. Indeed, the difference in CD4 expression between the CD4high (MFI, 16.7 +/- 2.2) and CD4low (MFI, 6.7 +/- 0.7) groups attained high significance (p < 0.005). Of note, susceptibility to infection of MDMs isolated from CD4high donors was strikingly enhanced as compared with CD4low subjects, as 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 the subjects were grouped according to the levels of CCR5 transcripts, even though 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 above the threshold required for efficient HIV-1 infection. Consistent with this 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.