Percentages of activated T cells correlate with HIV-1 disease progression, but the underlying mechanisms are not fully understood. We hypothesized that HLA-DR + CD38 + (DR + 38 +) CD4 + T cells produce the majority of HIV-1 due to elevated expression of CCR5 and CXCR4. In phytohemagglutinin (PHA)-stimulated CD8-depleted peripheral blood mononuclear cells (PBMC) infected with HIV-1 green fluorescent protein (GFP) reporter viruses, DR - 38 + T cells constituted the majority of CCR5 (R5)-tropic (median, 62%) and CXCR4 (X4)-tropic HIV-1-producing cells (median, 61%), although cell surface CCR5 and CXCR4 were not elevated in this subset of cells. In lymph nodes from untreated individuals infected with R5-tropic HIV-1, percentages of CCR5 + cells were elevated in DR + 38 + CD4 + T cells (median, 36.4%) compared to other CD4 + T-cell subsets (median values of 5.7% for DR - 38 - cells, 19.4% for DR + 38 - cells, and 7.6% for DR - 38 + cells; n = 18; P < 0.001). In sorted CD8 - lymph node T cells, median HIV-1 RNA copies/105 cells was higher for DR + 38 + cells (1.8 × 106) than for DR - 38 - (0.007 × 106), DR - 38 + (0.064 × 106), and DR + 38 - (0.18 × 106) subsets (n = 8; P < 0.001 for all). After adjusting for percentages of subsets, a median of 87% of viral RNA was harbored by DR + 38 + cells. Percentages of CCR5 + CD4 + T cells and concentrations of CCR5 molecules among subsets predicted HIV-1 RNA levels among CD8 - DR/38 subsets (P < 0.001 for both). Median HIV-1 DNA copies/105 cells was higher in DR + 38 + cells (5,360) than in the DR - 38 - (906), DR - 38 + (814), and DR + 38 - (1,984) subsets (n = 7; P ≤ 0.031). Thus, DR + 38 + CD4 + T cells in lymph nodes have elevated CCR5 expression, are highly susceptible to infection with R5-tropic virus, and produce the majority of R5-tropic HIV-1. PBMC assays failed to recapitulate in vivo findings, suggesting limited utility. Strategies to reduce numbers of DR + 38 + CD4 + T cells may substantially inhibit HIV-1 replication.
ASJC Scopus subject areas
- Insect Science