Accelerated In Vivo Proliferation of Memory Phenotype CD4+ T-cells in Human HIV-1 Infection Irrespective of Viral Chemokine Co-receptor Tropism

CD4 + T-cell loss is the hallmark of HIV-1 infection. CD4 counts fall more rapidly in advanced disease when CCR5-tropic viral strains tend to be replaced by X4-tropic viruses. We hypothesized: (i) that the early dominance of CCR5-tropic viruses results from faster turnover rates of CCR5 + cells, and (ii) that X4-tropic strains exert greater pathogenicity by preferentially increasing turnover rates within the CXCR4 + compartment. To test these hypotheses we measured in vivo turnover rates of CD4 + T-cell subpopulations sorted by chemokine receptor expression, using in vivo deuterium-glucose labeling. Deuterium enrichment was modeled to derive in vivo proliferation ( p ) and disappearance ( d* ) rates which were related to viral tropism data. 13 healthy controls and 13 treatment-naive HIV-1-infected subjects (CD4 143–569 cells/ul) participated. CCR5-expression defined a CD4 + subpopulation of predominantly CD45R0 + memory cells with accelerated in vivo proliferation ( p  = 2.50 vs 1.60%/d, CCR5 + vs CCR5 − ; healthy controls; P<0.01). Conversely, CXCR4 expression defined CD4 + T-cells (predominantly CD45RA + naive cells) with low turnover rates. The dominant effect of HIV infection was accelerated turnover of CCR5 + CD45R0 + CD4 + memory T-cells ( p  = 5.16 vs 2.50%/d, HIV vs controls; P<0.05), naïve cells being relatively unaffected. Similar patterns were observed whether the dominant circulating HIV-1 strain was R5-tropic (n = 9) or X4-tropic (n = 4). Although numbers were small, X4-tropic viruses did not appear to specifically drive turnover of CXCR4-expressing cells ( p  = 0.54 vs 0.72 vs 0.44%/d in control, R5-tropic, and X4-tropic groups respectively). Our data are most consistent with models in which CD4 + T-cell loss is primarily driven by non-specific immune activation.