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. © 2013 zhang et al.