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

PLoS Pathogens

Andrea Hegedus¹  Karoliina Laamanen¹  Yan Zhang¹  Derek Macallan¹  Andrew Worth²  Catherine de Lara²  Peter Beverley² 

[1] Infection and Immunity Research Centre, St George's, University of London, London, United Kingdom;Nuffield Department of Medicine, University of Oxford, Oxford, United Kingdom

关键词: T cells;    HIV infections;    HIV;    Memory T cells;    Viral tropism;    Viral load;    Immune activation;    Homeostasis;   

DOI  :  10.1371/journal.ppat.1003310

学科分类：生物科学（综合）

来源: Public Library of Science

【 摘 要 】

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.

【 授权许可】

CC BY