Frequency and cytokine profile of HPRT mutant T cells in HIV-infected and healthy donors: implications for T cell proliferation in HIV disease.
It has been postulated that HIV-infected patients undergo an active production of virus and CD4+ T cell destruction from the early stages of the disease, and that an extensive postthymic expansion of CD4+ T cells prevents a precipitous decline in CD4+ T cell number. Based on the rebound of the CD4+ T cell number observed in patients undergoing antiretroviral therapy with protease inhibitors, it has been calculated that, on average, 5% of T cells are replaced every day in HIV-infected patients. To obtain an independent estimate of the recycling rate of T cells in the patients, we measured the frequency of cells carrying a loss-of-function mutation at the hypoxanthine guanine phosphoribosyl transferase (hprt) locus. Assuming a recycling rate of 5%/d, an accumulation of 2.6 mutations/10(6)/yr over the physiological accumulation was predicted. Indeed, we observed an elevated frequency of HPRT mutants in the CD4+ T cells of most patients with < 300 CD4+ T cells/mm3 of blood and in the CD8+ T cells of most patients with < 200 CD4+ T cells/mm3, consistent with an elevated and protracted increased division rate in both subsets. However, in earlier stages of the disease the mutant frequency in both CD4+ and CD8+ T cells was lower than in healthy controls. The cytokine production profile of most HPRT mutant CD4+ T cell clones from both healthy and HIV-infected patients was typical of T helper cells type 2 (high IL-4 and IL-10, low IFN-gamma), whereas the cytokine production pattern of wild-type clones was heterogeneous. The cytokine profile of CD8+ clones was indistinguishable between HPRT mutants and wild type. Our data provide evidence of increased CD4+ and CD8+ T cell recycling in the HIV-infected patients.
Paganin
C
C
Wistar Institute of Anatomy and Biology, University of Pennsylvania, Philadelphia 19104, USA.
Monos
D S
DS
Marshall
J D
JD
Frank
I
I
Trinchieri
G
G
D000328:Adult; D018791:CD4 Lymphocyte Count; D015496:CD4-Positive T-Lymphocytes / Q000201:enzymology* / Q000276:immunology* / Q000378:metabolism; D018414:CD8-Positive T-Lymphocytes / Q000378:metabolism; D002455:Cell Division / Q000235:genetics / Q000276:immunology; D002999:Clone Cells; D016207:Cytokines / Q000096:biosynthesis*; D005260:Female; D015658:HIV Infections / Q000201:enzymology* / Q000276:immunology*; D006801:Humans; D007041:Hypoxanthine Phosphoribosyltransferase / Q000235:genetics*; D007371:Interferon-gamma / Q000096:biosynthesis; D016753:Interleukin-10 / Q000096:biosynthesis; D015847:Interleukin-4 / Q000096:biosynthesis; D008213:Lymphocyte Activation / Q000235:genetics; D008297:Male; D008875:Middle Aged; D009154:Mutation / Q000276:immunology
D016207:Cytokines; D016753:Interleukin-10; D015847:Interleukin-4; D007371:Interferon-gamma; D007041:Hypoxanthine Phosphoribosyltransferase