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  • Title: Distinct mechanisms for mitochondrial DNA loss in T and B lymphocytes from HIV-infected patients exposed to nucleoside reverse-transcriptase inhibitors and those naive to antiretroviral treatment.
    Author: Maagaard A, Holberg-Petersen M, Løvgården G, Holm M, Pettersen FO, Kvale D.
    Journal: J Infect Dis; 2008 Nov 15; 198(10):1474-81. PubMed ID: 18851688.
    Abstract:
    OBJECTIVE: Mitochondrial DNA (mtDNA) loss in peripheral blood mononuclear cells (PBMCs) has been found in both nucleoside reverse-transcriptase inhibitor (NRTI)-exposed and antiretroviral therapy (ART)-naive patients with human immunodeficiency virus (HIV) infection. Persistent immune activation might play a role in this phenomenon in HIV-infected, ART-naive patients. PBMC subsets with differential growth kinetics were therefore purified to study this similarity. METHODS: CD4(+) and CD8(+) T cells, CD19(+) B cells, and CD14(+) monocytes were purified from PBMCs. mtDNA levels were quantified using real-time polymerase chain reaction and compared among the 2 groups of HIV-infected patients and a group of HIV-negative control subjects. mtDNA levels in a separate group of ART-naive patients stratified by the rate of disease progression were also evaluated with respect to their relationship to immune-activation markers (i.e., CD38 and programmed cell death-1 [PD-1]) on CD8(+) T cells and the rate of CD4(+) T cell loss. RESULTS: mtDNA levels in CD8(+) T cells and B cells from 15 ART-naive patients were approximately 50% less than those observed for 14 control subjects (P < or = .01). mtDNA levels in all lymphocyte subsets correlated negatively with CD38(+)PD-1(+) expression (r= -0.66 P < -0.9; P < or = .03), and mtDNA levels in B cells correlated with the rate of CD4(+) T cell loss (r =0.66; P< .3). In 17 HIV-infected, NRTI-exposed patients, mtDNA loss was observed in both T cell subsets (P < or = .02) and was most pronounced in patients who received didanosine (P < or = .002). CONCLUSIONS: In HIV-infected, ART-naive patients, mtDNA loss was found in CD8(+) T cells and B cells. These losses correlated with immune activation and, in B cells, with the rate of CD4(+) T cell loss. In patients receiving ART, only T lymphocytes had reduced mtDNA levels. This finding was probably associated with NRTI use, because it was most pronounced in patients with a history of didanosine exposure.
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