Mitochondrial DNA decline in T cells of HIV-1 seroconverters may be dependent on immune activation.

BACKGROUND: Earlier reports have indicated that human immunodeficiency virus type 1 (HIV-1) infection itself might cause mitochondrial DNA (mtDNA) decline in peripheral blood mononuclear cells (PBMCs). However, the mtDNA dynamics within this heterogeneous cell population during HIV-1 infection are not fully understood. METHODS: mtDNA content was assessed longitudinally in PBMCs and in isolated CD4(+) and CD8(+) T cells from 16 documented HIV-1 seroconverters who were naive to antiretroviral therapy. The correlation between the mtDNA content of CD4(+) and CD8(+) T cells and their immunologically activated proportion was studied. Additionally, mtDNA content was measured within isolated activated and nonactivated CD4(+) and CD8(+) T cells obtained from 5 antiretroviral-naive men with chronic HIV-1 infection. RESULTS: In the seroconverter group, mtDNA content in CD8(+) T cells decreased 5 years after seroconversion (P=.007). mtDNA content in either CD4(+) or CD8(+) T cells did not correlate with the proportion of activated cells within either population. However, for the chronically infected men, mtDNA content in activated CD8(+) T cells was lower than that in nonactivated cells (P=.043). A similar trend was observed in the CD4(+) T cell fraction. CONCLUSIONS: These findings indicate that HIV-1 infection affects mtDNA content, particularly in the most immunologically activated cells. Furthermore, the importance of measuring mtDNA in specific cell fractions rather than in the heterogeneous PBMC population is emphasized.

Mitochondrial DNA and RNA increase in peripheral blood mononuclear cells from HIV-1-infected patients randomized to receive stavudine-containing or stavudine-sparing combination therapy.

BACKGROUND: Mitochondrial DNA (mtDNA) in peripheral blood mononuclear cells (PBMCs) has been suggested as a potential marker of mitochondrial toxicity associated with nucleoside analogue reverse-transcriptase inhibitor-containing therapy. METHODS: We quantified mtDNA and mitochondrial RNA (mtRNA) in PBMCs over the course of 48 weeks in 78 patients infected with human immunodeficiency virus type 1 (HIV-1) who were randomly assigned to receive ritonavir-boosted indinavir and efavirenz with or without stavudine. Furthermore, we analyzed the association of mtDNA and mtRNA with clinical signs and symptoms and/or abnormalities in laboratory markers attributed to mitochondrial toxicity. RESULTS: No statistically significant difference was found in mtDNA and mtRNA content over time between the 2 treatment arms. When arms were combined, both median mtDNA and mtRNA content showed statistically significant increases over the course of 48 weeks, from 206 to 278 copies/cell (P < .001) and from 154 to 288 copies/cell (P = .003), respectively. No statistically significant difference in mtDNA and mtRNA content was found between patients with and those without adverse events attributed to mitochondrial toxicity. CONCLUSIONS: The observed increases in mtDNA and mtRNA content during the first year of treatment may represent a restorative trend resulting from suppression of HIV-1 infection, independent of the treatment used. Future studies should focus on well-defined mitochondrial toxicities and changes in these markers within the corresponding affected tissues simultaneously with those in PBMCs. Furthermore, with respect to studies of peripheral blood, mtDNA and mtRNA content in individual cell subtypes rather than in PBMCs may be better markers of toxicity and deserve further investigation.

Infection with HIV-1 induces a decrease in mtDNA.

Cross-sectional studies have suggested that infection with human immunodeficiency virus (HIV) type 1 could reduce the mitochondrial DNA (mtDNA) content of blood cells. We investigated mtDNA content in peripheral blood mononuclear cells (PBMCs) obtained from 36 antiretroviral therapy-naive documented HIV-1 seroconverters, before and after seroconversion. mtDNA content statistically significantly decreased 1 year after seroconversion and showed a nonsignificant decrease during the subsequent 4 years. These findings confirm that infection with HIV-1 may, itself, reduce mtDNA content, at least within PBMCs. This could have implications for the subsequent development of mitochondrial toxicities associated with the use of nucleoside analogue reverse-transcriptase inhibitors.

Prevalence of lipoatrophy and mitochondrial DNA content of blood and subcutaneous fat in HIV-1-infected patients randomly allocated to zidovudine- or stavudine-based therapy.

INTRODUCTION: Mitochondrial toxicity resulting from mitochondrial DNA (mtDNA) depletion is suggested to be involved in the pathogenesis of lipodystrophy. METHODS: We cross-sectionally assessed lipodystrophy both clinically and radiographically in patients who, 4 years before, had been enrolled in a randomized comparative trial of stavudine- or zidovudine-based therapy. mtDNA content was measured in peripheral blood mononuclear cells (PBMCs) and subcutaneous adipose tissue from the thigh and back. RESULTS: Twenty-eight of the 45 patients enrolled in the original trial were included. Despite comparable exposure to stavudine or zidovudine (51 and 50 months, respectively), lipoatrophy prevalence by intent-to-treat analysis was significantly greater in stavudine recipients (82 vs 9%, P=0.0001). Likewise, those allocated to stavudine had significantly less peripheral fat. In an analysis restricted to patients who had remained on randomly allocated nucleoside reverse transcriptase inhibitors (NRTIs), mtDNA in PBMCs decreased after the start of treatment in both groups (P<0.0001) (-73% for stavudine and -67% for zidovudine, P=0.11), resulting in significantly lower levels in patients with lipoatrophy (P=0.007). The mtDNA content in subcutaneous adipose tissue from the thigh, but not from the back, was significantly lower in patients allocated to stavudine compared to zidovudine (P=0.01). mtDNA in adipose tissue from either location did not differ significantly between those with or without lipoatrophy. DISCUSSION: This study objectively confirms that regimens containing stavudine are associated with a greater risk of lipoatrophy than those containing zidovudine. mtDNA in PBMCs markedly declined with both treatments and was lowest in patients with lipoatrophy. The lack of difference in mtDNA in adipose tissue from patients with as opposed to without lipoatrophy may have been masked by a relative preponderance of stromal and vascular tissue in the subcutaneous tissue samples from these patients, combined with compensatory mitochondrial proliferation in remaining adipocytes. However, our findings may also suggest that the different risk of lipoatrophy observed between NRTIs cannot solely be explained by differences in mtDNA depletion directly at the level of peripheral adipose tissue.