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Excess Mitochondrial DNA Damage in Brain of People With HIV
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7th International Workshop on HIV and Aging, September 26-27, 2016, Washington, DC
Mark Mascolini
Compared with HIV-negative controls, people with HIV had more mitochondrial DNA (mtDNA) damage in postmortem brain samples [1]. The finding, which was not associated with d-nucleoside use, adds to the understanding of neuropathology in people with HIV.
Persistent cognitive impairment in HIV populations responding well to antiretroviral therapy remains incompletely understood. Researchers from Newcastle University and Wellcome Trust, who conducted the mtDNA study, noted that normal aging and neurodegenerative disease in aging people are marked by changes in mtDNA. Previous work by this team found excess age-associated mtDNA mutations in skeletal muscle of antiretroviral-treated people [2]. Because the natural history of mtDNA mutations is similar in muscle and brain, the investigators hypothesized people with HIV may have mtDNA deficits in brain that contribute to decreased cognitive function.
From US and UK brain biobanks, the researchers collected postmortem frontal cortex samples of 25 HIV-positive people and 10 similarly aged people without HIV. Everyone had neurocognitive testing within about 6 months of death, and no one had brain opportunistic infections. The researchers used multiplex qPCR to assess mtDNA content and presence of the mitochondrial delta4977 common deletion mutation. They correlated molecular data with premortem clinical variables including viral control, antiretroviral treatment, and cognitive function.
At death only 5 HIV-positive people (20%) had normal neurocognition, while 4 (16%) had subclinical neuropsychological impairment, 8 (32%) had mild cognitive motor disorder, and 8 (32%) had HIV-associated dementia.
Compared with controls, people with HIV had significantly lower mtDNA content in brain (average 364 versus 706 copies/cell, P < 0.001). In HIV-positive people, the researchers verified a significant association between low mtDNA in brain and low CD4 count (r = 0.65, P = 0.0007). Sixteen HIV-positive people with a plasma viral load above 1000 copies had lower mtDNA brain content than 9 people with lower viral load (295 versus 482 copies/cell, P = 0.02). The investigators found no association between mtDNA content and age at death, severity of neurocognitive impairment, or exposure to mitochondria-toxic nucleosides at the time of death or in the past.
The common deletion mutation proved significantly more prevalent in the brain of people with than without HIV (-2.87 versus -3.21 log10(common deletion/mtDNA genome copy), P = 0.03). In people with HIV, further analysis saw a trend toward higher common deletion levels with older age at death (r = 0.37, P = 0.07). The researchers detected no other associations between common deletion prevalence and clinical, cognitive, or treatment parameters. mtDNA levels did not correlate with common deletion levels.
The Newcastle-Wellcome team concluded that brains of people with HIV have more mtDNA damage than brains of HIV-negative people, indicated both by lower mtDNA content and more mtDNA deletion mutations. They underlined the finding that mtDNA damage did not correlate with use of mitochondria-toxic nucleosides, in contrast to findings of mitochondrial toxicity in sites outside the brain. mtDNA content did correlate with markers of HIV disease activity (lower CD4 count, higher plasma load), findings the researchers believe are consistent with virally mediated neuronal damage.
References
1. Roca C, Lim LY, Payne BA. Mitochondrial DNA damage in brain associated with HIV infection. 7th International Workshop on HIV and Aging, September 26-27, 2016, Washington, DC. Abstract 9.
2. Payne BA, Wilson IJ, Hateley CA, et al. Mitochondrial aging is accelerated by anti-retroviral therapy through the clonal expansion of mtDNA mutations. Nat Genet. 2011;43:806-810. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3223397/
Mitochondrial aging is accelerated by anti-retroviral therapy through the clonal expansion of mtDNA mutations...."Here we show that patients treated with commonly used nucleoside analog anti-retroviral drugs (NRTIs) progressively accumulate somatic mitochondrial DNA (mtDNA) mutations, mirroring that seen much later in life due to normal aging....A finite NRTI exposure predicted a period of temporary mtDNA depletion which was concordant with reported mtDNA levels 12,23, and the COX-defects observed 12 in acutely treated HIV patients. This resulted in accelerated clonal expansion of pre-existing mtDNA mutations, and led to an irreversible increase in the frequency of COX-deficient muscle fibers....In silico modeling is thus consistent with the hypothesis that accelerated clonal expansion of pre-existing (age-associated) mtDNA somatic mutations is sufficient to explain our observations in NRTI-treated subjects. Having established the model, we explored the effect of timing of NRTI exposure and showed that later periods of therapy predicted a higher frequency of COX deficiency (Figure 5d). This is due to older subjects harboring a greater number of age-related somatic mtDNA mutations than younger subjects, which rapidly clonally segregate during NRTI therapy. This is in keeping with the observation that mitochondrially-mediated clinical complications of NRTI therapy appear to be more common in older individuals 24. Finally we modeled the longer-term effects of treatment. Using this approach, an HIV-infected individual treated with NRTIs during their 3rd decade is predicted to develop ~5% COX deficient cells by age 60 (Figure 5b-d). This is similar to or exceeds that seen in the healthy very old 4."
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