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Mitochondrial Genome Analysis Yields Novel Findings in Antiretroviral-Treated HIV Patients

Tuesday, July 26, 2016

Scientists from Yale University and Memorial Sloan Kettering Cancer Center used SMRT Sequencing to determine whether antiretroviral therapies were triggering mitochondrial genome mutations in HIV patients. The results were recently published in HIV Medicine (“High frequency of mitochondrial DNA mutations in HIV-infected treatment-experienced individuals”).

The publication, from lead author Min Li, senior author Elijah Paintsil, and collaborators, reports results from an analysis of 71 people, including 47 HIV patients who had received antiretroviral therapy (about half had mitochondrial toxicity) and 24 healthy controls. DNA was isolated from peripheral blood mononuclear cells and mitochondrial genome sequencing performed on a PacBio System.

SMRT Sequencing was chosen for its long reads and accuracy, according to the authors. “PacBio technology overcomes some of the limitations of current next-generation sequencing platforms by providing significantly longer reads (> 1 kb), single molecule sequencing, and a single-pass error rate of < 15%,” Li et al. write. “Moreover, SMRT sequencing exceeds the consensus accuracy achieved by other sequencing methods because of the random nature of the errors. The SMRT sequencing achieves results with > 99.999% accuracy.”

The team found that HIV-infected patients, regardless of whether they experienced mitochondrial toxicity or not, had a higher frequency of mitochondrial mutations — in particular, large-scale deletions — than their healthy counterparts. However, they did not find statistically significant differences in mutation load between HIV patients with and without mitochondrial toxicity. “We did not observe mtDNA depletion in HIV-infected treatment-experienced patients with toxicity as expected,” the scientists report. “To our surprise, HIV-infected treatment-experienced patients with toxicity had significantly higher mRNA expression of Pol-γ in comparison with HIV-infected treatment-experienced patients without toxicity (P < 0.05) and HIV-uninfected controls (P < 0.01). This contradicts the Pol-γ inhibition theory.”

The authors attribute some of these novel findings to sequencing and analyzing the whole mitochondrial genome, whereas previous studies have taken less comprehensive approaches. The work also paves the way for increased use of peripheral blood mononuclear cells to characterize the biology of HIV patients, compared to the more commonly used invasive tissue biopsies.

Additional studies will be needed to follow up on these discoveries, the scientists note. “There are currently two proposed mechanisms to explain the association between mtDNA mutations and [antiretroviral therapy (ART)],” they write, “ART directly or indirectly provides a permissive environment for sporadic mtDNA mutagenesis; and ART pressure leads to clonal expansion of existing mutations.”

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