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Mitochondrial DNA mutations and interruptions in combination antiretroviral therapy : a retrospective cohort study Ziada, Adam
Abstract
HIV therapy has transformed the lives of people living with HIV (PLWH), turning a once lethal condition into a chronic disease that can be carefully managed over a patient’s lifetime. However, PLWH seem to experience accelerated aging, with a reported decrease in lifespan of up to 10 years, as well as earlier onset and higher prevalence of age-related diseases. Many of these diseases have been linked to interruptions in HIV therapy and/or mutations in the mitochondrial DNA (mtDNA). Current theories of aging implicate the gradual accumulation of mtDNA mutations as a driver of biological aging and may provide a mechanism by which interruptions in HIV therapy could lead to an increased occurrence of age-related diseases. These mutations can be somatic (i.e., de novo) mutations, or higher frequency mtDNA variants (i.e., heteroplasmy). My goal was to determine if interruptions in HIV therapy are associated with an increase in mtDNA somatic or heteroplasmic mutations. Blood mtDNA mutations were characterized among participants living with (n = 219) and without (n = 72) HIV, ranging between 1 and 75 years of age, and enrolled in the Children and Women: AntiRetrovirals and Markers of Aging (CARMA) cohort. Participants living with HIV had between 0 and 17 interruptions in HIV therapy. Mutations were measured in a 264bp region of the mitochondrial D-loop, using a single strand unique molecular identifier-based sequencing to detect ultra-rate substitution mutations. Somatic mtDNA substitution mutations were independently associated with older age (p < 0.001), Indigenous ethnicity (p = 0.001), and having a peak HIV viral load ≥100,000 copies/ml among adult participants. Among all participants having exactly two interruptions was associated with a lower somatic mtDNA substitution burden (p = 0.035). The occurrence of heteroplasmy was independently associated with older age (p = 0.002) and smoking (p = 0.05) among all participants, after considering an age-smoking interaction term. Our results are consistent with the current understanding of mitochondrial aging; however, they do not support the hypothesis that interruption in HIV therapy may be driving mutations in the mitochondrial DNA. However, interruptions remain a risk factor for age-related disease and are almost universally discouraged.
Item Metadata
Title |
Mitochondrial DNA mutations and interruptions in combination antiretroviral therapy : a retrospective cohort study
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Creator | |
Supervisor | |
Publisher |
University of British Columbia
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Date Issued |
2022
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Description |
HIV therapy has transformed the lives of people living with HIV (PLWH), turning a once lethal condition into a chronic disease that can be carefully managed over a patient’s lifetime. However, PLWH seem to experience accelerated aging, with a reported decrease in lifespan of up to 10 years, as well as earlier onset and higher prevalence of age-related diseases. Many of these diseases have been linked to interruptions in HIV therapy and/or mutations in the mitochondrial DNA (mtDNA). Current theories of aging implicate the gradual accumulation of mtDNA mutations as a driver of biological aging and may provide a mechanism by which interruptions in HIV therapy could lead to an increased occurrence of age-related diseases. These mutations can be somatic (i.e., de novo) mutations, or higher frequency mtDNA variants (i.e., heteroplasmy). My goal was to determine if interruptions in HIV therapy are associated with an increase in mtDNA somatic or heteroplasmic mutations.
Blood mtDNA mutations were characterized among participants living with (n = 219) and without (n = 72) HIV, ranging between 1 and 75 years of age, and enrolled in the Children and Women: AntiRetrovirals and Markers of Aging (CARMA) cohort. Participants living with HIV had between 0 and 17 interruptions in HIV therapy. Mutations were measured in a 264bp region of the mitochondrial D-loop, using a single strand unique molecular identifier-based sequencing to detect ultra-rate substitution mutations.
Somatic mtDNA substitution mutations were independently associated with older age (p < 0.001), Indigenous ethnicity (p = 0.001), and having a peak HIV viral load ≥100,000 copies/ml among adult participants. Among all participants having exactly two interruptions was associated with a lower somatic mtDNA substitution burden (p = 0.035). The occurrence of heteroplasmy was independently associated with older age (p = 0.002) and smoking (p = 0.05) among all participants, after considering an age-smoking interaction term.
Our results are consistent with the current understanding of mitochondrial aging; however, they do not support the hypothesis that interruption in HIV therapy may be driving mutations in the mitochondrial DNA. However, interruptions remain a risk factor for age-related disease and are almost universally discouraged.
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Genre | |
Type | |
Language |
eng
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Date Available |
2023-01-03
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Provider |
Vancouver : University of British Columbia Library
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Rights |
Attribution-NonCommercial-NoDerivatives 4.0 International
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DOI |
10.14288/1.0422935
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URI | |
Degree | |
Program | |
Affiliation | |
Degree Grantor |
University of British Columbia
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Graduation Date |
2023-05
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Campus | |
Scholarly Level |
Graduate
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Rights URI | |
Aggregated Source Repository |
DSpace
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Rights
Attribution-NonCommercial-NoDerivatives 4.0 International