Jennifer Jao1, Kathleen M Powis, Brian Kirmse, Chunli Yu, Fanny Epie, Emmanuel Nshom, Elaine J Abrams, Rhoda S Sperling, Derek Leroith, Mitchell E Geffner, Irwin J Kurland, Hélène C F Côté. 1. aDepartment of Medicine, Icahn School of Medicine at Mount Sinai, New York, New York bDepartment of Pediatrics and Internal Medicine, Massachusetts General Hospital cDepartment of Immunology and Infectious Diseases, Harvard T.H. Chan School of Public Health, Boston, Massachusetts dDepartment of Medical Genetics, University of Mississippi Medical Center, Jackson, Mississippi, USA eCameroon Baptist Convention Health Services, Bamenda, Cameroon fICAP, Mailman School of Public Health and College of Physicians and Surgeons, Columbia University gDepartment of Obstetrics, Gynecology, and Reproductive Science, Icahn School of Medicine at Mount Sinai, New York, New York hKeck School of Medicine of USC, The Saban Research Institute of Children's Hospital Los Angeles, Los Angeles, California iDepartment of Medicine, Stable Isotope and Metabolomics Core Facility, Albert Einstein College of Medicine, Bronx, New York, USA jDepartment of Pathology and Laboratory Medicine, University of British Columbia, Vancouver, British Columbia, Canada.
Abstract
OBJECTIVE: Evaluate blood mitochondrial DNA (mtDNA) content in HIV/antiretroviral-exposed uninfected (HEU) vs. HIV-unexposed uninfected (HUU) infants and investigate differences in mitochondrial-related metabolites by exposure group. DESIGN: We enrolled a prospective cohort of HIV-infected and HIV-uninfected pregnant woman/infant pairs in Cameroon. METHODS: Dried blood spot mtDNA : nuclear DNA ratio was measured by monochrome multiplex quantitative polymerase chain reaction in HEU infants exposed to in-utero antiretrovirals and postnatal zidovudine (HEU-Z) or nevirapine (HEU-N), and in HUU infants at 6 weeks of life. Acylcarnitines and branch-chain amino acids (BCAAs) were measured via tandem mass spectrometry and consolidated into seven uncorrelated components using principal component analysis. Linear regression models were fit to assess the association between in-utero/postnatal HIV/antiretroviral exposure and infant mtDNA, adjusting for confounders and principal component analysis-derived acylcarnitine/BCAA component scores. RESULTS: Of 364 singleton infants, 38 were HEU-Z, 117 HEU-N, and 209 HUU. Mean mtDNA content was lowest in HEU-Z infants (140 vs. 160 in HEU-N vs. 174 in HUU, P = 0.004). After adjusting for confounders, HEU-Z infants remained at increased risk for lower mtDNA content compared with HUU infants (β: -4.46, P = 0.045), whereas HEU-N infants did not, compared with HUU infants (β: -1.68, P = 0.269. Furthermore, long-chain acylcarnitines were associated with lower (β: -2.35, P = 0.002) and short-chain and BCAA-related acylcarnitines were associated with higher (β: 2.96, P = 0.001) mtDNA content. CONCLUSION: Compared with HUU infants, HEU infants receiving postnatal zidovudine appear to be at increased risk for decreased blood mtDNA content which may be associated with altered mitochondrial fuel utilization in HEU-Z infants.
OBJECTIVE: Evaluate blood mitochondrial DNA (mtDNA) content in HIV/antiretroviral-exposed uninfected (HEU) vs. HIV-unexposed uninfected (HUU) infants and investigate differences in mitochondrial-related metabolites by exposure group. DESIGN: We enrolled a prospective cohort of HIV-infected and HIV-uninfected pregnant woman/infant pairs in Cameroon. METHODS: Dried blood spot mtDNA : nuclear DNA ratio was measured by monochrome multiplex quantitative polymerase chain reaction in HEUinfants exposed to in-utero antiretrovirals and postnatal zidovudine (HEU-Z) or nevirapine (HEU-N), and in HUU infants at 6 weeks of life. Acylcarnitines and branch-chain amino acids (BCAAs) were measured via tandem mass spectrometry and consolidated into seven uncorrelated components using principal component analysis. Linear regression models were fit to assess the association between in-utero/postnatal HIV/antiretroviral exposure and infant mtDNA, adjusting for confounders and principal component analysis-derived acylcarnitine/BCAA component scores. RESULTS: Of 364 singleton infants, 38 were HEU-Z, 117 HEU-N, and 209 HUU. Mean mtDNA content was lowest in HEU-Z infants (140 vs. 160 in HEU-N vs. 174 in HUU, P = 0.004). After adjusting for confounders, HEU-Z infants remained at increased risk for lower mtDNA content compared with HUU infants (β: -4.46, P = 0.045), whereas HEU-N infants did not, compared with HUU infants (β: -1.68, P = 0.269. Furthermore, long-chain acylcarnitines were associated with lower (β: -2.35, P = 0.002) and short-chain and BCAA-related acylcarnitines were associated with higher (β: 2.96, P = 0.001) mtDNA content. CONCLUSION: Compared with HUU infants, HEUinfants receiving postnatal zidovudine appear to be at increased risk for decreased blood mtDNA content which may be associated with altered mitochondrial fuel utilization in HEU-Z infants.
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