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Lower mitochondrial DNA and altered mitochondrial fuel metabolism in HIV-exposed uninfected infants in Cameroon.

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 (?: -4.46, P?=?0.045), whereas HEU-N infants did not, compared with HUU infants (?: -1.68, P?=?0.269. Furthermore, long-chain acylcarnitines were associated with lower (?: -2.35, P?=?0.002) and short-chain and BCAA-related acylcarnitines were associated with higher (?: 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.

SUBMITTER: Jao J

PROVIDER: S-EPMC5680102 | biostudies-literature | 2017 Nov

REPOSITORIES: biostudies-literature

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Lower mitochondrial DNA and altered mitochondrial fuel metabolism in HIV-exposed uninfected infants in Cameroon.

Jao Jennifer J Powis Kathleen M KM Kirmse Brian B Yu Chunli C Epie Fanny F Nshom Emmanuel E Abrams Elaine J EJ Sperling Rhoda S RS Leroith Derek D Geffner Mitchell E ME Kurland Irwin J IJ Côté Hélène C F HCF

AIDS (London, England) 20171101 18

<h4>Objective</h4>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.<h4>Design</h4>We enrolled a prospective cohort of HIV-infected and HIV-uninfected pregnant woman/infant pairs in Cameroon.<h4>Methods</h4>Dried blood spot mtDNA : nuclear DNA ratio was measured by monochrome multiplex quantitative polymerase chain reaction in ...[more]

PMID: 28926411

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Project description:ObjectivesHIV-exposed uninfected (HEU) infants have higher rates of severe and fatal infections compared with HIV-unexposed (HUU) infants, likely due to immune perturbations. We hypothesized that alterations in natural killer (NK) cell activity might occur in HEU infants and predispose them to severe infections.DesignCase-control study using cryopreserved peripheral blood mononuclear cells (PBMCs) at birth and 6 months from HEU infants enrolled from 2002 to 2009 and HUU infants enrolled from 2011 to 2013.MethodsNK cell phenotype and function were assessed by flow cytometry after 20-h incubation with and without K562 cells.ResultsThe proportion of NK cells among PBMCs was lower at birth in 12 HEU vs. 22 HUU (1.68 vs. 10.30%, p < 0.0001) and at 6 months in 52 HEU vs. 72 HUU (3.09 vs. 4.65%, p = 0.0005). At birth, HEU NK cells demonstrated increased killing of K562 target cells (p < 0.0001) and increased expression of CD107a (21.65 vs. 12.70%, p = 0.047), but these differences resolved by 6 months. Stimulated HEU NK cells produced less interferon (IFN)γ at birth (0.77 vs. 2.64%, p = 0.008) and at 6 months (4.12 vs. 8.39%, p = 0.001), and showed reduced perforin staining at 6 months (66.95 vs. 77.30%, p = 0.0008). Analysis of cell culture supernatants indicated that lower NK cell activity in HEU was associated with reduced interleukin (IL)-12, IL-15, and IL-18. Addition of recombinant human IL-12 to stimulated HEU PBMCs restored IFNγ production to that seen in stimulated HUU cultures.ConclusionNK cell proportion, phenotype, and function are altered in HEU infants. NK cell cytotoxicity and degranulation are increased in HEU at birth, but HEU NK cells have reduced IFNγ and perforin production, suggesting an adequate initial response, but decreased functional reserve. NK cell function improved with addition of exogenous IL-12, implicating impaired production of IL-12 by accessory cells. Alterations in NK cell and accessory cell function may contribute to the increased susceptibility to infection in HEU infants.

Dataset Information

Lower mitochondrial DNA and altered mitochondrial fuel metabolism in HIV-exposed uninfected infants in Cameroon.

Publications

Lower mitochondrial DNA and altered mitochondrial fuel metabolism in HIV-exposed uninfected infants in Cameroon.

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