We also selleck compound previously showed an increased mtDNA level in HIV/ART-exposed infants at birth compared with controls in an AIDS Clinical Trials Group study [13]. A primate study showed comparable results with pregnant Erythrocebus patas monkeys who received human-equivalent doses of various combinations of NRTIs for the last 20% or 50% of gestation, which was continued in the infants for 6 weeks after birth [25]. Hearts from the 1-year-old ART-exposed monkeys were then analysed and all were found to have elevated levels of mtDNA compared with controls. Interestingly, in a study evaluating
HIV-infected children receiving ART, investigators similarly showed increases in mtDNA levels longitudinally as the duration of ART exposure increased [26]. Finally, another study that investigated mtDNA content in HIV-exposed, yet uninfected infants showed that mtDNA levels increased progressively in infants depending on whether they were exposed to HIV without ART vs. HIV and only ZDV vs. HIV and a combination of NRTIs, respectively [8]. While the aforementioned studies
all support our data, there are some studies that have shown mtDNA depletion [7,9,10,28] or no difference in mtDNA content in HIV/ART-exposed infants compared with controls [11]. The discrepancies in these studies, and the inconsistencies with our data, may be attributable to differences Alpelisib mw in the timing of the ART exposure during pregnancy, and/or the length of the exposure, and/or the number of NRTIs that comprise the exposure. In support of this possibility,
a study investigating chronic exposure of HeLA cells to ZDV found that ZDV induced an abnormal proliferation of mitochondria at earlier passages, but by later passages there was widespread mitochondrial morphological damage and severe mtDNA depletion [29]. Also, mice enough models have suggested that a cumulative NRTI dose (i.e. ZDV+3TC) is more damaging than either ZDV or 3TC alone [30,31]. This may also partly explain why studies have produced conflicting results regarding whether perinatal ART exposure causes increased serum lactate levels [32–34], a sign of mitochondrial toxicity. For example, lactate levels were similar in HIV-exposed infants compared with controls in a study in the Ivory Coast; however, infants were exposed to ZDV for either 4 or 8 weeks in utero and for 1 week postnatally or were given an NRTI-sparing regimen [34]. Conversely, in another study that showed increased lactate levels in ART-exposed infants, 92% of infants were exposed in utero to at least three antiretrovirals for a mean duration of 17 weeks and received a mean of 5 weeks of postnatal ZDV [33].
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