Mitochondrial toxicity and caspase activation in HIV pregnant women

Abstract

To assess the impact of HIV‐infection and highly active anti‐retroviral treatment in mitochondria and apoptotic activation of caspases during pregnancy and their association with adverse perinatal outcome. Changes of mitochondrial parameters and apoptotic caspase activation in maternal peripheral blood mononuclear cells were compared at first trimester of pregnancy and delivery in 27 HIV‐infected and ‐treated pregnant women versus 24 uninfected pregnant controls. We correlated immunovirological, therapeutic and perinatal outcome with experimental findings: mitochondrial DNA (mtDNA) content, mitochondrial protein synthesis, mitochondrial function and apoptotic caspase activation. The HIV pregnancies showed increased adverse perinatal outcome (OR: 4.81 [1.14–20.16]; P < 0.05) and decreased mtDNA content (42.66 ± 5.94%, P < 0.01) compared to controls, even higher in naïve participants. This depletion caused a correlated decrease in mitochondrial protein synthesis (12.82 ± 5.73%, P < 0.01) and function (20.50 ± 10.14%, P < 0.001), not observed in controls. Along pregnancy, apoptotic caspase‐3 activation increased 63.64 ± 45.45% in controls (P < 0.001) and 100.00 ± 47.37% in HIV‐pregnancies (P < 0.001), in correlation with longer exposure to nucleoside analogues. HIV‐infected women showed increased obstetric problems and declined genetic and functional mitochondrial parameters during pregnancy, especially those firstly exposed to anti‐retrovirals. The apoptotic activation of caspases along pregnancy is emphasized in HIV pregnancies promoted by nucleoside analogues. However, we could not demonstrate direct mitochondrial or apoptotic implication in adverse obstetric outcome probably because of the reduced sample size.

Pregnancy outcomes in perinatally HIV-infected young women in Madrid, Spain: 2000-2015

“…[ 12 ] Although the numbers are small to draw conclusions, it may be a matter of concern if confirmed in other studies with larger number of PHIV women. Further studies are needed to determine the causal mechanisms and the possible role of long-term exposure to ART [ 36 ] and chronic inflammation. [ 37 ] HIV-exposed children born SGA may thus warrant an appropriate follow-up throughout adulthood.…”

Antiretroviral Therapy for Mitochondrial Toxicity in HIV-Infected Pregnant Women

“…We included 5 observational studies among which four cross sectional studies and one prospective cohort study [5,7,8,12,13] (Table 1). The results were reported narratively.…”

“…All included studies included double-NRTI based regimens. Among them, three studies included AZT contained regimens [5,7,8]. As explained above, AZT based regimens may cause severe mitochondrial deflections implying highly statistically significant results in AZT based regimens studies.…”

“…In fact, mitochondrial defections have been associated with increased rates of preterm delivery, stillbirth, IUGR, and sudden infant death [5][6][7][8]. Reviewing the literature, ART can induce subclinical transplacental mitochondrial lesions.…”

Histopathological changes in Oreochromis mossambicus (Peters, 1852) ovaries after a chronic exposure to a mixture of the HIV drug nevirapine and the antibiotics sulfamethoxazole and trimethoprim

“…The negative effects observed in male HIV patients on HAART regimen include histopathological changes such as seminiferous tubules atrophy, and alteration in semen parameters including reduced sperm motility and altered sperm mitochondrial DNA ( Pavili et al., 2010 ; Savasi et al., 2019 ). Conflicting results have been reported on female HIV patients receiving the HAART; some studies reported no negative effects either on the reproductive system or the foetus ( Patel et al., 2005 ; Myer et al., 2010 ; Kushnir and Lewis 2011 ) while other studies reported impaired oocyte mitochondrial DNA that may lead to reduced fertility ( Lopez et al., 2008 ; Kushnir and Lewis 2011 ; Hernandez et al., 2017 ). Research data on rats treated with ARVs and their combinations have reported testicular alterations including degeneration of seminiferous tubules as well as a decrease in sperm motility in male rats ( Azu et al., 2014 ; Awodele et al., 2018 ; Oyeyipo et al., 2018 ).…”