Mitochondrial genome study in HIV pregnancies: beyond depletion and over time
 
Morén C¹, Carreño L², Sánchez E³, González I¹, Noguera A⁴, Guitart M¹, Juárez-Flores D¹, Cardellach F¹, Garrabou G¹, Garcia E², Fortuny C^4
1IDIBAPS-CIBERER-UB-HCB, Spain; ²Vall Hebron-CIBERER, Barcelona, Spain; ³Blanquerna School of Health Science, Ramon Llull University, Barcelona, Spain; ⁴Infectious Diseases Unit, Hospital Sant Joan de Déu of Barcelona, Spain
 
Whether mutational changes rely at the basis of nucleoside-reverse-transcriptase-inhibitors-(NRTIs)-derived mtDNA depletion and whether recent ART present lower mitochondrial toxicity than earlier ones remain unclear. We aimed to assess the presence of mutations and depletion of mtDNA in the context of HIV-infected pregnant women and their exposed infants.
Subjects: 48 HIV-infected-mothers, who received ART during pregnancy and/or at childbirth (34-corresponded to 2007-2009 and 14 to 2014-2015 periods) and their 50-exposed infants (36 belonged to the first period, most of whom exposed to ZDV, d4T and/or ddI, and 14 to the second where only 5 of them were exposed to ZDV), and a control group of 29-pairs of HIV-uninfected controls. Mitochondrial genome studies were performed in peripheral-blood-mononuclear-cells obtained simultaneously 6-weeks after birth from the mother and the infant. Long range PCR was used to study heteroplasmic mutations. Sample libraries were prepared [Nextera-XT-kit-Illumina] and sequenced (MiSeq). mtDNA content was measured by multiplex qrPCR (mt12SrRNA/nRNAseP).Significant mtDNA depletion typically observed in HIV-patients receiving NRTIs was confirmed in our cohorts when compared to controls. MtDNA content showed significant differences between the two periods in mothers: [Period 2007-2009 48.9 (19.1 - 71.8) vs Period 2014-2015 101.1 (58.8 - 161.1), p=0.002] as well as in infants [2007-2009 period 47.4 (22.9 - 72.0) vs 2014-2015 period 94.2 (77.7 - 215.6), p <0.001]. Regarding mutations, mothers (mean±SD: 4.33±3.67) and infants (3.71±3.47) from Period 2007-2009 showed a non-significant higher number of mtDNA heteroplasmic variants when compared to Period 2014-2015 group (3.21±2.83 in mothers, p=0.326; and 3.00±2.15 in infants, p=0.418). Our findings suggest that newer ART-regimens are less toxic to mitochondria, both for HIV-infected pregnant women and their HIV-uninfected ART-exposed babies. MtDNA content was significantly higher in Period 2014-2015 and heteroplasmic variants do not differ between periods.