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Mitochondrial DNA and sperm quality in patients under antiretroviral therapy
  Antiretroviral therapy (ART) decreases HIV-associated morbidity and mortality by reducing viral concentrations in plasma, and may also decrease HIV transmissibility by decreasing viral shedding in the semen. In seminal plasma, some nucleoside analogue reverse transcriptase inhibitors (NRTI; zidovudine, didanosine and lamivudine) have been identified in high concentrations, whereas others (abacavir) were found to be rapidly cleared from the male genital tract. Recently, several side-effects of ART have been associated with the prolonged use of NRTI and their ability to inhibit polymerase gamma, the enzyme responsible for the replication of mitochondrial DNA. Decreased mtDNA levels have been identified in the subcutaneous adipose tissue of patients suffering from HIV-associated lipoatrophy, and it has been suggested that mtDNA levels in the blood might be employed to monitor this form of toxicity. A functionally intact mitochondrial genome is also pivotal to sperm motility. Any toxic effect of ART on sperm quality may have important clinical implications with regard to the fertilization technique, as artificial insemination with motile, virus-free spermatozoa prepared from HIV-infected men is used in HIV-discordant couples wishing to conceive.
We performed a cross-sectional study to investigate whether mtDNA depletion resulting from long-term NRTI use might be identified in the seminal compartment. We explored whether such a depletion might be associated with a reduced quantity or quality of sperm.
Semen samples were collected after at least 4 days of sexual abstinence from 31 consecutive HIV-positive patients willing to give written informed, ethics committee-approved, consent. At the time of semen collection, 24 HIV patients were receiving ART and seven were not (five ART-naive). An additional seven HIV-negative individuals with normal mobility were analysed. After liquefaction, the sperm count and motility was recorded according to WHO standards. Genomic DNA was extracted from an aliquot of the ejaculate and mtDNA was quantified using a Southern blot technique.
There was no statistical difference with regard to the mtDNA content and sperm characteristics (sperm count, motility) between HIV patients receiving ART, HIV patients without ART, or HIV-negative individuals. The sperm count, sperm motility and mtDNA content varied widely within all groups, the standard deviation of the means being in the order of 50, 30 and 50%, respectively. 'D' drugs consisting of didanosine (ddI), zalzitabine (ddC) and stavudine (d4T) are thought to be relatively strong inhibitors of mtDNA replication, but there was no statistical difference with regard to the sperm count, sperm motility and mtDNA content when the HIV-positive patients were divided into a subgroup (n = 19) currently receiving any of the 'd' drugs and a subgroup not currently receiving 'd' drugs (n = 12). However there was a weak negative correlation between the time on 'd' drugs with the mtDNA content (P = 0.04, r = 0.44). None of the groups and subgroups differed with regard to the CD4 cell count and viral load (when applicable). MtDNA deletions were never observed.
Our study may have a number of limitations. Seminal fluid contains cells other than spermatozoa, and an influence of these sperm components on our measurements cannot be ruled out. We observed epithelial cells in a relative frequency of up to 20% in some of our samples, and these cells are likely to harbour higher copy numbers of mtDNA per cell than spermatocytes. The stage of HIV disease itself may also have an influence on sperm function, as a correlation between the CD4 cell count and sperm motility has been identified by others. Finally, an effect of ART on sperm count, sperm motility and mtDNA content may have been obscured by the high inter-individual variability of the parameters in each group. We conclude that sperm does not appear to be useful in monitoring mitochondrial toxicity, but that longitudinal studies are prudent to rule out the potential adverse effects of ART on the reproductive tract.
AIDS 2003; 17(3):450-451
Susanne Diehla; Pietro Vernazzab; Andreas Treinc; Eiko Schnaitmannc; Bodo Grimbachera; Bernhard Setzera; Ulrich A. Walkera aMedizinische UniversitŠtsklinik, Department of Rheumatology and Clinical Immunology, Freiburg, Germany; bKantonsspital, St Gallen, Switzerland; and cHIV-Practice, Stuttgart, Germany.
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