The Impact of Human Immunodeficiency Virus (HIV) Antiretroviral Drug Exposure in Utero on Later Fertility

Candidate: Saba Zafar

Supervisor: Dr. Sarah Sabatinos

Abstract:
Human immunodeficiency virus (HIV) antiretroviral drugs reduce the risk of HIV transmission from mother to child during pregnancy. The World Health Organization (WHO) recommends that all pregnancy women living with HIV should be treated with combination antiretroviral therapy, which includes at least three different HIV drugs, most often two nucleoside reverse transcriptase inhibitors (NRTI), plus either a protease inhibitor (PI), a non-NRTI, or an integrase strand transfer inhibitor. The efficacy of combination antiretroviral therapy has been extensively studies, but a significant knowledge gap exists concerning the effects of in utero exposure to these drugs on developing fetuses. We have previously shown that exposure to a different combination antiretroviral therapies can variably disrupt hormones necessary for a healthy pregnancy. Hormonal dysregulation is pregnancy could have long-term effects on offspring reproductive development and fertility. Using fission yeast, we have also observed that specific types of antiretrovirals prescribed during pregnancy increase DNA mutations. In this project, we assessed whether HIV antiretrovirals commonly used in pregnancy reduce later fertility. We hypothesized that in utero antiretroviral exposure lowers reproductive potential by reducing genomic stability and adversely affecting meiotic development. Using S. pombe, we have shown that genomic stability but not toxicity is adversely affected after dual-NRTI exposure. In our mouse pregnancy model, we have used hematoxylin and eosin (H&E) staining to analyze gonad morphology. We have observed low Sertoli cell numbers and altered seminiferous tubule morphology in male mice exposed to cART in utero¸ thus indicating an adverse effect on meiotic development. Meiotic development in female mice exposed to cART in utero was not affected. However, our study of in utero effects is limited in sample size and we aim to improve this by quantifying more gonad sections. Ultimately, we hope to find the safest drug regimen for pregnancy women living with HIV and provide more insight on the potential long-term fertility issues faced by children previously exposed to antiretrovirals in utero.