Identifying the long-term metabolic complications of in-utero and lactational antiretroviral exposure

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Project Summary / Abstract The increased use of combination antiretroviral therapy (cART) has significantly reduced the perinatal transmission of HIV. However, as more HIV-infected women take cART, there is an increasing population of children exposed to cART in-utero and while nursing. The World Health Organization (WHO) now recommends dolutegravir (DTG)-based cART as first-line treatment for all people living with HIV, including pregnant women. Although early exposure to non-DTG based cART has been associated with bone and fat-related complications, the long-term consequences of in-utero and lactational exposure to DTG are completely unknown and will take decades to determine. The current proposal aims to address this gap in knowledge by leveraging banked bone and fat samples from an 18-month rat experiment to test the hypothesis that developmental exposure to DTG-based cART will cause lasting deleterious effects on bone and fat tissues. To test this hypothesis, we will determine the effects of in-utero and lactational exposure to DTG-based cART on (1) bone mass and quality using micro-computed tomography, Raman microspectroscopy, and mechanical testing and (2) fat tissue using RNAsequencing, RT-qPCR, and western blot analysis. The current proposal is significant because it addresses a critical clinical concern. The research question is timely, as DTG-based cART has become the recommended first line cART for all people living with HIV, including pregnant women. The hypothesis is conceptually innovative, as the metabolic consequences of early DTG exposure are unknown. Finally, the proposed aims are well-matched to the R03 programmatic goals as they represent a secondary analysis of an existing dataset. Results from this proposal will begin to establish the long-term effects of developmental exposure to DTG on bone and fat tissues and begin to determine the driving mechanisms.