Elijah Paintsil, FAAP, MD

Our research focuses on understanding the determinants of individual differences in response to antiretroviral therapy (ART) (e.g., virologic suppression, resistance evolution, and clinical toxicities). This research interest was fostered by an NIH career development award (K08) from 2008 to 2013. During this period, we studied various host determinants such as individual differences in the intracellular concentrations of antiretroviral drugs, cellular kinases involved in the phosphorylation of nucleoside analogs, and ATP-binding Cassette (ABC) transport proteins, and effect of treatment on mitochondrial function. These findings challenged the existing paradigm that only nucleoside reverse transcriptase inhibitors (NRTIs) caused mitochondrial dysfunction through inhibition of mitochondrial DNA polymerase gamma (Pol-ɣ) – the “Pol-ɣ hypothesis.” The studies identified other Pol-ɣ-independent pathways that can lead to mitochondrial dysfunction such as depletion of nucleotide pool and mitochondria DNA mutations. This led to the development of the novel hypothesis that ART causes mitochondrial dysfunction through both pol-γ-dependent and pol-γ-independent mechanisms, which results in a decrease in cellular dNTP and rNTP pools and genomic instability resulting in clinical toxicity and aging-related disorders in HIV-infected.