Human PrimPol: A Novel Mechanism of Antiviral Toxicity

Although significant advances in treating the nearly one million Americans infected with HIV-1 have been achieved with the use of antiviral nucleoside reverse transcriptase inhibitors (NRTIs), NRTI-associated mitochondrial toxicities and side effects pose serious risks of non-HIV related morbidity and challenge patient adherence to the daily drug regimens necessary to maintain reduced viral loads and prevent viral transmission. Prominent NRTI-associated toxicities arise from viral versus host polymerase selectivity, wherein NRTIs not only function to halt viral replication by chain termination for reverse transcriptase (RT) but can also serve as substrates for host polymerases and result in severe mitochondrial dysfunction. The recent discovery of a novel human primase-polymerase, PrimPol, operating in the mitochondria suggests a novel mechanism of antiviral toxicity that has yet to be explored. Biochemical experiments have been conducted to investigate mechanisms of PrimPol's catalytic activities and eva...