Human immunodeficiency virus type 1 reverse transcriptase (HIV-1 RT) (HIV-1 RT)

Human immunodeficiency virus type 1 reverse transcriptase (HIV-1 RT) is a multifunctional enzyme essential for the replication of HIV-1. It converts the viral single-stranded RNA genome into double-stranded DNA, a process required for integration into the host cell genome (UniProt P03366). The enzyme exists as a p66/p51 heterodimer and possesses RNA-dependent DNA polymerase, DNA-dependent DNA polymerase, and RNase H activities (NIH, 2023). Islatravir (MK-8591) is a novel nucleoside reverse transcriptase translocation inhibitor (NRTTI) that targets this enzyme with high potency. Unlike traditional NRTIs, islatravir contains a 4'-ethynyl group that enables a dual mechanism: it functions as a chain terminator and physically blocks the translocation of the enzyme along the DNA template (Michailidis et al., 2014). While islatravir shows a high genetic barrier to resistance, its clinical development has been impacted by observations of dose-dependent decreases in total lymphocyte and CD4+ T-cell counts (Merck, 2022).

Other names

RNA-directed DNA polymerasep66/p51 heterodimerHIV-1 Pol proteinReverse transcriptase

Islatravir is a nucleoside reverse transcriptase translocation inhibitor (NRTTI). It is phosphorylated intracellularly to its active triphosphate form, which binds to the active site of HIV-1 reverse transcriptase, acting as a chain terminator and preventing the translocation of the primer-template complex, thereby halting viral DNA synthesis (Michailidis et al., 2014; PubMed, 2021).