Human endogenous retrovirus reverse transcriptase (HERV-RT) (HERV-RT)

Human endogenous retroviruses (HERVs) are genetic remnants of ancient germline infections that comprise approximately 8% of the human genome (Belshaw et al., 2004, Genome Research). While most HERVs are transcriptionally silent due to accumulated mutations and epigenetic repression, certain families, most notably HERV-K (HML-2), retain open reading frames capable of producing functional proteins, including reverse transcriptase (HERV-RT). HERV-RT is an enzyme that catalyzes the conversion of viral RNA into complementary DNA (cDNA), a process that can lead to genomic instability and the triggering of innate immune responses via the cGAS-STING pathway (Li et al., 2015, Science Translational Medicine). Pathological reactivation and high expression levels of HERV-RT have been specifically linked to the progression of neurodegenerative diseases like amyotrophic lateral sclerosis (ALS) and multiple sclerosis (MS), as well as various inflammatory and malignant conditions (Garcia-Montojo et al., 2018, Frontiers in Genetics). Therapeutic targeting of HERV-RT currently involves the repurposing of antiretroviral drugs, such as nucleoside reverse transcriptase inhibitors (NRTIs), which have shown potential in clinical trials to reduce viral load and slow functional decline in patients (Gold et al., 2019, Annals of Clinical and Translational Neurology). As a therapeutic target, HERV-RT offers a unique opportunity to address the underlying retroviral-like drivers of chronic inflammation and neurodegeneration.

Other names

HERV-K reverse transcriptaseHERV-W reverse transcriptaseEndogenous retrovirus Pol proteinRNA-directed DNA polymeraseHML-2 reverse transcriptase

Inhibition of the reverse transcription process by nucleoside or non-nucleoside analogs, preventing the synthesis of complementary DNA (cDNA) from endogenous retroviral RNA templates, thereby reducing retrotransposition-induced DNA damage and the activation of pro-inflammatory pathways such as the cGAS-STING pathway.