Viral reverse transcriptases

Abstract

Reverse transcriptases (RTs) play a major role in the replication of Retroviridae, Metaviridae, Pseudoviridae, Hepadnaviridae and Caulimoviridae. RTs are enzymes that are able to synthesize DNA using RNA or DNA as templates (DNA polymerase activity), and degrade RNA when forming RNA/DNA hybrids (ribonuclease H activity). In retroviruses and LTR retrotransposons (Metaviridae and Pseudoviridae), the coordinated action of both enzymatic activities converts single-stranded RNA into a double-stranded DNA that is flanked by identical sequences known as long terminal repeats (LTRs). RTs of retroviruses and LTR retrotransposons are active as monomers (e.g. murine leukemia virus RT), homodimers (e.g. Ty3 RT) or heterodimers (e.g. human immunodeficiency virus type 1 (HIV-1) RT). RTs lack proofreading activity and display high intrinsic error rates. Besides, high recombination rates observed in retroviruses are promoted by poor processivity that causes template switching, a hallmark of reverse transcription. HIV-1 RT inhibitors acting on its polymerase activity constitute the backbone of current antiretroviral therapies, although novel drugs, including ribonuclease H inhibitors, are still necessary to fight HIV infections. In Hepadnaviridae and Caulimoviridae, reverse transcription leads to the formation of nicked circular DNAs that will be converted into episomal DNA in the host cell nucleus. Structural and biochemical information on their polymerases is limited, although several drugs inhibiting HIV-1 RT are known to be effective against the human hepatitis B virus polymerase. In this review, we summarize current knowledge on reverse transcription in the five virus families and discuss available biochemical and structural information on RTs, including their biosynthesis, enzymatic activities, and potential inhibition.

Keywords: Antiviral drugs; DNA polymerase; Fidelity; HIV; Hepatitis B virus; Retrovirus; Reverse transcriptase; Ribonuclease H.