Department of Molecular Microbiology, School of Biotechnology, Madurai Kamaraj University, Madurai – 625 021, India
Research Article
World Journal of Advanced Research and Reviews, 2024, 22(03), 409-426
Received on 26 April 2024; revised on 04 June 2024; accepted on 06 June 2024
It is well-known that human immunodeficiency viruses (HIVs) cause the chronic, potentially life-threatening condition known as human Acquired Immuno-Deficiency Syndrome (AIDS). As the lifecycle of HIVs heavily depends on the crucial enzyme, the reverse transcriptase (RT), it has been used as a potential therapeutic target to treat and control the spread of AIDS. The active site amino acids of the polymerase domain of the RTs and their anti-HIV drug-binding sites are analyzed. The catalytic region of HIV RTs and the E. coli DNA polymerase I showed very similar active site amino acids, suggesting that HIV RTs would have possibly evolved from the bacterial DNA polymerase. The catalytic proton abstractor is identified as a K and the nucleotide selection amino acid as an N. However, the regular template-binding pair –YG- is slightly modified to a –YXG- in HIV RTs. Three completely conserved Ds in HIV RTs are involved in binding to the catalytic Mg2+. The sensitive and resistant strains of HIV-1 for the HIV antiretroviral drug, azidothymidine (AZT), a nucleoside analogue of thymidine, show only a few non-isofunctional amino acid replacements and are located mainly in the palm and thumb subdomains of the RT polymerase, whereas the rest of the polymerase catalytic core and metal-binding sites are completely conserved in AZT-sensitive and -resistant HIV-1 strains. In the drug-resistant mutants of non-nucleoside RT inhibitors of HIV-2, the crucial mutations are located mainly near the -MDD- motif of the catalytic metal-binding region. Even though a large number of amino acid replacements are seen between the RTs of HIV-1 and HIV-2, the polymerase active sites are completely conserved in both. The HIV-1 and HIV-2 catalytic and metal-binding sites are completely conserved in simian immunodeficiency virus (SIV) as well. The absence of DEDD-superfamily of proofreading exonuclease domain in the HIV RTs, might cause the virus to evolve rapidly in patients. A possible mechanism of action for the HIV RTs is also proposed.
Human Immunodeficiency Viruses; AIDS; Reverse Transcriptases; Reverse Transcriptase Inhibitors; Polymerase Domain; Active Sites; Mechanism of Action.
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Peramachi Palanivelu. Human Immunodeficiency Viral Reverse Transcriptases: Analyses of the Active Sites of the Polymerase Domain and Drug-Resistant Mutants of the Reverse Transcriptases. World Journal of Advanced Research and Reviews, 2024, 22(3), 409-426. Article DOI: https://doi.org/10.30574/wjarr.2024.22.3.1699