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Structure and Function of HIV-1 Reverse Transcriptase: Molecular Mechanisms of Polymerization and Inhibition

Christopher Bond Life Sciences Center, Department of Molecular Microbiology & Immunology, University of Missouri School of Medicine, Columbia, MO 65211, USA.
Journal of Molecular Biology (Impact Factor: 4.33). 12/2008; 385(3):693-713. DOI: 10.1016/j.jmb.2008.10.071
Source: PubMed

ABSTRACT The rapid replication of HIV-1 and the errors made during viral replication cause the virus to evolve rapidly in patients, making the problems of vaccine development and drug therapy particularly challenging. In the absence of an effective vaccine, drugs are the only useful treatment. Anti-HIV drugs work; so far drug therapy has saved more than three million years of life. Unfortunately, HIV-1 develops resistance to all of the available drugs. Although a number of useful anti-HIV drugs have been approved for use in patients, the problems associated with drug toxicity and the development of resistance means that the search for new drugs is an ongoing process. The three viral enzymes, reverse transcriptase (RT), integrase (IN), and protease (PR) are all good drug targets. Two distinct types of RT inhibitors, both of which block the polymerase activity of RT, have been approved to treat HIV-1 infections, nucleoside analogs (NRTIs) and nonnucleosides (NNRTIs), and there are promising leads for compounds that either block the RNase H activity or block the polymerase in other ways. A better understanding of the structure and function(s) of RT and of the mechanism(s) of inhibition can be used to generate better drugs; in particular, drugs that are effective against the current drug-resistant strains of HIV-1.

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    • "Reverse transcription and reverse transcriptases All retroviruses, as well as retrotransposons, undergo a unique DNA synthesis process called reverse transcription, which converts single stranded RNA genomes into double stranded DNA. This process is catalyzed by virally encoded DNA polymerases, reverse transcriptases (RT) (reviewed in Hu and Hughes, 2012; Sarafianos et al., 2009). Unlike cellular DNA polymerases, which synthesize DNA from DNA templates, RTs can execute DNA polymerization from RNA templates as well. "
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    • "Reverse transcription consists of a complex series of reactions that culminate in conversion of the single-stranded viral RNA genome into a linear, double-stranded DNA copy that is ultimately integrated into host chromosomal DNA (reviewed in Herschhorn and Hizi, 2010; Sarafianos et al., 2009). This process is catalyzed by the viral reverse transcriptase (RT) enzyme (Baltimore, 1970; Mizutani et al., 1970). "
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    • "The synthesis of the DNA first strand is initiated from the region of polypurine from the genomic RNA that is resistant to RNase-H and that remains on the new negative strand of DNA (-). All other reverse transcription steps include elongation of the primer DNA (Brautigam & Steitz, 1998; Sarafianos et al., 2009). HIV-1 RT has the ability to interact with substrates of different conformational structures (doublestranded DNA and single stranded RNA), but with low fidelity or processing capacity. "
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