Journal of Molecular Biology
Volume 385, Issue 3, 23 January 2009, Pages 693-713
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Review
Structure and Function of HIV-1 Reverse Transcriptase: Molecular Mechanisms of Polymerization and Inhibition

https://doi.org/10.1016/j.jmb.2008.10.071Get rights and content

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.

Section snippets

Role of HIV-1 reverse transcriptase in viral replication

Viral infections are initiated by the fusion of the viral and cellular membranes; this fusion reaction is caused by the interactions of the viral envelope glycoprotein with its receptor (CD4) and a co-receptor, usually either CCR5 or CXCR4 (for a review of the retroviral life-cycle, and an overview of reverse transcription, see Ref. 1). Binding the receptor and co-receptor causes changes in the structure of the envelope glycoprotein, which leads to membrane fusion. Membrane fusion places the

Structure of HIV-1 reverse transcriptase

The RT of HIV-1 is an asymmetric heterodimer composed of two related subunits, p66 and p51. Both subunits derive, by cleavage by the viral protease (PR), from a Gag-Pol polyprotein that is synthesized from unspliced viral RNA.4, 5 p66 and p51 share a common amino terminus; p66 is 560 amino acids in length, p51 is 440 amino acids long. As has been discussed briefly, both of the enzymatic functions of RT, the DNA polymerase and RNase H, are essential for copying the single-stranded RNA genome

Molecular mechanism of polymerization

The mechanism of DNA polymerization by HIV RT is reasonably well understood; extensive biochemical and crystallographic data have helped define the individual steps of the process (Fig. 4). The reaction begins with the binding of RT to the nucleic acid substrate, which results in a conformational change in the position of the p66 thumb, from a closed to an open conformation. Like many other DNA polymerases, RT requires both a primer and a template. In most sequence contexts, RT preferentially

Molecular mechanism of RNase H activity

As mentioned earlier, RNase H is responsible for the degradation of the RNA portion of the RNA/DNA substrate that is formed during minus strand synthesis. It is responsible also for the removal of the priming tRNA108, 109 and the PPT.110 Viruses deficient in RNase H activity are non-infectious,111, 112 making RNase H an interesting target for anti-HIV inhibitors. HIV-1 RNase H was the first segment of RT to be crystallized.113 It was shown to be structurally similar to other forms of RNase H,

Acknowledgements

S.G.S. acknowledges support by NIH (grants AI076119, AI079801, and AI074389). Support for B.M. comes from an amfAR Mathilde Kim Fellowship grant. S.H.H. was supported by the Intramural Research Program of NIH, NCI, Center for Cancer Research, and NIGMS. M.A.P. was supported by NIH grants AI060452, AI73975, AI076119, AI07980. E.A. is grateful for support from NIH (grants AI27690 MERIT Award and P01 GM 066671).

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