HIV is notorious for the ability to escape many drugs designed to stop its action. However, these viruses do not readily develop resistance to tenofovir, a drug that inhibits a viral protein called reverse transcriptase (RT) that is crucial for replicating the viral genome. A study in the May issue of Nature Structural & Molecular Biology reports two related structures of RT with bound tenofovir. The results explain the unusually low resistance of HIV to tenofovir.
HIV RT synthesizes a single-stranded DNA based on the viral genome RNA template. Similar to other drugs in its class, tenofovir resembles one of the four building blocks of DNA and can be incorporated into the growing DNA chain by HIV RT. After incorporation, these inhibitors stop further chain growth, therefore preventing the production of new viral genome. However, HIV resistance to tenofovir develops much slower than that to other inhibitors in this class, such as AZT.
To understand the basis for this low resistance, Eddy Arnold and colleagues have determined the structures of HIV RT bound to RNA-DNA template-primer and tenofovir. The structures show that mutations in RT that could reduce tenofovir incorporation would also substantially diminish the natural function of the enzyme. Furthermore, incorporated tenofovir can escape 'correction' activity of RT by moving out of the active site of the enzyme with the growing chain. The structures thus provide insights into the mechanisms of HIV drug resistance.
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(C) Nature Structural & Molecular Biology press release.
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