Abstract
Nucleoside reverse transcriptase (RT) inhibitors of HIV block viral replication through the ability of HIV RT to incorporate chain-terminating nucleotide analogs during viral DNA synthesis. Once incorporated, the chain-terminating residue must be removed before DNA synthesis can continue. Removal can be accomplished by the excision activity of HIV RT, which catalyzes the transfer of the 3′-terminal residue on the blocked DNA chain to an acceptor substrate, probably ATP in most infected cells. Mutations of RT that enhance excision activity are the most common cause of resistance to 3′-azido-3′-deoxythymidine (AZT) and exhibit low-level cross-resistance to most other nucleoside RT inhibitors. The resistance to AZT is suppressed by a number of additional mutations in RT, most of which were identified because they conferred resistance to other RT inhibitors. Here we review current understanding of the biochemical mechanisms responsible for increased or decreased excision activity due to these mutations.
Highlights
Reverse transcriptase (RT) is the replication enzyme for HIV and a major target for antiretroviral drug development
Enhanced nucleotide-dependent excision is a major mechanism of AZT resistance by mutants of HIV-1 and these mutations confer some degree of resistance to most nucleoside RT inhibitors (NRTIs)
Mutations in RT that enhance excision act primarily on the catalytic rate and stimulate the reverse reaction, suggesting that they facilitate the formation of a reaction intermediate that is rate-limiting for the reaction in both directions
Summary
Reverse transcriptase (RT) is the replication enzyme for HIV and a major target for antiretroviral drug development. Specific RNA fragments (characterized by the presence of a polypurine tract (PPT) sequence) preferentially escape displacement or degradation and serve as primers for initiation of second strand (plus-strand) DNA synthesis at two sites on the genome of HIV. Drugs that inhibit HIV replication by this mechanism are termed nucleoside RT inhibitors (NRTIs). [Table 1], and several additional NRTIs are currently in pre-clinical and clinical stages of development Another class of RT inhibitors (non-nucleoside RT inhibitors, NNRTIs) acts by binding to a separate site on the enzyme and allosterically inhibiting DNA synthesis. Zalcitabine (ddC), which is not currently in use, is FDA approved; From the current listing of mutations associated with antiretroviral drug resistance compiled by the International AIDS Society—USA, Drug Resistance Mutations Group [19]; Prodrug is tenofovir disoproxil fumarate (TDF)
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