2010
DOI: 10.3390/v2020372
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The Role of Nucleotide Excision by Reverse Transcriptase in HIV Drug Resistance

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 t… Show more

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Cited by 19 publications
(16 citation statements)
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References 133 publications
(152 reference statements)
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“…HIV reverse transcriptase (RT) has nucleotide excision activity [7679] (Figure 4A). When RT incorporates a nucleoside analog, it can excise the incorporated nucleotide analog in an ATP-dependent fashion [7679].…”
Section: Reverse Transcriptase and Hiv Cell-to-cell Transmissionmentioning
confidence: 99%
See 1 more Smart Citation
“…HIV reverse transcriptase (RT) has nucleotide excision activity [7679] (Figure 4A). When RT incorporates a nucleoside analog, it can excise the incorporated nucleotide analog in an ATP-dependent fashion [7679].…”
Section: Reverse Transcriptase and Hiv Cell-to-cell Transmissionmentioning
confidence: 99%
“…HIV reverse transcriptase (RT) has nucleotide excision activity [7679] (Figure 4A). When RT incorporates a nucleoside analog, it can excise the incorporated nucleotide analog in an ATP-dependent fashion [7679]. Interestingly, when an HIV mutant defective in its ability to excise the nucleoside analog zidovudine was tested [80, 81], this drug was now able to effectively block HIV infection regardless of the mode of transmission.…”
Section: Reverse Transcriptase and Hiv Cell-to-cell Transmissionmentioning
confidence: 99%
“…R everse transcriptase (RT) of human immunodeficiency virus type 1 (HIV-1) is the key enzyme responsible for the synthesis of a double-stranded copy of the HIV genome that is subsequently integrated into the host chromosome during HIV infection. Treatment of HIV-1-infected patients with RT inhibitors such as 3=-deoxy-3=-azidothymidine (zidovudine, AZT) leads to selection of mutations in RT known as thymidine analogue resistance mutations (TAMs), which include M41L, D67N, K70R, L210W, T215Y or F, and K219Q or E. RTs containing various combinations of these mutations have an elevated excision activity that allows them to remove AZT monophosphate (AZTMP) and other chain-terminating nucleotides after they have been incorporated (1,2,10,33). Treatment of HIV-1-infected patients with (Ϫ)2=,3=-dideoxy-3=-thiacytidine (lamivudine, 3TC) or (Ϫ)2=, 3=-dideoxy-5-fluoro-3=-thiacytidine (emtricitabine, FTC) leads to selection of the M184I mutation in RT, which is rapidly replaced with M184V (7,25,52,57).…”
mentioning
confidence: 99%
“…With the exception of the chemokine receptor antagonists (CRAs), which bind a host protein involved in entry, antiretroviral drugs target virally encoded structures. Mutations in the viral genome appearing in response to specific drugs are well defined (summarized in Clark et al, 2007; Johnson et al, 2010), and, the molecular mechanisms by which these mutations confer resistance are understood (Acosta-Hoyos and Scott, 2010; Krishnan et al, 2010; Lobritz et al, 2010; Margeridon-Thermet and Shafer, 2011; Sarafianos et al, 2004; Wensing et al, 2010). Most resistance mutations interfere with drug binding.…”
Section: Hiv-1mentioning
confidence: 99%
“…The NRTIs are chain terminators lacking a 3′ hydroxyl group. Resistance to the thymidine analogue zidovudine (AZT) results from mutations that create a binding site on RT for ATP, the β and γ phosphates of which are positioned to function like pyrophosphate in an excision reaction that is the reverse of the reaction that incorporates the chain terminator (Acosta-Hoyos and Scott, 2010; Sarafianos et al, 2004). This remarkable adaptation can be viewed as the evolution of a new enzymatic activity that reverses drug inhibition.…”
Section: Hiv-1mentioning
confidence: 99%