Diminished efficiency of HIV-1 reverse transcriptase containing the K65R and M184V drug resistance mutations

Frankel, Fernando; Invernizzi, Cédric; Oliveira, Maureen; Wainberg, Mark A.

doi:10.1097/qad.0b013e3280187505

Cited by 47 publications

(54 citation statements)

References 55 publications

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“…Previous studies have shown that M184V added to a TAM background reduced excision on RNA templates (32,48,58,62) and DNA templates (9,21,22,27,38,49,62) by 16 to 58%, though no decrease was detected in one study (39). We found the effect on a DNA template to be variable, ranging from no effect to a 34% decrease.…”

Section: Discussionmentioning

confidence: 99%

“…K65R is also a suppressor of AZT resistance by TAMs (6,36,43,59), and AZTMP excision activity is reduced in RTs containing this mutation (21,36,59). In contrast to the results obtained with M184V, the addition of K65R to the RT D67N/K70R/T215Y/K219Q background reduced AZTMP excision activity to similar extents on both DNA (Fig.…”

Section: Figmentioning

confidence: 99%

“…Selection experiments in a TAM background resulted in M184V with no evidence of an M184I intermediate (30), and M184V is usually the only mutation detected at RT position 184 in HIV-1-infected patients undergoing prolonged 3TC therapy (53). The present study focused on M184V since it is the mutation most relevant to ongoing clinical suppression of AZT resistance.The biochemical basis of M184V suppression of TAMs has been the subject of several studies (9,21,22,27,32,38,39,49,58,62). Typically, the M184V mutation confers a reduction in excision activity that can be observed on either RNA or DNA templates.…”

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confidence: 99%

“…The biochemical basis of M184V suppression of TAMs has been the subject of several studies (9,21,22,27,32,38,39,49,58,62). Typically, the M184V mutation confers a reduction in excision activity that can be observed on either RNA or DNA templates.…”

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confidence: 99%

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A Role of Template Cleavage in Reduced Excision of Chain-Terminating Nucleotides by Human Immunodeficiency Virus Type 1 Reverse Transcriptase Containing the M184V Mutation

Acosta-Hoyos

Matsuura

Meyer

et al. 2012

J Virol

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Resistance to nucleoside reverse transcriptase (RT) inhibitors is conferred on human immunodeficiency virus type 1 through thymidine analogue resistance mutations (TAMs) that increase the ability of RT to excise chain-terminating nucleotides after they have been incorporated. The RT mutation M184V is a potent suppressor of TAMs. In RT containing TAMs, the addition of M184V suppressed the excision of 3′-deoxy-3′-azidothymidine monophosphate (AZTMP) to a greater extent on an RNA template than on a DNA template with the same sequence. The catalytically inactive RNase H mutation E478Q abolished this difference. The reduction in excision activity was similar with either ATP or pyrophosphate as the acceptor substrate. Decreased excision of AZTMP was associated with increased cleavage of the RNA template at position −7 relative to the primer terminus, which led to increased primer-template dissociation. Whether M184V was present or not, RT did not initially bind at the −7 cleavage site. Cleavage at the initial site was followed by RT dissociation and rebinding at the −7 cleavage site, and the dissociation and rebinding were enhanced when the M184V mutation was present. In contrast to the effect of M184V, the K65R mutation suppressed the excision activity of RT to the same extent on either an RNA or a DNA template and did not alter the RNase H cleavage pattern. Based on these results, we propose that enhanced RNase H cleavage near the primer terminus plays a role in M184V suppression of AZT resistance, while K65R suppression occurs through a different mechanism.

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Section: Discussionmentioning

confidence: 99%

Section: Figmentioning

confidence: 99%

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confidence: 99%

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confidence: 99%

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A Role of Template Cleavage in Reduced Excision of Chain-Terminating Nucleotides by Human Immunodeficiency Virus Type 1 Reverse Transcriptase Containing the M184V Mutation

Acosta-Hoyos

Matsuura

Meyer

et al. 2012

J Virol

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“…64 Furthermore, the presence of the M184V/I mutation typically results in impaired viral replication capacity, which has been shown to decrease HIV RNA levels by about 0.5 logs. 65,66 When ABC + 3TC are used in combination with another class, the M184V mutation typically appears first and most frequently; the K65R mutation and L74V mutation are seen much less frequently. The abacavir-selected mutations K65R, L74V and Y115F each individually confer about three-to fourfold resistance to ABC, but in combinations of 2 or 3, they confer up to 8-to 10-fold resistance.…”

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confidence: 99%