Biochemical Mechanism of HIV-1 Resistance to Rilpivirine

Singh, Kamalendra; Marchand, Bruno; Devendra, K.; Sharma, Bechan; Michailidis, Eleftherios; Ryan, Emily M.; Matzek, Kayla B.; Leslie, Maxwell D.; Hagedorn, Ariel N.; Li, Zhe; Norden, Pieter R.; Hachiya, Atsuko; Parniak, Michael A.; Xu, Hongtao; Wainberg, Mark A.; Sarafianos, Stefan G.

doi:10.1074/jbc.m112.398180

Cited by 62 publications

(72 citation statements)

References 98 publications

(118 reference statements)

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“…The mechanism of E138K-mediated RPV resistance is an increase in the dissociation rate of RPV, which overcomes a smaller enhancement in its rate of association (11). E138K and M184I/V have a mutual compensatory effect in regard to RT processivity and viral replication capacity (9,11,43,44). However, unlike N348I, E138K is relatively rare in treatment-experienced patients (40,(45)(46)(47), despite the fact that it can mutually compensate for M184I/V (43,44).…”

mentioning

confidence: 93%

“…Although E138K confers modestly reduced susceptibility to ETR and RPV (37)(38)(39)(40), it does not result in reduced susceptibility to EFV and NVP (40)(41)(42). The mechanism of E138K-mediated RPV resistance is an increase in the dissociation rate of RPV, which overcomes a smaller enhancement in its rate of association (11). E138K and M184I/V have a mutual compensatory effect in regard to RT processivity and viral replication capacity (9,11,43,44).…”

mentioning

confidence: 99%

“…The polymerase domain consists of the finger, palm, and thumb subdomains, which are analogous to a right hand in shape (7). Subunit-specific mutational analyses have shown that p51 is involved in the fine-tuning of RT enzymatic activities (8)(9)(10)(11).…”

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confidence: 99%

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The Connection Domain Mutation N348I in HIV-1 Reverse Transcriptase Enhances Resistance to Etravirine and Rilpivirine but Restricts the Emergence of the E138K Resistance Mutation by Diminishing Viral Replication Capacity

Colby-Germinario

Oliveira

et al. 2014

J Virol

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Clinical resistance to rilpivirine (RPV), a novel nonnucleoside reverse transcriptase (RT) inhibitor (NNRTI), is associated an E-to-K mutation at position 138 (E138K) in RT together with an M184I/V mutation that confers resistance against emtricitabine (FTC), a nucleoside RT inhibitor (NRTI) that is given together with RPV in therapy. These two mutations can compensate for each other in regard to fitness deficits conferred by each mutation alone, raising the question of why E138K did not arise spontaneously in the clinic following lamivudine (3TC) use, which also selects for the M184I/V mutations. In this context, we have investigated the role of a N348I connection domain mutation that is prevalent in treatment-experienced patients. N348I confers resistance to both the NRTI zidovudine (ZDV) and the NNRTI nevirapine (NVP) and was also found to be associated with M184V and to compensate for deficits associated with the latter mutation. Now, we show that both N348I alone and N348I/ M184V can prevent or delay the emergence of E138K under pressure with RPV or a related NNRTI, termed etravirine (ETR). N348I also enhanced levels of resistance conferred by E138K against RPV and ETR by 2.2-and 2.3-fold, respectively. The presence of the N348I or M184V/N348I mutation decreased the replication capacity of E138K virus, and biochemical assays confirmed that N348I, in a background of E138K, impaired RT catalytic efficiency and RNase H activity. These findings help to explain the low viral replication capacity of viruses containing the E138K/N348I mutations and how N348I delayed or prevented the emergence of E138K in patients with M184V-containing viruses.

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The Connection Domain Mutation N348I in HIV-1 Reverse Transcriptase Enhances Resistance to Etravirine and Rilpivirine but Restricts the Emergence of the E138K Resistance Mutation by Diminishing Viral Replication Capacity

Colby-Germinario

Oliveira

et al. 2014

J Virol

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“…The K d values of rilpivirine, efavirenz, and nevirapine have been reported in the literatures. 31,32) described. 14) Briefly, the heterodimeric HIV-1 RT protein was purified from cell lysates with sequential use of a diethylaminoethyl (DEAE) cellulose column (Whatman), phosphocellulose P11 column (Whatman), Chelating Sepharose Fast Flow (GE Healthcare) charged with nickel sulfate, and RESOURCE S column (GE Healthcare).…”

Section: Preparation Of Hiv-1 Rt Proteinmentioning

confidence: 99%

Mass Spectrometric Characterization of HIV-1 Reverse Transcriptase Interactions with Non-nucleoside Reverse Transcriptase Inhibitors

Thammaporn

Ishii

Yagi-Utsumi

et al. 2016

Biological & Pharmaceutical Bulletin

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Non-nucleoside reverse transcriptase inhibitors (NNRTIs) of human immunodeficiency virus type 1 reverse transcriptase (HIV-1 RT) have been developed for the treatment of acquired immunodeficiency syndrome. HIV-1 RT binding to NNRTIs has been characterized by various biophysical techniques. However, these techniques are often hampered by the low water solubility of the inhibitors, such as the current promising diarylpyrimidine-based inhibitors rilpivirine and etravirine. Hence, a conventional and rapid method that requires small sample amounts is desirable for studying NNRTIs with low water solubility. Here we successfully applied a recently developed mass spectrometric technique under non-denaturing conditions to characterize the interactions between the heterodimeric HIV-1 RT enzyme and NNRTIs with different inhibitory activities. Our data demonstrate that mass spectrometry serves as a semi-quantitative indicator of NNRTI binding affinity for HIV-1 RT using low and small amounts of samples, offering a new high-throughput screening tool for identifying novel RT inhibitors as anti-HIV drugs.

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“…The mechanism of viral resistance to RPV has been studied using transient kinetics approaches (quench-flow and stopped-flow) transient kinetics approaches to determine how subunit-specific mutations in p66 or p51 subunits of HIV-1RT influence association and dissociation of RPV to the NNRIs' binding hydrophobic pocket in RT. They have suggested that E138K mutation in p51 confers reduced susceptibility to RPV in presence and absence of M184V mutation [20].…”

Section: Editorialmentioning

confidence: 99%

Drug Resistance in HIV-1: Genetic and Molecular Bases, Mechanisms and Strategies to Combat the Issue

2014

Biochem Anal Biochem

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Biochemical Mechanism of HIV-1 Resistance to Rilpivirine

Cited by 62 publications

References 98 publications

The Connection Domain Mutation N348I in HIV-1 Reverse Transcriptase Enhances Resistance to Etravirine and Rilpivirine but Restricts the Emergence of the E138K Resistance Mutation by Diminishing Viral Replication Capacity

The Connection Domain Mutation N348I in HIV-1 Reverse Transcriptase Enhances Resistance to Etravirine and Rilpivirine but Restricts the Emergence of the E138K Resistance Mutation by Diminishing Viral Replication Capacity

Mass Spectrometric Characterization of HIV-1 Reverse Transcriptase Interactions with Non-nucleoside Reverse Transcriptase Inhibitors

Drug Resistance in HIV-1: Genetic and Molecular Bases, Mechanisms and Strategies to Combat the Issue

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