HIV-1 Reverse Transcriptase (RT) Polymorphism 172K Suppresses the Effect of Clinically Relevant Drug Resistance Mutations to Both Nucleoside and Non-nucleoside RT Inhibitors

Hachiya, Atsuko; Marchand, Bruno; Kirby, Karen A.; Michailidis, Eleftherios; Tu, Xiaoming; Palczewski, Krzysztof; Ong, Yee Tsuey; Li, Zhe; Griffin, Daniel T; Schuckmann, Matthew M.; Tanuma, Junko; Oka, Shinichi; Singh, Kamalendra; Kodama, Eiichi; Sarafianos, Stefan G.

doi:10.1074/jbc.m112.351551

Cited by 10 publications

(16 citation statements)

References 63 publications

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“…Moreover, the 3TC/FTC-resistance mutation M184V also increases HIV sensitivity to AZT by decreasing the excision efficiency of AZT-MP [22,53,59-61]. Finally, we have recently shown that the 172K polymorphism can enhance susceptibility to both NRTIs and NNRTIs [62]. …”

Section: Discussionmentioning

confidence: 99%

Hypersusceptibility mechanism of Tenofovir-resistant HIV to EFdA

et al. 2013

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BackgroundThe K65R substitution in human immunodeficiency virus type 1 (HIV-1) reverse transcriptase (RT) is the major resistance mutation selected in patients treated with first-line antiretroviral tenofovir disoproxil fumarate (TDF). 4'-ethynyl-2-fluoro-2'-deoxyadenosine (EFdA), is the most potent nucleoside analog RT inhibitor (NRTI) that unlike all approved NRTIs retains a 3'-hydroxyl group and has remarkable potency against wild-type (WT) and drug-resistant HIVs. EFdA acts primarily as a chain terminator by blocking translocation following its incorporation into the nascent DNA chain. EFdA is in preclinical development and its effect on clinically relevant drug resistant HIV strains is critically important for the design of optimal regimens prior to initiation of clinical trials.ResultsHere we report that the K65R RT mutation causes hypersusceptibility to EFdA. Specifically, in single replication cycle experiments we found that EFdA blocks WT HIV ten times more efficiently than TDF. Under the same conditions K65R HIV was inhibited over 70 times more efficiently by EFdA than TDF. We determined the molecular mechanism of this hypersensitivity using enzymatic studies with WT and K65R RT. This substitution causes minor changes in the efficiency of EFdA incorporation with respect to the natural dATP substrate and also in the efficiency of RT translocation following incorporation of the inhibitor into the nascent DNA. However, a significant decrease in the excision efficiency of EFdA-MP from the 3’ primer terminus appears to be the primary cause of increased susceptibility to the inhibitor. Notably, the effects of the mutation are DNA-sequence dependent.ConclusionWe have elucidated the mechanism of K65R HIV hypersusceptibility to EFdA. Our findings highlight the potential of EFdA to improve combination strategies against TDF-resistant HIV-1 strains.

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Section: Discussionmentioning

confidence: 99%

Hypersusceptibility mechanism of Tenofovir-resistant HIV to EFdA

et al. 2013

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“…A polymorphism is a nucleotide variation from the consensus sequence within a subtype, arbitrarily defined as a position-specific difference occurring in >1% of sequences [ 147 ]. Biochemical and virological data have demonstrated that polymorphisms can affect the magnitude of resistance conferred by known resistance mutations [ 10 , 11 , 15 , 148 , 149 ], not only in different HIV-1 subtypes but also in different HIV types. For example, HIV-2 and group O viruses have high-level innate resistance to NNRTIs because of drug-resistance polymorphisms [ 150 , 151 ].…”

Section: Polymorphisms In Hiv-non-bmentioning

confidence: 99%

“…The genetic differences can also impact the extent of cross-resistance to ARVs of the same class and lead to virologic failure, which may affect clinical outcome and immunological response [ 7 , 9 ]. Moreover, there is a considerable body of evidence that shows naturally occurring polymorphisms affect ARV response in subtype B virus [ 10 , 11 , 12 , 13 , 14 , 15 , 16 , 17 ]. A similar effect of polymorphisms can also be hypothesized for HIV-non-B viruses.…”

Section: Introductionmentioning

confidence: 99%

Drug Resistance in Non-B Subtype HIV-1: Impact of HIV-1 Reverse Transcriptase Inhibitors

Singh

Flores

Kirby

et al. 2014

Viruses

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Human immunodeficiency virus (HIV) causes approximately 2.5 million new infections every year, and nearly 1.6 million patients succumb to HIV each year. Several factors, including cross-species transmission and error-prone replication have resulted in extraordinary genetic diversity of HIV groups. One of these groups, known as group M (main) contains nine subtypes (A-D, F-H and J-K) and causes ~95% of all HIV infections. Most reported data on susceptibility and resistance to anti-HIV therapies are from subtype B HIV infections, which are prevalent in developed countries but account for only ~12% of all global HIV infections, whereas non-B subtype HIV infections that account for ~88% of all HIV infections are prevalent primarily in low and middle-income countries. Although the treatments for subtype B infections are generally effective against non-B subtype infections, there are differences in response to therapies. Here, we review how polymorphisms, transmission efficiency of drug-resistant strains, and differences in genetic barrier for drug resistance can differentially alter the response to reverse transcriptase-targeting therapies in various subtypes.

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“…For example, in the case of the most commonly used drugs that target HIV reverse transcriptase (RT), the virus can develop multidrug resistance by either the Q151M complex pathway (Kavlick et al, 1998, Shirasaka et al, 1995) or by accumulation of thymidine associated mutations (TAMs) (Hachiya et al, 2008, Kosalaraksa et al, 1999). We recently report some of background polymorphisms can also influence resistance pathways, such 172R/K in the RT region (Hachiya et al, 2012). In the case of the T-20S138A inhibitor, the N43D/S138A may also act as such polymorphisms despite the presence of primary mutations (Izumi et al, 2009) and preferentially affect the emergence of specific mutations.…”

Section: Discussionmentioning

confidence: 99%

Mechanism of resistance to S138A substituted enfuvirtide and its application to peptide design

Izumi

Kawaji

Miyamoto

et al. 2013

The International Journal of Biochemistry & Cell Biology

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T-20 (enfuvirtide) resistance is caused by the N43D primary resistance mutation at its presumed binding site at the N-terminal heptad repeat (N-HR) of gp41, accompanied by the S138A secondary mutation at the C-terminal HR of gp41 (C-HR). We have discovered that modifying T-20 to include S138A (T-20S138A) allows it to efficiently block wild-type and T20-resistant viruses, by a mechanism that involves improved binding of T-20S138A to the N-HR that contains the N43D primary mutation. To determine how HIV-1 in turn escapes T-20S138A we used a dose escalation method to select T-20S138A-resistant HIV-1 starting with either wild-type (HIV-1WT) or T-20-resistant (HIV-1N43D/S138A) virus. We found that when starting with WT background, I37N and L44M emerged in the N-HR of gp41, and N126K in the C-HR. However, when starting with HIV-1N43D/S138A, L33S and I69L emerged in N-HR, and E137K in C-HR. T-20S138A-resistant recombinant HIV-1 showed cross-resistance to other T-20 derivatives, but not to C34 derivatives, suggesting that T-20S138A suppressed HIV-1 replication by a similar mechanism to T-20. Furthermore, E137K enhanced viral replication kinetics and restored binding affinity with N-HR containing N43D, indicating that it acts as a secondary, compensatory mutation. We therefore introduced E137K into T-20S138A (T-20E137K/S138A) and revealed that T-20E137K/S138A moderately suppressed replication of T-20S138A-resistant HIV-1. T-20E137K/S138A retained activity to HIV-1 without L33S, which seems to be a key mutation for T-20 derivatives. Our data demonstrate that secondary mutations can be consistently used for the design of peptide inhibitors that block replication of HIV resistant to fusion inhibitors.

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HIV-1 Reverse Transcriptase (RT) Polymorphism 172K Suppresses the Effect of Clinically Relevant Drug Resistance Mutations to Both Nucleoside and Non-nucleoside RT Inhibitors

Cited by 10 publications

References 63 publications

Hypersusceptibility mechanism of Tenofovir-resistant HIV to EFdA

Hypersusceptibility mechanism of Tenofovir-resistant HIV to EFdA

Drug Resistance in Non-B Subtype HIV-1: Impact of HIV-1 Reverse Transcriptase Inhibitors

Mechanism of resistance to S138A substituted enfuvirtide and its application to peptide design

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