Subtype diversity associated with the development of HIV‐1 resistance to integrase inhibitors

Brenner, Bluma G.; Lowe, Matthew; Moïsi, Daniela; Hardy, Isabelle; Gagnon, Simon; Charest, Hugues; Baril, Jean Guy; Wainberg, Mark A.; Roger, Michel

doi:10.1002/jmv.22047

Cited by 64 publications

(53 citation statements)

References 63 publications

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“…Whether resistance or fitness ac- counts for the change from R263K to S153Y is under investigation. Initially, R263K was identified as a secondary resistance mutation for EVG, arising in the presence of the major resistance mutation T66I (32) and has also been reported in patients treated with RAL (6). Other selection studies with EVG did not show the emergence of R263K (60).…”

Section: Discussionmentioning

confidence: 99%

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Characterization of the R263K Mutation in HIV-1 Integrase That Confers Low-Level Resistance to the Second-Generation Integrase Strand Transfer Inhibitor Dolutegravir

Quashie

Mésplède

Han

et al. 2012

J Virol

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214

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Integrase (IN) strand transfer inhibitors (INSTIs) have been developed to inhibit the ability of HIV-1 integrase to irreversibly link the reverse-transcribed viral DNA to the host genome. INSTIs have proven their high efficiency in inhibiting viral replication in vitro and in patients. However, first-generation INSTIs have only a modest genetic barrier to resistance, allowing the virus to escape these powerful drugs through several resistance pathways. Second-generation INSTIs, such as dolutegravir (DTG, S/GSK1349572), have been reported to have a higher resistance barrier, and no novel drug resistance mutation has yet been described for this drug. Therefore, we performed in vitro selection experiments with DTG using viruses of subtypes B, C, and A/G and showed that the most common mutation to emerge was R263K. Further analysis by site-directed mutagenesis showed that R263K does confer low-level resistance to DTG and decreased integration in cell culture without altering reverse transcription. Biochemical cell-free assays performed with purified IN enzyme containing R263K confirmed the absence of major resistance against DTG and showed a slight decrease in 3= processing and strand transfer activities compared to the wild type. Structural modeling suggested and in vitro IN-DNA binding assays show that the R263K mutation affects IN-DNA interactions.T he high mutation rate of HIV-1 reverse transcriptase (RT) allows the virus to escape pressure through adaptive mutations that include drug resistance mutations that limit the effectiveness of antiretroviral drugs (5,31,66,69,70). The use of multiple drugs in combination can hamper this process by restraining viral replication, limiting the emergence of resistant strains. The addition of integrase inhibitors to the arsenal of drugs against HIV-1 is important since these inhibitors are active against viruses resistant to other drug classes (16,49,63).The HIV-1 integrase enzyme catalyzes two reactions. The first is 3= processing, which consists of cleavage of a dinucleotide at both 3= ends of the reverse-transcribed linear viral DNA and results in the exposure of reactive hydroxyl groups. The second step termed "strand transfer" is carried out through a nucleophilic attack by exposed 3= hydroxyl groups on host genomic DNA (26, 47). Even though 3= processing may be a suitable therapeutic target, the integrase inhibitors developed so far are integrase strand transfer inhibitors (INSTIs) that preferentially inhibit strand transfer while only modestly affecting 3= processing (18,24,26). Raltegravir (RAL) was the first INSTI to be approved for therapy in 2007 (64) and is safe and efficient in both treatment-naïve and treatment-experienced subjects (11,17,23,35,49,62,63). Elvitegravir (EVG) is another INSTI currently in advanced clinical trials (10,12,77).Although first-generation INSTIs strongly inhibit HIV-1 replication, they possess only a modest genetic barrier to resistance. Three main resistance pathways have been identified for RAL, involving initial mutations of the N1...

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Section: Discussionmentioning

confidence: 99%

“…Briefly, CBMCs infected with the specified viruses were serially passaged in the presence of increasing concentrations of DTG. Mutations were identified by sequencing the IN region of the pol gene according to the procedure described previously (6). Viral strains 5331, 5326, 12197, 6399, and 4742 are primary isolates.…”

Section: Methodsmentioning

confidence: 99%

Characterization of the R263K Mutation in HIV-1 Integrase That Confers Low-Level Resistance to the Second-Generation Integrase Strand Transfer Inhibitor Dolutegravir

Quashie

Mésplède

Han

et al. 2012

J Virol

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214

306

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“…It was shown that the genetic barriers among subtypes B, C, A, CRF02_AG are similar in most of the major IN mutations related to RAL and EVG resistance; some mutations, V151I, G140C, and especially G140S which is associated with the Q148K/R/H pathway, have a lower genetic barrier in subtype B [9,13]. However, there are limited data on subtype CRF01_AE, a highly predominant isolate in Southeast Asia which is the cause of a number of people infected with HIV-1 in the region and is also frequently seen in France with an increasing proportion of people newly infected with HIV-1 non-B subtype strains [14,15].…”

Section: Introductionmentioning

confidence: 99%

Genetic Barrier to the Development of Resistance to Integrase Inhibitors in HIV-1 Subtypes CRF01_AE and B

2012

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Objective: The genetic barrier for the evolution of integrase inhibitors (INIs) including raltegravir (RAL), elvitegravir (EVG), and dolutegravir (DTG) resistance was compared between HIV-1 subtypes CRF01_AE and B. Methods: Analysis of 66 substitutions associated with INI resistance at 41 amino acid positions in 144 nucleotide sequences (109 HIV-1 subtype CRF01_AE and 35 HIV-1 subtype B) of integrase-coding region of polymerase gene derived from INI-naive patients. Results: 28/41 studied amino acid positions were conserved, leading to a similar genetic barrier between the two subtypes. At six codon positions with different genetic barriers, six mutations (V72I, L101I, A124T, T125K, and G140C/S) displayed a higher genetic barrier and one mutation (V201I) showed a lower genetic barrier in subtype CRF01_AE than subtype B. Conclusions: Most studied amino acid positions including all corresponding to RAL and EVG primary mutations show a high level of conservation, indicating the same genetic barrier between subtypes CRF01_AE and B. Nevertheless, different genetic barriers were observed in two mutations described to be associated with DTG resistance (L101I, A124T) and other five RAL and EVG secondary mutations (V72I, T125K, G140C/S, V201I), which could have an impact on the development of resistance to RAL, EVG, and DTG.

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“…Biochemical, virological, and clinical studies of HIV-1 subtype B and non-B subtypes have shown that genetic diversity can affect drug resistance pathways and the outcome of HAART (9,10,12). For example, the K65R substitution is known to occur at a higher frequency among individuals infected with HIV-1 subtype C (42-44), which may limit the success of some TFV-based regimens (45,46).…”

Section: Discussionmentioning

confidence: 99%

“…Most currently available antiretrovirals (ARVs) were developed based on the ability to block replication of subtype B viruses, but the development of resistance to all ARVs is a major obstacle in the face of long-term treatment success (7,8). The high genetic diversity of HIV-1 subtypes may lead to distinct pathways to drug resistance (9)(10)(11)(12), necessitating the development of novel effective ARVs that possess distinct mechanisms and superior resistance profiles for all HIV-1 subtypes.…”

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confidence: 99%

Subtype-Specific Analysis of the K65R Substitution in HIV-1 That Confers Hypersusceptibility to a Novel Nucleotide-Competing Reverse Transcriptase Inhibitor

Colby-Germinario

Quashie

et al. 2015

Antimicrob Agents Chemother

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Compound A is a novel nucleotide-competing HIV-1 reverse transcriptase (RT) inhibitor (NcRTI) that selects for a unique W153L substitution that confers hypersusceptibility to tenofovir, while the K65R substitution in RT confers resistance against tenofovir and enhances susceptibility to NcRTIs. Although the K65R substitution is more common in subtype C viruses, the impact of subtype variability on NcRTI susceptibility has not been studied. In the present study, we performed experiments with compound A by using purified recombinant RT enzymes and viruses of subtypes B and C and circulating recombinant form CRF_A/G. We confirmed the hypersusceptibility of K65R substitution-containing RTs to compound A for subtype C, CRF_A/G, and subtype B. Steady-state kinetic analysis showed that K65R RTs enhanced the susceptibility to compound A by increasing binding of the inhibitor to the nucleotide binding site of RT in a subtype-independent manner, without significantly discriminating against the natural nucleotide substrate. These data highlight the potential utility of NcRTIs, such as compound A, for treatment of infections with K65R substitution-containing viruses, regardless of HIV-1 subtype. C urrently, over 35 million people are living with HIV, according to the World Health Organization (http://www.who.int /hiv/en/). Genetic diversity is characteristic of HIV-1 due to the error-prone nature of its reverse transcriptase (RT) enzyme and its high viral replication rate. The HIV-1 epidemic has rapidly evolved to include 9 major known circulating subtypes (A to D, F to H, J, and K) and over 60 known circulating recombinant forms (CRFs) that show 25 to 35% overall genetic variation; this includes 10 to 15% diversity in RT (1-4). HIV-1 subtype C accounts for 50 to 55% of all HIV infections worldwide, while HIV-1 subtype B is the most prevalent subtype in developed countries and accounts for ϳ12% of global HIV infections. CRF01_AE and CRF02_AG are two globally predominant CRFs that are found in Southeast Asia and West/Central Africa, respectively.Current standard anti-HIV-1 therapy, termed highly active antiretroviral therapy (HAART), consists of three or more antiretroviral compounds from six distinct classes, including nucleoside or nucleotide reverse transcriptase inhibitors (NRTIs), nonnucleoside reverse transcriptase inhibitors (NNRTIs), protease inhibitors (PIs), fusion inhibitors, entry inhibitors, and integrase inhibitors (INIs) (for reviews, see references 5 and 6). Most currently available antiretrovirals (ARVs) were developed based on the ability to block replication of subtype B viruses, but the development of resistance to all ARVs is a major obstacle in the face of long-term treatment success (7,8). The high genetic diversity of HIV-1 subtypes may lead to distinct pathways to drug resistance (9-12), necessitating the development of novel effective ARVs that possess distinct mechanisms and superior resistance profiles for all HIV-1 subtypes.Inhibitors that target RT constitute the largest class of ARVs and are ke...

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Subtype diversity associated with the development of HIV‐1 resistance to integrase inhibitors

Cited by 64 publications

References 63 publications

Characterization of the R263K Mutation in HIV-1 Integrase That Confers Low-Level Resistance to the Second-Generation Integrase Strand Transfer Inhibitor Dolutegravir

Characterization of the R263K Mutation in HIV-1 Integrase That Confers Low-Level Resistance to the Second-Generation Integrase Strand Transfer Inhibitor Dolutegravir

Genetic Barrier to the Development of Resistance to Integrase Inhibitors in HIV-1 Subtypes CRF01_AE and B

Subtype-Specific Analysis of the K65R Substitution in HIV-1 That Confers Hypersusceptibility to a Novel Nucleotide-Competing Reverse Transcriptase Inhibitor

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