Dataset Information

In Silico and In Vitro Comparison of HIV-1 Subtypes B and CRF02_AG Integrases Susceptibility to Integrase Strand Transfer Inhibitors.

ABSTRACT: Most antiretroviral medical treatments were developed and tested principally on HIV-1 B nonrecombinant strain, which represents less than 10% of the worldwide HIV-1-infected population. HIV-1 circulating recombinant form CRF02_AG is prevalent in West Africa and is becoming more frequent in other countries. Previous studies suggested that the HIV-1 polymorphisms might be associated to variable susceptibility to antiretrovirals. This study is pointed to compare the susceptibility to integrase (IN) inhibitors of HIV-1 subtype CRF02_AG IN respectively to HIV-1 B. Structural models of B and CRF02_AG HIV-1 INs as unbound enzymes and in complex with the DNA substrate were built by homology modeling. IN inhibitors-raltegravir (RAL), elvitegravir (ELV) and L731,988-were docked onto the models, and their binding affinity for both HIV-1 B and CRF02_AG INs was compared. CRF02_AG INs were cloned and expressed from plasma of integrase strand transfer inhibitor (INSTI)-naïve infected patients. Our in silico and in vitro studies showed that the sequence variations between the INs of CRF02_AG and B strains did not lead to any notable difference in the structural features of the enzyme and did not impact the susceptibility to the IN inhibitors. The binding modes and affinities of INSTI inhibitors to B and CRF02_AG INs were found to be similar. Although previous studies suggested that several naturally occurring variations of CRF02_AG IN might alter either IN/vDNA interactions or INSTIs binding, our study demonstrate that these variations do affect neither IN activity nor its susceptibility to INSTIs.

SUBMITTER: Ni X

PROVIDER: S-EPMC3398581 | biostudies-literature | 2012

REPOSITORIES: biostudies-literature

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In Silico and In Vitro Comparison of HIV-1 Subtypes B and CRF02_AG Integrases Susceptibility to Integrase Strand Transfer Inhibitors.

Ni Xiaoju X Abdel-Azeim Safwat S Laine Elodie E Arora Rohit R Osemwota Osamuede O Marcelin Anne-Geneviève AG Calvez Vincent V Mouscadet Jean-François JF Tchertanov Luba L

Advances in virology 20120705

Most antiretroviral medical treatments were developed and tested principally on HIV-1 B nonrecombinant strain, which represents less than 10% of the worldwide HIV-1-infected population. HIV-1 circulating recombinant form CRF02_AG is prevalent in West Africa and is becoming more frequent in other countries. Previous studies suggested that the HIV-1 polymorphisms might be associated to variable susceptibility to antiretrovirals. This study is pointed to compare the susceptibility to integrase (IN) ...[more]

PMID: 22829822

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Project description:UnlabelledStudies on the in vitro susceptibility of SIV to integrase strand transfer inhibitors (INSTIs) have been rare. In order to determine the susceptibility of SIVmac239 to INSTIs and characterize the genetic pathways that might lead to drug resistance, we inserted various integrase (IN) mutations that had been selected with HIV under drug pressure with raltegravir (RAL), elvitegravir (EVG), and dolutegravir (DTG) into the IN gene of SIV. We evaluated the effects of these mutations on SIV susceptibility to INSTIs and on viral infectivity. Sequence alignments of SIVmac239 IN with various HIV-1 isolates showed a high degree of homology and conservation of each of the catalytic triad and the key residues involved in drug resistance. Each of the G118R, Y143R, Q148R, R263K, and G140S/Q148R mutations, when introduced into SIV, impaired infectiousness and replication fitness compared to wild-type virus. Using TZM-bl cells, we demonstrated that the Q148R and N155H mutational pathways conferred resistance to EVG (36- and 62-fold, respectively), whereas R263K also displayed moderate resistance to EVG (12-fold). In contrast, Y143R, Q148R, and N155H all yielded low levels of resistance to RAL. The combination of G140S/Q148R conferred high-level resistance to both RAL and EVG (>300- and 286-fold, respectively). DTG remained fully effective against all site-directed mutants except G118R and R263K. Thus, HIV INSTI mutations, when inserted into SIV, resulted in a similar phenotype. These findings suggest that SIV and HIV may share similar resistance pathways profiles and that SIVmac239 could be a useful nonhuman primate model for studies of HIV resistance to INSTIs.ImportanceThe goal of our project was to establish whether drug resistance against integrase inhibitors in SIV are likely to be the same as those responsible for drug resistance in HIV. Our data answer this question in the affirmative and show that SIV can probably serve as a good animal model for studies of INSTIs and as an early indicator for possible emergent mutations that may cause treatment failure. An SIV-primate model remains an invaluable tool for investigating questions related to the potential role of INSTIs in HIV therapy, transmission, and pathogenesis, and the present study will facilitate each of the above.

Project description:There has been no systematic review of the prevalence of transmitted integrase strand transfer inhibitor (INSTI) resistance. We systematically searched the English-language PubMed database and GenBank to identify studies published since 2010 reporting 50 or more INSTI-naive HIV-1-infected adults undergoing integrase genotyping. We extracted data related to country, sample year, specimen type, sequencing method, and subtype. For studies with sequences in GenBank, we determined the prevalence of three categories of INSTI-associated resistance mutations: (1) nonpolymorphic INSTI-selected drug resistance mutations (DRMs) that we refer to as surveillance DRMs; (2) rarely selected nonpolymorphic INSTI-associated DRMs; and (3) common polymorphic accessory INSTI-selected DRMs. A total of 103 studies met inclusion criteria including 75 studies in GenBank containing integrase sequences from 16,481 INSTI-naive persons. The median sample year was 2013 (interquartile range: 2008-2014). The prevalence of INSTI surveillance DRMs, rarely selected DRMs, and common polymorphic accessory INSTI-selected DRMs were 0.5%, 0.8%, and 6.2%, respectively. There was no association between the presence of nonpolymorphic surveillance DRM and region, sample year, or subtype. Two surveillance DRMs, E138K and R263K occurred in 0.15% and 0.10% of naive sequences, respectively. Several lines of evidence suggested that the 0.5% prevalence of surveillance DRMs partly reflects the cumulative natural occurrence of these mutations in the absence of selective drug pressure. There was an unexplained temporal increase in the proportion of sequences with polymorphic accessory mutations. The prevalence of INSTI-associated surveillance DRMs is low even in regions where INSTIs have been a major component of antiretroviral therapy for several years. The presence of INSTI-associated surveillance DRMs in INSTI-naive persons likely results from actual cases of transmitted INSTI resistance and from a low background level reflecting the cumulative rare natural occurrence of several nonpolymorphic mutations.

Dataset Information

In Silico and In Vitro Comparison of HIV-1 Subtypes B and CRF02_AG Integrases Susceptibility to Integrase Strand Transfer Inhibitors.

Publications

In Silico and In Vitro Comparison of HIV-1 Subtypes B and CRF02_AG Integrases Susceptibility to Integrase Strand Transfer Inhibitors.

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