Hot Spots of Integrase Genotypic Changes Leading to HIV-2 Resistance to Raltegravir

Charpentier, Charlotte; Roquebert, Bénédicte; Delelis, Olivier; Larrouy, Lucile; Matheron, Sophie; Tubiana, Roland; Karmochkine, Marina; Duval, Xavier; Chêne, Geneviève; Storto, Alexandre; Collin, Gilles; Bénard, Antoine; Damond, Florence; Mouscadet, Jean‐François; Brun‐Vézinet, Françoise; Descamps, Diane

doi:10.1128/aac.00942-10

Cited by 30 publications

(39 citation statements)

References 12 publications

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“…Newer ARVs, including generic FTC and tenofovir disoproxil fumarate (TDF), ritonavir-boosted darunavir, and the INSTI raltegravir, have recently been made available to a limited number of HIV-2-infected patients in some West African HIV treatment programs. While these compounds may be beneficial, concerns regarding the extensive cross-resistance seen within the NRTI and PI classes in HIV-2 remain (5,7,9,19,21,22,25,54,67,68), and emergent resistance to raltegravir has been reported in HIV-2-infected individuals (18,20,23,24,26,27,69,70). Our analysis suggests that BMS-986001 might help fill the need for newer HIV-2-active ARVs.…”

Section: Discussionmentioning

confidence: 89%

“…Mutations that diminish the activity of NRTIs, PIs, and INSTIs have been reported in HIV-2 isolates from ARV-treated patients (9,(18)(19)(20)(21)(22)(23)(24)(25)(26)(27), and up to 30% of HIV-2-infected patients living in West Africa show evidence of multiclass (NRTI and PI) resistance (19,22). Once resistance emerges, HIV-2-infected individuals are left with few (if any) options for effective treatment.…”

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confidence: 99%

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The Nucleoside Analog BMS-986001 Shows GreaterIn VitroActivity against HIV-2 than against HIV-1

Smith

Raugi

et al. 2015

Antimicrob Agents Chemother

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Treatment options for individuals infected with human immunodeficiency virus type 2 (HIV-2) are restricted by the intrinsic resistance of the virus to nonnucleoside reverse transcriptase inhibitors (NNRTIs) and the reduced susceptibility of HIV-2 to several protease inhibitors (PIs) used in antiretroviral therapy (ART). In an effort to identify new antiretrovirals for HIV-2 treatment, we evaluated the in vitro activity of the investigational nucleoside analog BMS-986001 (2=,3=-didehydro-3=-deoxy-4=-ethynylthymidine; also known as censavudine, festinavir, OBP-601, 4=-ethynyl stavudine, or 4=-ethynyl-d4T). In single-cycle assays, BMS-986001 inhibited HIV-2 isolates from treatment-naive individuals, with 50% effective concentrations (EC 50 s) ranging from 30 to 81 nM. In contrast, EC 50 s for group M and O isolates of HIV-1 ranged from 450 to 890 nM. Across all isolates tested, the average EC 50 for HIV-2 was 9.5-fold lower than that for HIV-1 (64 ؎ 18 nM versus 610 ؎ 200 nM, respectively; mean ؎ standard deviation). BMS-986001 also exhibited full activity against HIV-2 variants whose genomes encoded the single amino acid changes K65R and Q151M in reverse transcriptase, whereas the M184V mutant was 15-fold more resistant to the drug than the parental HIV-2 ROD9 strain. Taken together, our findings show that BMS-986001 is an effective inhibitor of HIV-2 replication. To our knowledge, BMS-986001 is the first nucleoside analog that, when tested against a diverse collection of HIV-1 and HIV-2 isolates, exhibits more potent activity against HIV-2 than against HIV-1 in culture.

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Section: Discussionmentioning

confidence: 89%

mentioning

confidence: 99%

The Nucleoside Analog BMS-986001 Shows GreaterIn VitroActivity against HIV-2 than against HIV-1

Smith

Raugi

et al. 2015

Antimicrob Agents Chemother

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“…Only N155 and Q148 are reported to confer crossresistance to EVG (19,(45)(46)(47), while Y143 is reported to be specific for RAL (48). Primary substitutions at positions G118 and R263 and a secondary substitution at position H51 in integrase were previously shown in cell culture selections to confer resistance to INSTIs, including RAL, MK-2048, and DTG (21)(22)(23)49). Our goal in the present study was to evaluate these six mutations in SIV, in view of the fact that no group has yet documented the selection of INSTI resistance mutations in SIV.…”

Section: Discussionmentioning

confidence: 99%

“…After an initial loss of viral replicative fitness, secondary mutations at multiple positions may compensate for this deficit, while simultaneously increasing the overall levels of drug resistance. In contrast, a mutation at position R263K in integrase seems to confer low-level resistance against DTG, and it is uncertain whether this substitution, which is also associated with diminished replication competence in HIV, can be compensated (21)(22)(23). Although RAL and EVG can be compromised by extensive crossresistance conferred by mutations within IN, DTG possesses an improved resistance profile with far less cross-resistance with other drugs (21,(24)(25)(26)(27)(28).…”

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confidence: 99%

Effect of HIV-1 Integrase Resistance Mutations When Introduced into SIVmac239 on Susceptibility to Integrase Strand Transfer Inhibitors

Hassounah

Mésplède

Quashie

et al. 2014

J Virol

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Studies 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 highlevel 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.

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“…The latest versions of those algorithms are available on line (ANRS-AC11 2011; Gomes et al 2009). The first one is more specific, as the list includes only mutations for which the impact was clearly demonstrated in several publications: K65R, Q151M, M184V and S215 changes in the RT (Damond et al 2005), as well as mutations at positions 143, 148 and 155 in the integrase (Charpentier et al 2011). The second algorithm is probably more sensitive as the list includes other minor mutations for which an impact has been described, as well as primary protease mutations absent from the ANRS list.…”

Section: Interpretation Rulesmentioning

confidence: 99%

HIV-2: Testing Specificities

Ruelle¹

2012

HIV Testing

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Hot Spots of Integrase Genotypic Changes Leading to HIV-2 Resistance to Raltegravir

Cited by 30 publications

References 12 publications

The Nucleoside Analog BMS-986001 Shows GreaterIn VitroActivity against HIV-2 than against HIV-1

The Nucleoside Analog BMS-986001 Shows GreaterIn VitroActivity against HIV-2 than against HIV-1

Effect of HIV-1 Integrase Resistance Mutations When Introduced into SIVmac239 on Susceptibility to Integrase Strand Transfer Inhibitors

HIV-2: Testing Specificities

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