Drug resistance mutations in patients infected with HIV-2 living in Spain

Caballero, Estrella; Benito, Rafael; Cabezas, Teresa; Roc, Lourdes; Aguilera, Antonio; Rodrı́guez, Carmen; Romero, Jorge del; Tuset, C.; Marcaida, Goitzane; Tuset, T.; Molina, I.; Rodríguez-Calviño, Javier; Cortizo, S.; Regueiro, Benito J.; Borrás, M.; Lejarazu, Raúl Ortíz de; Eirós, José María; Miró, Júlia; López-Diéguez, María; Pumarola, Tomás; Paz, Ido; Calderón, Eva Alonso; Medrano, F.J.; Leal, M; Capote, Francisco; Vallejo, Alejandro; Dronda, Fernando; Moreno, Santiago; Escudero, Domingo; Pujol, Emilio; Trigo, Matilde; Diz, J.; Álvarez, Patrícia; García-Campello, Marta; Rodríguez-Iglesias, Manuel; Martin, A. M.; Hernandez-Betancor, A.; Ramos, José Manuel; Rodriguez, Judith. Calderon; Gutiérrez, Félix; Gómez-Hernando, César; Guelar, Ana; Cilla, Gustavo; Pérez-Trallero, E; López‐Aldeguer, José; Sola, Julio; Fernandez-Pereira, L.; Niubó, Jordi; Veloso, Sergio; Torres, Alex José Leite; Lirola, A M López; Sirvent, José L. Gómez; Force, Luis; Cifuentes, Celia; García, J. Víctor; Perez, S.; Raya, C.; González-Praetorius, Alejandro; Mena, Álvaro; Pérez, José Luís; Peñaranda, María; Montejo, José Miguel; Gutiérrez, Mar; Domingo, Peré; Sapina, A. Martinez; Viciana, Isabel; Lozano, Ana Belén Peinado; Fernández, Juan Manuel; García, Isabel Cristina Carbonell; Gaspar, G; García, Raúl López; Górgolas, Miguel; Treviño, Ana; Parra, Patricia; Mendoza, Carmen de; Soriano, Vicente

doi:10.1093/jac/dkr164

Cited by 27 publications

(25 citation statements)

References 24 publications

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“…This result makes sense in light of the fact that the excision reaction is closely related to the polymerase reaction run in reverse. None of the mutations in the Q151M complex are in positions where they would be expected to enhance ATP binding (37). Without enhanced ATP binding to HIV-1 RT, the excision reaction would depend primarily on the polymerase activity of the RT variants.…”

Section: Figmentioning

confidence: 99%

HIV-1 and HIV-2 Reverse Transcriptases: Different Mechanisms of Resistance to Nucleoside Reverse Transcriptase Inhibitors

Boyer

Clark

Hughes

2012

J Virol

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bAs anti-HIV therapy becomes more widely available in developing nations, it is clear that drug resistance will continue to be a major problem. The related viruses HIV-1 and HIV-2 share many of the same resistance pathways to nucleoside reverse transcriptase inhibitors (NRTIs). However, clinical data suggest that while HIV-1 reverse transcriptase (RT) usually uses an ATP-dependent excision pathway to develop resistance to the nucleoside analog zidovudine (AZT), HIV-2 RT does not appear to use this pathway. We previously described data that suggested that wild-type (WT) HIV-2 RT has a much lower ability to excise AZT monophosphate (AZTMP) than does WT HIV-1 RT and suggested that this is the reason that HIV-2 RT more readily adopts an exclusion pathway against AZT triphosphate (AZTTP), while HIV-1 RT is better able to exploit the ATP-dependent pyrophosphorolysis mechanism. However, we have now done additional experiments, which show that while HIV-1 RT can adopt either an exclusion-or excision-based resistance mechanism against AZT, HIV-2 RT can use only the exclusion mechanism. All of our attempts to make HIV-2 RT excision competent did not produce an AZT-resistant RT but instead yielded RTs that were less able to polymerize than the WT. This suggests that the exclusion pathway is the only pathway available to HIV-2. HIV-1 infection has been the target of various multidrug therapies, but to date, the effectiveness of all anti-HIV drugs has been blunted by drug-resistant mutations that arise in the genome of the virus. Reverse transcriptase (RT) is an enzyme that contains two enzymatic activities, a DNA polymerase that can copy either an RNA or DNA template, and an RNase H, which degrades RNA if the RNA is part of an RNA/DNA duplex. RT uses these two enzymatic activities to convert the single-stranded RNA genome of the virus into a double-stranded DNA that can be integrated into the genome of the host cell. The synthesis of a DNA copy of the viral genome is a crucial step in the life cycle of the virus, and RT has, for that reason, been the target of a number of different anti-HIV drugs (for reviews, e.g., see references 2, 12, 17, 19, 21, 23, 31, and 32). The earliest anti-HIV therapies involved nucleoside RT inhibitors (NRTIs). These analogs enter the cell and are converted to the triphosphate form (nucleoside RT inhibitor triphosphates [NRTI-TPs]) by host cell kinases. Because the NRTI-TPs are analogs of the normal deoxynucleoside triphosphates (dNTPs), NRTI-TPs are incorporated into the primer strand by RT. However, because the NRTI-TPs do not have a 3=-OH group on the sugar or pseudosugar moiety, an NRTI monophosphate (NRTI-MP) that has been incorporated into viral DNA cannot support continued DNA synthesis and the primer chain is terminated. Decreased susceptibility to NRTIs means that the mutant RT has an enhanced ability to select normal dNTPs over the NRTI-TPs. Two primary mechanisms have been identified by which HIV-1 RT becomes less susceptible to the NRTITPs. One mechanism is exclusion, in which the m...

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Section: Figmentioning

confidence: 99%

HIV-1 and HIV-2 Reverse Transcriptases: Different Mechanisms of Resistance to Nucleoside Reverse Transcriptase Inhibitors

Boyer

Clark

Hughes

2012

J Virol

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“…It is important to note that the EC 50 s for all HIV-2 ROD9 clones containing M184V (with or without other changes) were only 2-to 4-fold greater than the mean EC 50 for HIV-1 isolates from ART-naive individuals (2.6 nM). Although we cannot exclude the possibility that other amino acid replacements in HIV-2 RT confer higher levels of MK-8591 resistance, our analysis demonstrates that MK-8591 retains substantial activity against the types of drug-resistant variants that typically emerge in NRTI-treated HIV-2 patients (9,10,(35)(36)(37)(38)(39)(40)(41)(42)(43)(44)(45)(46)(47)(48)(49).…”

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confidence: 91%

“…We also evaluated the ability of MK-8591 to inhibit HIV-2 variants with mutations in RT that emerge in response to ART (9,10,(35)(36)(37)(38)(39)(40)(41)(42)(43)(44)(45)(46)(47)(48)(49) and that confer resistance to various NRTIs in culture (29,40,(50)(51)(52) and in biochemical assays with purified HIV-2 RT (30, 31). Unless otherwise specified, drug susceptibility measurements were performed using MAGIC-5A indicator cells, which are CD4 ϩ CXCR4 ϩ CCR5 ϩ HeLa cells containing an HIV-inducible reporter gene (HIV long terminal repeat [LTR]-␤-galactosidase).…”

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confidence: 99%

MK-8591 (4′-Ethynyl-2-Fluoro-2′-Deoxyadenosine) Exhibits Potent Activity against HIV-2 Isolates and Drug-Resistant HIV-2 Mutants in Culture

Smith

Masoum

et al. 2017

Antimicrob Agents Chemother

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There is a pressing need to identify more effective antiretroviral drugs for HIV-2 treatment. Here, we show that the investigational compound MK-8591 (4=-ethynyl-2-fluoro-2=-deoxyadenosine [EFdA]) is highly active against group A and B isolates of HIV-2; 50% effective concentrations [EC 50 ] for HIV-2 were, on average, 4.8-fold lower than those observed for HIV-1. MK-8591 also retains potent activity against multinucleoside-resistant HIV-2 mutants (EC 50 Յ 11 nM). These data suggest that MK-8591 may have antiviral activity in HIV-2-infected individuals.

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“…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%

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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Drug resistance mutations in patients infected with HIV-2 living in Spain

Cited by 27 publications

References 24 publications

HIV-1 and HIV-2 Reverse Transcriptases: Different Mechanisms of Resistance to Nucleoside Reverse Transcriptase Inhibitors

HIV-1 and HIV-2 Reverse Transcriptases: Different Mechanisms of Resistance to Nucleoside Reverse Transcriptase Inhibitors

MK-8591 (4′-Ethynyl-2-Fluoro-2′-Deoxyadenosine) Exhibits Potent Activity against HIV-2 Isolates and Drug-Resistant HIV-2 Mutants in Culture

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

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