Antiretroviral therapy and drug resistance in human immunodeficiency virus type 2 infection

Menéndez‐Arias, Luis; Saura, María

doi:10.1016/j.antiviral.2013.12.001

Cited by 83 publications

(84 citation statements)

References 196 publications

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“…Also, T20 has poor bioavailability, requiring large-dose injections (90 mg twice daily), which complicates patient adherence to treatment. Furthermore, we and others demonstrated that T20 displayed dramatically decreased activity in inhibiting HIV-2 isolates (14,24,25). Considerable efforts have been made to develop new fusion inhibitors with improved pharmaceutical profiles (26)(27)(28)(29).…”

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confidence: 99%

A Helical Short-Peptide Fusion Inhibitor with Highly Potent Activity against Human Immunodeficiency Virus Type 1 (HIV-1), HIV-2, and Simian Immunodeficiency Virus

Xiong

Borrego

Ding

et al. 2017

J Virol

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Human immunodeficiency virus type 2 (HIV-2) has already spread to different regions worldwide, and currently about 1 to 2 million people have been infected, calling for new antiviral agents that are effective on both HIV-1 and HIV-2 isolates. T20 (enfuvirtide), a 36-mer peptide derived from the C-terminal heptad repeat region (CHR) of gp41, is the only clinically approved HIV-1 fusion inhibitor, but it easily induces drug resistance and is not active on HIV-2. In this study, we first demonstrated that the M-T hook structure was also vital to enhancing the binding stability and inhibitory activity of diverse CHR-based peptide inhibitors. We then designed a novel short peptide (23-mer), termed 2P23, by introducing the M-T hook structure, HIV-2 sequences, and salt bridge-forming residues. Promisingly, 2P23 was a highly stable helical peptide with high binding to the surrogate targets derived from HIV-1, HIV-2, and simian immunodeficiency virus (SIV). Consistent with this, 2P23 exhibited potent activity in inhibiting diverse subtypes of HIV-1 isolates, T20-resistant HIV-1 mutants, and a panel of primary HIV-2 isolates, HIV-2 mutants, and SIV isolates. Therefore, we conclude that 2P23 has high potential to be further developed for clinical use, and it is also an ideal tool for exploring the mechanisms of HIV-1/2- and SIV-mediated membrane fusion. IMPORTANCE The peptide drug T20 is the only approved HIV-1 fusion inhibitor, but it is not active on HIV-2 isolates, which have currently infected 1 to 2 million people and continue to spread worldwide. Recent studies have demonstrated that the M-T hook structure can greatly enhance the binding and antiviral activities of gp41 CHR-derived inhibitors, especially for short peptides that are otherwise inactive. By combining the hook structure, HIV-2 sequence, and salt bridge-based strategies, the short peptide 2P23 has been successfully designed. 2P23 exhibits prominent advantages over many other peptide fusion inhibitors, including its potent and broad activity on HIV-1, HIV-2, and even SIV isolates, its stability as a helical, oligomeric peptide, and its high binding to diverse targets. The small size of 2P23 would benefit its synthesis and significantly reduce production cost. Therefore, 2P23 is an ideal candidate for further development, and it also provides a novel tool for studying HIV-1/2- and SIV-mediated cell fusion.

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confidence: 99%

A Helical Short-Peptide Fusion Inhibitor with Highly Potent Activity against Human Immunodeficiency Virus Type 1 (HIV-1), HIV-2, and Simian Immunodeficiency Virus

Xiong

Borrego

Ding

et al. 2017

J Virol

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“…HIV-2 is endemic in West Africa and is also prevalent in other areas with socioeconomic ties to the region (4,5). Choices of antiretroviral (ARV) drugs for HIV-2 treatment are constrained by the intrinsic resistance of the virus to non-nucleoside reverse transcriptase inhibitors (NNRTIs) and the reduced susceptibility of HIV-2 to most HIV-1-active protease inhibitors (5)(6)(7)(8). In addition, ART-experienced HIV-2 patients frequently harbor mutants resistant to both protease inhibitors and NRTIs (9)(10)(11), and newer ARV drugs, such as integrase strand transfer inhibitors, are not broadly available in areas where significant numbers of HIV-2-infected individuals reside.…”

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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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“…HIV-2 infection and HIV-1/2 dual infection are largely confined to West Africa, together with a few locales with socioeconomic ties to the region, and account for ϳ3 to 5% of the global burden of HIV (4). Currently, ART for HIV-2 relies entirely on compounds that were developed, optimized, and licensed for use for the treatment of HIV-1 (specifically, HIV-1 group M, subtype B) (5). The limited activity of many of these drugs against HIV-2 is a major obstacle to treatment; HIV-2 is intrinsically resistant to nonnucleoside reverse transcriptase (RT) inhibitors, the fusion inhibitor enfuvirtide (T-20), and the majority of the protease inhibitors (PIs) used for HIV-1 ART (6-11) but is sensitive to both integrase strand transfer inhibitors (INSTIs) and nucleoside reverse transcriptase inhibitors (NRTIs), with the 50% effective concentrations (EC 50 s) of these drugs for HIV-2 being comparable to those seen for HIV-1 (12)(13)(14)(15)(16)(17).…”

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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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Antiretroviral therapy and drug resistance in human immunodeficiency virus type 2 infection

Cited by 83 publications

References 196 publications

A Helical Short-Peptide Fusion Inhibitor with Highly Potent Activity against Human Immunodeficiency Virus Type 1 (HIV-1), HIV-2, and Simian Immunodeficiency Virus

A Helical Short-Peptide Fusion Inhibitor with Highly Potent Activity against Human Immunodeficiency Virus Type 1 (HIV-1), HIV-2, and Simian Immunodeficiency Virus

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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