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Volume 95, Issue 12

Novel inhibitors of human immunodeficiency virus type 2 infectivity Free

Abstract

Human immunodeficiency virus type 2 (HIV-2) infects about two million people worldwide. HIV-2 has fewer treatment options than HIV-1, yet may evolve drug resistance more quickly. We have analysed several novel drugs for anti-HIV-2 activity. It was observed that 5-azacytidine, clofarabine, gemcitabine and resveratrol have potent anti-HIV-2 activity. The EC values for 5-azacytidine, clofarabine and resveratrol were found to be significantly lower with HIV-2 than with HIV-1. A time-of-addition assay was used to analyse the ability of these drugs to interfere with HIV-2 replication. Reverse transcription was the likely target for antiretroviral activity. Taken together, several novel drugs have been discovered to have activity against HIV-2. Based upon their known activities, these drugs may elicit enhanced HIV-2 mutagenesis and therefore be useful for inducing HIV-2 lethal mutagenesis. In addition, the data are consistent with HIV-2 reverse transcriptase being more sensitive than HIV-1 reverse transcriptase to dNTP pool alterations.

  • Received:
  • Accepted:
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© 2014 The Authors
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2014-12-01
2023-11-28
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References

  1. Ahn J., Hao C., Yan J., DeLucia M., Mehrens J., Wang C., Gronenborn A. M., Skowronski J. 2012; HIV/simian immunodeficiency virus (SIV) accessory virulence factor Vpx loads the host cell restriction factor SAMHD1 onto the E3 ubiquitin ligase complex CRL4DCAF1. J Biol Chem 287:12550–12558 [View Article][PubMed]
     [Google Scholar]
  2. Amie S. M., Daly M. B., Noble E., Schinazi R. F., Bambara R. A., Kim B. 2013; Anti-HIV host factor SAMHD1 regulates viral sensitivity to nucleoside reverse transcriptase inhibitors via modulation of cellular deoxyribonucleoside triphosphate (dNTP) levels. J Biol Chem 288:20683–20691 [View Article][PubMed]
     [Google Scholar]
  3. Andreatta K., Miller M. D., White K. L. 2013; HIV-2 antiviral potency and selection of drug resistance mutations by the integrase strand transfer inhibitor elvitegravir and NRTIs emtricitabine and tenofovir in vitro. J Acquir Immune Defic Syndr 62:367–374 [View Article][PubMed]
     [Google Scholar]
  4. Baldauf H. M., Pan X., Erikson E., Schmidt S., Daddacha W., Burggraf M., Schenkova K., Ambiel I., Wabnitz G. other authors 2012; SAMHD1 restricts HIV-1 infection in resting CD4+ T cells. Nat Med 18:1682–1687 [View Article][PubMed]
     [Google Scholar]
  5. Balzarini J. 2004; Current status of the non-nucleoside reverse transcriptase inhibitors of human immunodeficiency virus type 1. Curr Top Med Chem 4:921–944[PubMed] [CrossRef]
     [Google Scholar]
  6. Biron F., Lucht F., Peyramond D., Fresard A., Vallet T., Nugier F., Grange J., Malley S., Hamedi-Sangsari F., Vila J. 1995; Anti-HIV activity of the combination of didanosine and hydroxyurea in HIV-1-infected individuals. J Acquir Immune Defic Syndr Hum Retrovirol 10:36–40 [View Article][PubMed]
     [Google Scholar]
  7. Bourée P., Lamour P., Bisaro F., Didier E. 1995; [Study of an HIV positive, tropical origin population in a refugee centre in France]. Bull Soc Pathol Exot 88:24–28 (in French) [PubMed]
     [Google Scholar]
  8. Boyer P. L., Sarafianos S. G., Clark P. K., Arnold E., Hughes S. H. 2006; Why do HIV-1 and HIV-2 use different pathways to develop AZT resistance?. PLoS Pathog 2:e10 [View Article][PubMed]
     [Google Scholar]
  9. Boyer P. L., Clark P. K., Hughes S. H. 2012; HIV-1 and HIV-2 reverse transcriptases: different mechanisms of resistance to nucleoside reverse transcriptase inhibitors. J Virol 86:5885–5894 [View Article][PubMed]
     [Google Scholar]
  10. Campbell-Yesufu O. T., Gandhi R. T. 2011; Update on human immunodeficiency virus (HIV)-2 infection. Clin Infect Dis 52:780–787 [View Article][PubMed]
     [Google Scholar]
  11. Clavel F., Guyader M., Guétard D., Sallé M., Montagnier L., Alizon M. 1986; Molecular cloning and polymorphism of the human immune deficiency virus type 2. Nature 324:691–695 [View Article][PubMed]
     [Google Scholar]
  12. Clouser C. L., Patterson S. E., Mansky L. M. 2010; Exploiting drug repositioning for discovery of a novel HIV combination therapy. J Virol 84:9301–9309 [View Article][PubMed]
     [Google Scholar]
  13. Clouser C. L., Holtz C. M., Mullett M., Crankshaw D. L., Briggs J. E., Chauhan J., VanHoutan I. M., Patterson S. E., Mansky L. M. 2011; Analysis of the ex vivo and in vivo antiretroviral activity of gemcitabine. PLoS ONE 6:e15840 [View Article][PubMed]
     [Google Scholar]
  14. Clouser C. L., Chauhan J., Bess M. A., van Oploo J. L., Zhou D., Dimick-Gray S., Mansky L. M., Patterson S. E. 2012a; Anti-HIV-1 activity of resveratrol derivatives and synergistic inhibition of HIV-1 by the combination of resveratrol and decitabine. Bioorg Med Chem Lett 22:6642–6646 [View Article][PubMed]
     [Google Scholar]
  15. Clouser C. L., Holtz C. M., Mullett M., Crankshaw D. L., Briggs J. E., O’Sullivan M. G., Patterson S. E., Mansky L. M. 2012b; Activity of a novel combined antiretroviral therapy of gemcitabine and decitabine in a mouse model for HIV-1. Antimicrob Agents Chemother 56:1942–1948 [View Article][PubMed]
     [Google Scholar]
  16. Costarelli S., Torti C., Rodella A., Baldanti F., Paolucci S., Lapadula G., Manca N., Quiros-Roldan E., Izzo I., Carosi G. 2008; Screening and management of HIV-2-infected individuals in northern Italy. AIDS Patient Care STDS 22:489–494 [View Article][PubMed]
     [Google Scholar]
  17. Daelemans D., Pauwels R., De Clercq E., Pannecouque C. 2011; A time-of-drug addition approach to target identification of antiviral compounds. Nat Protoc 6:925–933 [View Article][PubMed]
     [Google Scholar]
  18. Dapp M. J., Clouser C. L., Patterson S., Mansky L. M. 2009; 5-Azacytidine can induce lethal mutagenesis in human immunodeficiency virus type 1. J Virol 83:11950–11958 [View Article][PubMed]
     [Google Scholar]
  19. Dapp M. J., Patterson S. E., Mansky L. M. 2013; Back to the future: revisiting HIV-1 lethal mutagenesis. Trends Microbiol 21:56–62 [View Article][PubMed]
     [Google Scholar]
  20. Diamond T. L., Roshal M., Jamburuthugoda V. K., Reynolds H. M., Merriam A. R., Lee K. Y., Balakrishnan M., Bambara R. A., Planelles V. other authors 2004; Macrophage tropism of HIV-1 depends on efficient cellular dNTP utilization by reverse transcriptase. J Biol Chem 279:51545–51553 [View Article][PubMed]
     [Google Scholar]
  21. Frank I., Bosch R. J., Fiscus S., Valentine F., Flexner C., Segal Y., Ruan P., Gulick R., Wood K. other authors 2004; Activity, safety, and immunological effects of hydroxyurea added to didanosine in antiretroviral-naive and experienced HIV type 1-infected subjects: a randomized, placebo-controlled trial, ACTG 307. AIDS Res Hum Retroviruses 20:916–926 [View Article][PubMed]
     [Google Scholar]
  22. Gottlieb G. S., Badiane N. M., Hawes S. E., Fortes L., Toure M., Ndour C. T., Starling A. K., Traore F., Sall F. other authors 2009; Emergence of multiclass drug-resistance in HIV-2 in antiretroviral-treated individuals in Senegal: implications for HIV-2 treatment in resouce-limited West Africa. Clin Infect Dis 48:476–483 [View Article][PubMed]
     [Google Scholar]
  23. Harris K. S., Brabant W., Styrchak S., Gall A., Daifuku R. 2005; KP-1212/1461, a nucleoside designed for the treatment of HIV by viral mutagenesis. Antiviral Res 67:1–9 [View Article][PubMed]
     [Google Scholar]
  24. Kim B., Nguyen L. A., Daddacha W., Hollenbaugh J. A. 2012; Tight interplay among SAMHD1 protein level, cellular dNTP levels, and HIV-1 proviral DNA synthesis kinetics in human primary monocyte-derived macrophages. J Biol Chem 287:21570–21574 [View Article][PubMed]
     [Google Scholar]
  25. Lahouassa H., Daddacha W., Hofmann H., Ayinde D., Logue E. C., Dragin L., Bloch N., Maudet C., Bertrand M. other authors 2012; SAMHD1 restricts the replication of human immunodeficiency virus type 1 by depleting the intracellular pool of deoxynucleoside triphosphates. Nat Immunol 13:223–228 [View Article][PubMed]
     [Google Scholar]
  26. Lori F., Malykh A. G., Foli A., Maserati R., De Antoni A., Minoli L., Padrini D., Degli Antoni A. M., Barchi E. other authors 1997; Combination of a drug targeting the cell with a drug targeting the virus controls human immunodeficiency virus type 1 resistance. AIDS Res Hum Retroviruses 13:1403–1409 [View Article][PubMed]
     [Google Scholar]
  27. MacNeil A., Sarr A. D., Sankalé J. L., Meloni S. T., Mboup S., Kanki P. 2007; Direct evidence of lower viral replication rates in vivo in human immunodeficiency virus type 2 (HIV-2) infection than in HIV-1 infection. J Virol 81:5325–5330 [View Article][PubMed]
     [Google Scholar]
  28. Menéndez-Arias L., Alvarez M. 2014; Antiretroviral therapy and drug resistance in human immunodeficiency virus type 2 infection. Antiviral Res 102:70–86 [View Article][PubMed]
     [Google Scholar]
  29. Mullins J. I., Heath L., Hughes J. P., Kicha J., Styrchak S., Wong K. G., Rao U., Hansen A., Harris K. S. other authors 2011; Mutation of HIV-1 genomes in a clinical population treated with the mutagenic nucleoside KP1461. PLoS ONE 6:e15135 [View Article][PubMed]
     [Google Scholar]
  30. Nguyen L. A., Kim D. H., Daly M. B., Allan K. C., Kim B. 2014; Host SAMHD1 protein promotes HIV-1 recombination in macrophages. J Biol Chem 289:2489–2496 [View Article][PubMed]
     [Google Scholar]
  31. Ntemgwa M. L., d’Aquin Toni T., Brenner B. G., Camacho R. J., Wainberg M. A. 2009; Antiretroviral drug resistance in human immunodeficiency virus type 2. Antimicrob Agents Chemother 53:3611–3619 [View Article][PubMed]
     [Google Scholar]
  32. Post K., Guo J., Howard K. J., Powell M. D., Miller J. T., Hizi A., Le Grice S. F., Levin J. G. 2003; Human immunodeficiency virus type 2 reverse transcriptase activity in model systems that mimic steps in reverse transcription. J Virol 77:7623–7634 [View Article][PubMed]
     [Google Scholar]
  33. Rawson J. M., Heineman R. H., Beach L. B., Martin J. L., Schnettler E. K., Dapp M. J., Patterson S. E., Mansky L. M. 2013; 5,6-Dihydro-5-aza-2′-deoxycytidine potentiates the anti-HIV-1 activity of ribonucleotide reductase inhibitors. Bioorg Med Chem 21:7222–7228 [View Article][PubMed]
     [Google Scholar]
  34. Rey M. A., Krust B., Laurent A. G., Guétard D., Montagnier L., Hovanessian A. G. 1989; Characterization of an HIV-2-related virus with a smaller sized extracellular envelope glycoprotein. Virology 173:258–267 [View Article][PubMed]
     [Google Scholar]
  35. Rodés B., Holguín A., Soriano V., Dourana M., Mansinho K., Antunes F., González-Lahoz J. 2000; Emergence of drug resistance mutations in human immunodeficiency virus type 2-infected subjects undergoing antiretroviral therapy. J Clin Microbiol 38:1370–1374[PubMed]
     [Google Scholar]
  36. Roquebert B., Damond F., Collin G., Matheron S., Peytavin G., Bénard A., Campa P., Chêne G., Brun-Vézinet F. . other authors 2008; HIV-2 integrase gene polymorphism and phenotypic susceptibility of HIV-2 clinical isolates to the integrase inhibitors raltegravir and elvitegravir in vitro. J Antimicrob Chemother 62:914–920 [View Article][PubMed]
     [Google Scholar]
  37. Smith R. A., Gottlieb G. S., Anderson D. J., Pyrak C. L., Preston B. D. 2008; Human immunodeficiency virus types 1 and 2 exhibit comparable sensitivities to Zidovudine and other nucleoside analog inhibitors in vitro . Antimicrob Agents Chemother 52:329–332 [View Article][PubMed]
     [Google Scholar]
  38. Smith R. A., Anderson D. J., Pyrak C. L., Preston B. D., Gottlieb G. S. 2009; Antiretroviral drug resistance in HIV-2: three amino acid changes are sufficient for classwide nucleoside analogue resistance. J Infect Dis 199:1323–1326 [View Article][PubMed]
     [Google Scholar]
  39. Smith R. A., Raugi D. N., Kiviat N. B., Hawes S. E., Mullins J. I., Sow P. S., Gottlieb G. S. University of Washington-Dakar HIV-2 Study Group 2011; Phenotypic susceptibility of HIV-2 to raltegravir: integrase mutations Q148R and N155H confer raltegravir resistance. AIDS 25:2235–2241 [View Article][PubMed]
     [Google Scholar]
  40. Soares R. S., Tendeiro R., Foxall R. B., Baptista A. P., Cavaleiro R., Gomes P., Camacho R., Valadas E., Doroana M. other authors 2011; Cell-associated viral burden provides evidence of ongoing viral replication in aviremic HIV-2-infected patients. J Virol 85:2429–2438 [View Article][PubMed]
     [Google Scholar]
  41. St Gelais C., de Silva S., Amie S. M., Coleman C. M., Hoy H., Hollenbaugh J. A., Kim B., Wu L. 2012; SAMHD1 restricts HIV-1 infection in dendritic cells (DCs) by dNTP depletion, but its expression in DCs and primary CD4+ T-lymphocytes cannot be upregulated by interferons. Retrovirology 9:105 [View Article][PubMed]
     [Google Scholar]
  42. van der Ende M. E., Kroes A. C., Buitenwerf J., van der Poel C. L. 1990; [Aids caused by HIV-2 in The Netherlands]. Ned Tijdschr Geneeskd 134:495–497 (in Dutch) [PubMed]
     [Google Scholar]
  43. Witvrouw M., Pannecouque C., Switzer W. M., Folks T. M., De Clercq E., Heneine W. 2004; Susceptibility of HIV-2, SIV and SHIV to various anti-HIV-1 compounds: implications for treatment and postexposure prophylaxis. Antivir Ther 9:57–65[PubMed]
     [Google Scholar]
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Novel inhibitors of human immunodeficiency virus type 2 infectivity
J. Gen. Virol. 95, 2778 (2014); https://doi.org/10.1099/vir.0.069864-0
/content/journal/jgv/10.1099/vir.0.069864-0
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