A Multi-targeted Drug Candidate with Dual Anti-HIV and Anti-HSV Activity

English version České info

Human immunodeficiency virus (HIV) infection is often accompanied by infection with other pathogens, in particular herpes simplex virus type 2 (HSV-2). The resulting coinfection is involved in a vicious circle of mutual facilitations. Therefore, an important task is to develop a compound that is highly potent against both viruses to suppress their transmission and replication. Here, we report on the discovery of such a compound, designated PMEO-DAPym. We compared its properties with those of the structurally related and clinically used acyclic nucleoside phosphonates (ANPs) tenofovir and adefovir. We demonstrated the potent anti-HIV and -HSV activity of this drug in a diverse set of clinically relevant in vitro, ex vivo, and in vivo systems including (i) CD4⁺ T-lymphocyte (CEM) cell cultures, (ii) embryonic lung (HEL) cell cultures, (iii) organotypic epithelial raft cultures of primary human keratinocytes (PHKs), (iv) primary human monocyte/macrophage (M/M) cell cultures, (v) human ex vivo lymphoid tissue, and (vi) athymic nude mice. Upon conversion to its diphosphate metabolite, PMEO-DAPym markedly inhibits both HIV-1 reverse transcriptase (RT) and HSV DNA polymerase. However, in striking contrast to tenofovir and adefovir, it also acts as an efficient immunomodulator, inducing β-chemokines in PBMC cultures, in particular the CCR5 agonists MIP-1β, MIP-1α and RANTES but not the CXCR4 agonist SDF-1, without the need to be intracellularly metabolized. Such specific β-chemokine upregulation required new mRNA synthesis. The upregulation of β-chemokines was shown to be associated with a pronounced downmodulation of the HIV-1 coreceptor CCR5 which may result in prevention of HIV entry. PMEO-DAPym belongs conceptually to a new class of efficient multitargeted antivirals for concomitant dual-viral (HSV/HIV) infection therapy through inhibition of virus-specific pathways (i.e. the viral polymerases) and HIV transmission prevention through interference with host pathways (i.e. CCR5 receptor down regulation).

Vyšlo v časopise: A Multi-targeted Drug Candidate with Dual Anti-HIV and Anti-HSV Activity. PLoS Pathog 9(7): e32767. doi:10.1371/journal.ppat.1003456
Kategorie: Research Article
prolekare.web.journal.doi_sk: https://doi.org/10.1371/journal.ppat.1003456

Souhrn

Zdroje

1. BlowerS, MaL (2004) Calculating the contribution of herpes simplex virus type 2 epidemics to increasing HIV incidence: treatment implications. Clin Infect Dis 39, Suppl 5: S240–S247.

2. CoreyL (2007) Synergistic copathogens–HIV-1 and HSV-2. N Engl J Med 356: 854–856.

3. BuvéA (2010) Can we reduce the spread of HIV infection by suppressing herpes simplex virus type 2 infection? F1000 Med Rep 2: 41.

4. FreemanEE, WeissHA, GlynnJR, CrossPL, WhitworthJA, et al. (2006) Herpes simplex virus 2 infection increases HIV acquisition in men and women: systematic review and meta-analysis of longitudinal studies. AIDS 20: 73–83.

5. MartinelliE, TharingerH, FrankI, ArthosJ, PiatakMJr, et al. (2011) HSV-2 infection of dendritic cells amplifies a highly susceptible HIV-1 cell target. PLoS Pathog 7: e1002109.

6. SchackerT, RyncarzAJ, GoddardJ, DiemK, ShaughnessyM, et al. (1998) Frequent recovery of HIV-1 from genital herpes simplex virus lesions in HIV-1-infected men. JAMA 280: 61–66.

7. LehnerT, HussainL, WilsonJ, ChapmanM (1991) Mucosal transmission of HIV. Nature 353: 709.

8. SpiraAI, MarxPA, PattersonBK, MahoneyJ, KoupRA, et al. (1996) Cellular targets of infection and route of viral dissemination after an intravaginal inoculation of simian immunodeficiency virus into rhesus macaques. J Exp Med 183: 215–225.

9. MoriuchiM, MoriuchiH, WilliamsR, StrausSE (2000) Herpes simplex virus infection induces replication of human immunodeficiency virus type 1. Virology 278: 534–540.

10. BalzariniJ, HolýA, JindrichJ, NaesensL, SnoeckR, et al. (1993) Differential antiherpesvirus and antiretrovirus effects of the (S) and (R) enantiomers of acyclic nucleoside phosphonates: potent and selective in vitro and in vivo antiretrovirus activities of (R)-9-(2-phosphonomethoxypropyl)-2,6-diaminopurine. Antimicrob Agents Chemother 37: 332–338.

11. ElionGB, FurmanPA, FyfeJA, de MirandaP, BeauchampL, et al. (1977) Selectivity of action of an antiherpetic agent, 9-(2-hydroxyethoxymethyl) guanine. Proc Natl Acad Sci US A 74: 5716–5720.

12. NagotN, OuédraogoA, FoulongneV, KonatéI, WeissHA, et al. (2007) Reduction of HIV-1 RNA levels with therapy to suppress herpes simplex virus. N Engl J Med 356: 790–799.

13. DelanyS, MlabaN, ClaytonT, AkpomiemieG, CapovillaA, et al. (2009) Impact of aciclovir on genital and plasma HIV-1 RNA in HSV-2/HIV-1 co-infected women: a randomized placebo-controlled trial in South Africa. AIDS 23: 461–469.

14. LudemaC, ColeSR, PooleC, ChuH, EronJJ (2011) Meta-analysis of randomized trials on the association of prophylactic acyclovir and HIV-1 viral load in individuals coinfected with herpes simplex virus-2. AIDS 25: 1265–1269.

15. MugwanyaK, BaetenJM, MugoNR, IrunguE, NgureK, et al. (2011) High-dose valacyclovir HSV-2 suppression results in greater reduction in plasma HIV-1 levels compared with standard dose acyclovir among HIV-1/HSV-2 coinfected persons: a randomized, crossover trial. J Infect Dis 204: 1912–1917.

16. Abdool KarimQ, Abdool KarimSS, FrohlichJA, GroblerAC, BaxterC, et al. (2010) Effectiveness and safety of tenofovir gel, an antiretroviral microbicide, for the prevention of HIV infection in women. Science 329: 1168–1174.

17. CatesWJr (2010) After CAPRISA 004: time to re-evaluate the HIV lexicon. Lancet 376: 495–496.

18. LiscoA, VanpouilleC, TchesnokovEP, GrivelJC, BiancottoA, et al. (2008) Acyclovir is activated into a HIV-1 reverse transcriptase inhibitor in herpesvirus-infected human tissues. Cell Host Microbe 4: 260–270.

19. AndreiG, LiscoA, VanpouilleC, IntroiniA, BalestraE, et al. (2011) Topical tenofovir, a microbicide effective against HIV, inhibits herpes simplex virus-2 replication. Cell Host Microbe 10: 379–389.

20. De ClercqE, SakumaT, BabaM, PauwelsR, BalzariniJ, et al. (1987) Antiviral activity of phosphonylmethoxyalkyl derivatives of purine and pyrimidines. Antiviral Res 8: 261–272.

21. PauwelsR, BalzariniJ, ScholsD, BabaM, DesmyterJ, et al. (1988) Phosphonylmethoxyethyl purine derivatives, a new class of anti-human immunodeficiency virus agents. Antimicrob Agents Chemother 32: 1025–1030.

22. HeijtinkRA, De WildeGA, KruiningJ, BerkL, BalzariniJ, et al. (1993) Inhibitory effect of 9-(2-phosphonylmethoxyethyl)-adenine (PMEA) on human and duck hepatitis B virus infection. Antiviral Res 21: 141–153.

23. LehnerT, HussainL, WilsonJ, ChapmanM (1991) Mucosal transmission of HIV. Nature 353: 709.

24. GrivelJC, MargolisL (2009) Use of human tissue explants to study human infectious agents. Nat Protoc 4: 256–269.

25. BalzariniJ, ScholsD, Van LaethemK, De ClercqE, HockováD, et al. (2007) Pronounced in vitro and in vivo antiretroviral activity of 5-substituted 2,4-diamino-6-[2-(phosphonomethoxy)ethoxy] pyrimidines. J Antimicrob Chemother 59: 80–86.

26. ThurmanAR, DoncelGF (2012) Herpes simplex virus and HIV: genital infection synergy and novel approaches to dual prevention. Int J STD AIDS 23: 613–619.

27. JiangY, JollyPE (1999) Effect of beta-chemokines on human immunodeficiency virus type 1 replication, binding, uncoating, and CCR5 receptor expression in human monocyte-derived macrophages. J Hum Virol 2: 123–132.

28. CremerI, VieillardV, De MaeyerE (2000) Retrovirally mediated IFN-beta transduction of macrophages induces resistance to HIV, correlated with up-regulation of RANTES production and down-regulation of C-C chemokine receptor-5 expression. J Immunol 164: 1582–1587.

29. BergmeierLA, WangY, LehnerT (2002) The role of immunity in protection from mucosal SIV infection in macaques. Oral Dis 8, Suppl 2: 63–68.

30. DudleyDM, WentzelJL, LalondeMS, VeazeyRS, ArtsEJ (2009) Selection of a simian-human immunodeficiency virus strain resistant to a vaginal microbicide in macaques. J Virol 83: 5067–5076.

31. AhmedRK, MakitaloB, KarlenK, NilssonC, BiberfeldG, et al. (2002) Spontaneous production of RANTES and antigen-specific IFN-gamma production in macaques vaccinated with SHIV-4 correlates with protection against SIVsm challenge. Clin Exp Immunol 129: 11–18.

32. IntroiniA, VanpouilleC, LiscoA, GrivelJC, MargolisL (2013) Interleukin-7 facilitates HIV-1 transmission to cervico-vaginal tissue ex vivo. PLoS Pathog 9: e1003148.

33. TaubDD, LloydAR, ConlonK, WangJM, OrtaldoJR, et al. (1993) Recombinant human interferon-inducible protein 10 is a chemoattractant for human monocytes and T lymphocytes and promotes T cell adhesion to endothelial cells. J Exp Med 177: 1809–1814.

34. WerryTD, WilkinsonGF, WillarsGB (2003) Cross talk between P2Y2 nucleotide receptors and CXC chemokine receptor 2 resulting in enhanced Ca2+ signaling involves enhancement of phospholipase C activity and is enabled by incremental Ca2+ release in human embryonic kidney cells. J Pharmacol Exp Ther 307: 661–669.

35. HuskensD, VermeireK, ProfyAT, ScholsD (2009) The candidate sulfonated microbicide, PRO 2000, has potential multiple mechanisms of action against HIV-1. Antiviral Res 84: 38–47.

36. Abdool KarimSS, RichardsonBA, RamjeeG, HoffmanIF, ChirenjeZM, et al. (2011) Safety and effectiveness of BufferGel and 0.5% PRO2000 gel for the prevention of HIV infection in women. AIDS 25: 957–966.

37. KedzierskaK, CroweSM (2001) Cytokines and HIV-1: interactions and clinical implications. Antivir Chem Chemother 12: 133–150.

38. KedzierskaK, CroweSM, TurvilleS, CunninghamAL (2003) The influence of cytokines, chemokines and their receptors on HIV-1 replication in monocytes and macrophages. Rev Med Virol 13: 39–56.

39. LehnerT, WangY, CranageM, TaoL, MitchellE, et al. (2009) Up-regulation of beta-chemokines and down-modulation of CCR5 co-receptors inhibit simian immunodeficiency virus transmission in non-human primates. Immunology 99: 569–577.

40. PastoriC, WeiserB, BarassiC, Uberti-FoppaC, GhezziS, et al. (2006) Long-lasting CCR5 internalization by antibodies in a subset of long-term nonprogressors: a possible protective effect against disease progression. Blood 107: 4825–4833.

41. HerediaA, AmorosoA, DavisC, LeN, ReardonE, et al. (2003) Rapamycin causes down-regulation of CCR5 and accumulation of anti-HIV beta-chemokines: an approach to suppress R5 strains of HIV-1. Proc Natl Acad Sci U S A 100: 10411–10416.

42. RohanLC, MonclaBJ, Kunjara Na AyudhyaRP, CostM, et al. (2010) In vitro and ex vivo testing of tenofovir shows it is effective as an HIV-1 microbicide. PLoS One 5: e9310.

43. Schwartz JL, Rountree R, Kashuba A, et al.. (2009) A multi-compartment, single and multiple dose pharmacokinetic study of the candidate vaginal microbicide 1% tenofovir gel. 5th IAS Conference on HIV Pathogenesis, Treatment and Prevention, Cape Town, South Africa, 19–22 July 2009, Abstract LBDECO3.

44. AndreiG, van den OordJ, FitenP, OpdenakkerG, De Wolf-PeetersC, et al. (2005) Organotypic epithelial raft cultures as a model for evaluating compounds against alphaherpesviruses. Antimicrob Agents Chemother 49: 4671–4680.

45. MontefioriDC (2009) Measuring HIV neutralization in a luciferase reporter gene assay. Methods Mol Biol 485: 395–405.

46. BalzariniJ, PannecouqueC, De ClercqE, AquaroS, PernoC-F, et al. (2002) Antiretrovirus activity of a novel class of acyclic pyrimidine nucleoside phosphonates. Antimicrob Agents Chemother 46: 2185–2193.

47. HolýA, VotrubaI, MasojídkováM, AndreiG, SnoeckR, et al. (2002) 6-[2-(Phosphonomethoxy)alkoxy]pyrimidines with antiviral activity. J Med Chem 45: 1918–1929.

48. AndreiG, SnoeckR, De ClercqE, EsnoufR, FitenP, et al. (2000) Resistance of herpes simplex virus type 1 against different phosphonylmethoxyalkyl derivatives of purines and pyrimidines due to specific mutations in the viral DNA polymerase gene. J Gen Virol 81: 639–648.

49. BrandG, SchiavanoGF, BalestraE, TavazziB, PernoC-F, et al. (2001) The potency of acyclovir can be markedly different in different cell types. Life Sci 69: 1285–1290.

50. BiancottoA, BrichacekB, ChenSS, FitzgeraldW, LiscoA, et al. (2009) A highly sensitive and dynamic immunofluorescent cytometric bead assay for the detection of HIV-1 p24. J Virol Methods 157: 98–101.

51. AquaroS, MentenP, StruyfS, ProostP, Van DammeJ, et al. (2001) The LD78beta isoform of MIP-1alpha is the most potent CC-chemokine in inhibiting CCR5-dependent human immunodeficiency virus type 1 replication in human macrophages. J Virol 75: 4402–4406.

52. HuskensD, FérirG, VermeireK, KehrJC, BalzariniJ, et al. (2010) Microvirin, a novel alpha(1,2)-mannose-specific lectin isolated from Microcystis aeruginosa, has anti-HIV-1 activity comparable with that of cyanovirin-N but a much higher safety profile. J Biol Chem 285: 24845–24854.

53. YingC, HolýA, HockováD, HavlasZ, De ClercqE, et al. (2005) Novel acyclic nucleoside phosphonate analogues with potent anti-hepatitis B virus activities. Antimicrob Agents Chemother 49: 1177–1180.

54. HermanBD, VotrubaI, HolýA, Sluis-CremerN, BalzariniJ (2010) The acyclic 2,4-diaminopyrimidine nucleoside phosphonate acts as a purine mimetic in HIV-1 reverse transcriptase DNA polymerization. J Biol Chem 285: 12101–12108.