Inhibition of HIV-1 Replication in Human Primary Cells by a Dolabellane Diterpene Isolated from the Marine Algae Dictyota pfaffii

Abstract

We describe in this paper that the dolabellane diterpene 8,10,18-trihydroxy-2,6-dolabelladiene (3), isolated from the marine algae Dictyota pfaffii, inhibits the HIV-1 infection in human primary cells and tumor cell lines. We initially observed that compound 3 inhibited the activity of a purified HIV-1 enzyme reverse transcriptase (RT) in a dose-dependent manner, with an IC₅₀ value of 16.5 ± 4.3 μM. Next, we found that compound 3 inhibited HIV-1 infection by an R5-tropic isolate in peripheral blood mononuclear cells (PBMCs) in a dose-dependent manner with an EC₅₀ value of 8.4 ± 2.8 μM. The replication of HIV-1 isolates presenting distinct tropism for chemokine receptors was also inhibited, as analyzed in PBMCs or U87 cells infected with R5-, X4- or R5X4-tropic isolates. Likewise, compound 3 blocked HIV-1 infection in macrophages by R5 and R5X4 viruses in a dose-dependent manner with EC₅₀ values of 1.7 ± 0.6 μM and 1.85 ± 0.75 μM, respectively. Compound 3 sustained antiretroviral activity even when added to HIV-1-infected Sup-T1 cells at 12 h after infection, suggesting that, as well as inhibiting HIV-1 RT, it also blocks HIV-1 replication at a post transcriptional step. Our results support further investigations on compound 3 pharmacokinetics and we propose that this diterpene could be considered as a potential compound for HIV-1 therapy.

Dictyota pfaffii - HIV-1 - AIDS - diterpenes - dolabellane

References

• 1 Berger E A, Murphy P M, Farber J M. Chemokine receptors as HIV-1 coreceptors: roles in viral entry, tropism, and disease.  Annu Rev Immunol. 1999;  17 657-700
• 2 Peterlin B M, Trono D. Hide, shield and strike back: how HIV-infected cells avoid immune eradication. Nat Rev Immunol 2003: 97-107
• 3 Stevenson M. HIV-1 pathogenesis.  Nat Med. 2003;  9 853-60
• 4 Richman D D. HIV chemotherapy.  Nature. 2001;  410 995-1001
• 5 Blankson J N, Persaud D, Siliciano R. The challenge of viral reservoir in HIV-1 infection.  Annu Rev Med. 2002;  53 557-93
• 6 Condra J H, Miller M D, Hazuda D J, Emini E A. Potential new therapies for the treatment of HIV-1 infection.  Annu Rev Med. 2002;  53 541-55
• 7 Jung M, Lee S, Kim H. Recent studies on natural products as anti-HIV agents.  Curr Med Chem. 2000;  7 649-61
• 8 Huang L, Chen C H. Molecular targets of anti-HIV-1 triterpenes.  Curr Drug Targets Infect Disord. 2002;  2 33-6
• 9 Pereira H S, Leão-Ferreira L R, Moussatché N, Teixeira V L, Cavalcanti D N, Costa L J. et al . Antiviral activity of diterpenes isolated from the Brazilian marine alga Dictyota menstrualis against human immunodeficiency virus type 1 (HIV-1).  Antiviral Res. 2004;  64 69-76
• 10 Aiken C, Chen C H. Betulinic acid derivatives as HIV-1 antivirals.  Trends Mol Med. 2005;  11 31-6
• 11 Mengoni F, Lichtner M, Battinelli L, Marzi M, Mastroianni C M, Vullo V. et al . In vitro anti-HIV activity of oleanolic acid on infected human mononuclear cells.  Planta Med. 2002;  68 111-4
• 12 Xu H X, Zeng F Q, Wan M, Sim K Y. Anti-HIV triterpene acids from Geum japonicum .  J Nat Prod. 1996;  59 643-5
• 13 Barbosa J P, Pereira R C, Abrantes J L, Santos C CC, Rebello M A, Frugulhetti I CPP. et al . Antiviral diterpenes from the Brazilian brown alga Dictyota pfaffii .  Planta Med. 2004;  70 856-60
• 14 Verani A, Scarlatti G, Comar M, Tresoldi E, Polo S, Giacca M. et al . C-C chemokines released by lipopolysaccharide (LPS)-stimulated human macrophages suppress HIV-1 infection in both macrophages and T cells.  J Exp Med. 1997;  185 805-16
• 15 Hill C M, Deng H, Unutmaz D, Kewalramani V N, Bastiani L, Gorny M K. et al . Envelope glycoproteins from human immunodeficiency virus types 1 and 2 and simian immunodeficiency virus can use human CCR5 as a coreceptor for viral entry and make direct CD4-dependent interactions with this chemokine receptor.  J Virol. 1997;  71 6296-304
• 16 Brazilian Network for HIV Isolation and C haracterization. HIV-1 diversity in Brazil: genetic, biologic, and immunologic characterization of HIV-1 strains in thee potential HIV vaccine evaluation sites.  J Acquir Immune Defic Syndr. 2000;  23 184-93
• 17 Ferraro G A, Mello M AG, Sutmoller F, Van Weyenberg J, Brazilian Network for HIV Isolation and C haracterization, Shindo N. et al . Biological characterization and chemokine receptor usage of HIV type 1 isolates prevalent in Brazil.  AIDS Res Hum Retroviruses. 2001;  17 1241-7
• 18 Da Matta A D, Santos C VE, Pereira H S, Frugulhetti I CPP, Oliveira M RP, Souza M CBV. Synthesis of novel nucleosides of 4-oxoquinoline-3-carboxylic acid analogues.  Heteroatom Chem. 1999;  10 197-202
• 19 Scudiero D A, Shoemaker R H, Paull K D, Monks A, Tierney S, Nozfziger T H. et al . Evaluation of a soluble tetrazolium/formazan assay for cell growth and drug sensitivity in culture using human and other tumor cell lines.  Cancer Res. 1988;  48 4827-33
• 20 Bou-Habib D C, Gregory R, Oravecz T, Phillip W B, Lusso P, Norcross M A. Cryptic nature of envelope V3 region epitopes protects primary monocytotropic human immunodeficiency virus type 1 from antibody neutralization.  J Virol. 1994;  68 6006-13
• 21 Siliciano J D, Siliciano R F. A long-term latent reservoir for HIV-1: discovery and clinical implications.  J Antimicrob Chemother. 2004;  54 6-9
• 22 De Clercq E. HIV inhibitors targeted at the reverse transcriptase.  AIDS Res Hum Retroviruses. 1992;  8 119-34
• 23 Bell C, Matthews G V, Nelson M R. Non-nucleoside reverse transcriptase inhibitors - an overview.  Int J STD AIDS. 2003;  14 71-7
• 24 Ninomya M, Matsuka S, Kawakubo A, Bito N. HIV-1 reverse transcriptase inhibitors containing hydroxydictyodial or dictyodial.  Jpn Kokai Tokkyo Koho JP. 1995;  285 877
• 25 Schuitemaker H, Koot M, Kootstra N A, Derckensen M W, De Goede R E, van Steenwijk R P. et al . Biological phenotype of human immunodeficiency virus type 1 clones at different stages of infection: progression of disease is associated with a shift from monocytotropic to T-cell-tropic virus population.  J Virol. 1992;  66 1354-60