Skip to main content
PMC home page
The AAPS Journal logoLink to The AAPS Journal
. 2005 Oct 19;7(3):E572–E578. doi: 10.1208/aapsj070358

RNAi-directed inhibition of DC-SIGN by dendritic cells: Prospects for HIV-1 therapy

Madhavan P N Nair 1,✉, Jessica L Reynolds 1, Supriya D Mahajan 1, Stanley A Schwartz 1, Ravikumar Aalinkeel 1, B Bindukumar 1, Don Sykes 1
PMCID: PMC2751260  PMID: 16353935

Abstract

Drug-resistant human immunodeficiency virus (HIV) infections are increasing globally, especially in North America. Therefore, it is logical to develop new therapies directed against HIV binding molecules on susceptible host cells in addition to current treatment modalities against virus functions. Inhibition of the viral genome can be achieved by degrading or silencing posttranslational genes using small interfering (si) ribonucleic acids (RNAs) consisting of double-stranded forms of RNA. These siRNAs usually contain 21–23 base pairs (bp) and are highly specific for the nucleotide sequence of the target messenger RNA (mRNA). These siRNAs form a complex with helicase and nuclease enzymes known as “RNA-induced silencing complex” (RISC) that leads to target RNA degradation. Thus, siRNA has become a method of selective destruction of HIV now used by various investigators around the globe. However, given the sequence divesity of the HIV genomes of infected subjects, it is difficult to target a specific HIV sequence. Therefore, targeting nonvariable HIV binding receptors on susceptible cells or other molecules of host cells that are directly or indirectly involved in HIV infections may be an interesting alternative to targeting the virus itself. Thus, the simultaneous use of siRNAs specific for HIV and host cells may be a unique, new approach to the therapy that siRNA directed at the CD4 independent attachment receptor (DC-SIGN) significantly inhibits HIV infection of dendritic cells (DCs). This effect may be mediated by modulation of p38 mitogen activated protein kinase (MAPK).

Keywords: siRNA, DC-SIGN, HIV-1, dendritic cells, costimulatory molecules, HIV-LTR/U5, MAPK

Full Text

The Full Text of this article is available as a PDF (330.4 KB).

References

  • 1.Fire A, Xu S, Montgomery MK, Kostas SA, Driver SE, Mello CC. Potent and specific genetic interference by double-stranded RNA in Caenorhabditis elegans. Nature. 1998;391:806–811. doi: 10.1038/35888. [DOI] [PubMed] [Google Scholar]
  • 2.Caplen NJ, Parrish S, Imani F, Fire A, Morgan RA. Specific inhibition of gene expression by small double-stranded RNAs in invertebrate and vertebrate systems. Proc Natl Acad Sci USA. 2001;98:9742–9747. doi: 10.1073/pnas.171251798. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 3.Clemens JC, Worby CA, Simonson-Leff N, et al. Use of double-stranded RNA interference in Drosophila cell lines to dissect signal transduction pathways. Proc Natl Acad Sci USA. 2000;97:6499–6503. doi: 10.1073/pnas.110149597. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 4.Elbashir SM, Harborth J, Lendeckel W, Yalcin A, Weber K, Tuschl T. Duplexes of 21-nucleotide RNAs mediate RNA interference in cultured mammalian cells. Nature. 2001;411:494–498. doi: 10.1038/35078107. [DOI] [PubMed] [Google Scholar]
  • 5.Elbashir SM, Lendeckel W, Tuschl T. RNA interference is mediated by 21- and 22-nucleotide RNAs. Genes Dev. 2001;15:188–200. doi: 10.1101/gad.862301. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 6.Bass BL. Double-stranded RNA as a template for gene silencing. Cell. 2000;101:235–238. doi: 10.1016/S0092-8674(02)71133-1. [DOI] [PubMed] [Google Scholar]
  • 7.Hamilton AJ, Baulcombe DC. A species of small antisense RNA in posttranscriptional gene silencing in plants. Science. 1999;286:950–952. doi: 10.1126/science.286.5441.950. [DOI] [PubMed] [Google Scholar]
  • 8.Zamore PD, Tuschl T, Sharp PA, Bartel DP. RNAi: double-stranded RNA directs the ATP-dependent cleavage of mRNA at 21 to 23 nucleotide intervals. Cell. 2000;101:25–33. doi: 10.1016/S0092-8674(00)80620-0. [DOI] [PubMed] [Google Scholar]
  • 9.Sodroski J, Patarca R, Rosen C, Wong-Staal F, Haseltine W. Location of the trans-activating region on the genome of human T-cell lymphotropic virus type III. Science. 1985;229:74–77. doi: 10.1126/science.2990041. [DOI] [PubMed] [Google Scholar]
  • 10.Jacque JM, Triques K, Stevenson M. Modulation of HIV-1 replication by RNA interference. Nature. 2002;418:435–438. doi: 10.1038/nature00896. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 11.Coburn GA, Cullen BR. Potent and specific inhibition of human immunodeficiency virus type 1 replication by RNA interference. J Virol. 2002;76:9225–9231. doi: 10.1128/JVI.76.18.9225-9231.2002. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 12.Novina CD, Murray MF, Dykxhoom DM, et al. siRNA-directed inhibition of HIV-1 infection. Nat Med. 2002;8:681–686. doi: 10.1038/nm725. [DOI] [PubMed] [Google Scholar]
  • 13.Park WS, Miyano-Kurosaki N, Hayafune M, et al. Prevention of HIV-1 infection in human peripheral blood mononuclear cells by specific RNA interference. Nucleic Acids Res. 2002;30:4830–4835. doi: 10.1093/nar/gkf627. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 14.Hu WY, Bushman FD, Siva AC. RNA interference against retroviruses. Virus Res. 2004;102:59–64. doi: 10.1016/j.virusres.2004.01.016. [DOI] [PubMed] [Google Scholar]
  • 15.Anderson J, Banerjea A, Akkina R. Bispecific short hairpin siRNA constructs targeted to CD4, CXCR4, and CCR5 confer HIV-1 resistance. Oligonucleotides. 2003;19:303–312. doi: 10.1089/154545703322616989. [DOI] [PubMed] [Google Scholar]
  • 16.Anderson J, Banerjea A, Planelles V, Akkina R. Potent suppression of HIV type 1 infection by a short hairpin anti-CXCR4 siRNA. AIDS Res Hum Retroviruses. 2003;19:699–706. doi: 10.1089/088922203322280928. [DOI] [PubMed] [Google Scholar]
  • 17.Martinez MA, Gutierez A, Armand-Ugon M, et al. Suppression of chemokine receptor expression by RNA interference allows for inhibition of HIV-1 replications. AIDS. 2002;16:2385–2390. doi: 10.1097/00002030-200212060-00002. [DOI] [PubMed] [Google Scholar]
  • 18.Qin XF, An DS, Chen IS, Baltimore D. Inhibiting HIV-1 infection in human T cells by lentiviral-mediated delivery of small interfering RNA against CCR5. Proc Natl Acad Sci USA. 2003;100:183–188. doi: 10.1073/pnas.232688199. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 19.Cordelier P, Morse B, Strayer DS. Targeting CCR5 with siRNAs: using recombinant SV40-derived vectors to protect macrophages and microglia from R5-tropic HIV. Oligonucleotides. 2003;13:281–294. doi: 10.1089/154545703322616961. [DOI] [PubMed] [Google Scholar]
  • 20.Arrighi JF, Pion M, Garcia E, et al. DC-SIGN-mediated infectious synapse formation enhances X4 HIV-1 transmission from dendritic cells to T cells. J Exp Med. 2004;200:1279–1288. doi: 10.1084/jem.20041356. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 21.Arrighi JF, Pion M, Wiznerowicz M, et al. Lentivirus-mediated RNA interference of DC-SIGN expression inhibits human immunodeficiency virus transmission from dendritic cells to T cells. J Virol. 2004;78:10848–10855. doi: 10.1128/JVI.78.20.10848-10855.2004. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 22.Smithgall MD, Wong JG, Linsley PS, Haffar OK. Costimulation of CD4+ T cells via CD28 modulates human immunodeficiency virus type 1 infection and replication in vitro. AIDS Res Hum Retroviruses. 1995;11:885–892. doi: 10.1089/aid.1995.11.885. [DOI] [PubMed] [Google Scholar]
  • 23.Hiscott J, Kwon H, Genin P. Hostile takeovers: viral appropriation of the NF-kappaB pathway. J Clin Invest. 2001;107:143–151. doi: 10.1172/JCI11918. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 24.Daner M, Obermaier B, Herten J, et al. Mature dendritic cells derived from human monocytes within 48 hours: a novel strategy for dendritic cell differentiation from blood precursors. J Immunol. 2003;170:4069–4076. doi: 10.4049/jimmunol.170.8.4069. [DOI] [PubMed] [Google Scholar]
  • 25.Chomczynski P, Sacchi N. Single-step method of RNA isolation by acid guanidinium thiocyanate-phenol-chloroform extraction. Anal Biochem. 1987;162:156–159. doi: 10.1016/0003-2697(87)90021-2. [DOI] [PubMed] [Google Scholar]
  • 26.Shively L, Chang L, LeBon JM, Liu Q, Riggs AD, Singer-Sam J. Real-time PCR assay for quantitative mismatch detection. Biotechniques. 2003;34:498–502. doi: 10.2144/03343st01. [DOI] [PubMed] [Google Scholar]
  • 27.Secchiero P, Zella D, Curreli S, et al. Engagement of CD28 modulates CXC chemokine receptor 4 surface expression in both resting and CD3-stimulated CD4+ cells. J Immunol. 2000;164:4018–4024. doi: 10.4049/jimmunol.164.8.4018. [DOI] [PubMed] [Google Scholar]
  • 28.Bashirova AA, Wu L, Cheng J, Kewal-Ramani VN, Hughes A, Carrington M. Novel member of the CD209 (DC-SIGN) gene family in primates. J Virol. 2003;77:217–227. doi: 10.1128/JVI.77.1.217-227.2003. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 29.Steinman RM, Young JW. Signals arising from antigen-presenting cells. Curr Opin Immunol. 1991;3:361–372. doi: 10.1016/0952-7915(91)90039-4. [DOI] [PubMed] [Google Scholar]
  • 30.Steinman RM. DC-SIGN: a guide to some mysteries of dendritic cells. Cell. 2000;100:491–494. doi: 10.1016/S0092-8674(00)80684-4. [DOI] [PubMed] [Google Scholar]
  • 31.Bender A, Sapp M, Schuler G, Steinman RM, Bhardwaj N. Improved methods for the generation of dendritic cells from nonproliferating progenitors in human blood. J Immunol Methods. 1996;196:121–135. doi: 10.1016/0022-1759(96)00079-8. [DOI] [PubMed] [Google Scholar]
  • 32.Cella M, Engering A, Pinet V, Pieters J, Lanzavecchia A. Inflammatory stimuli induce accumulation of MHC class II complexes on dendritic cells. Nature. 1997;388:782–787. doi: 10.1038/42030. [DOI] [PubMed] [Google Scholar]
  • 33.Romani N, Gruner S, Brang D, et al. Proliferating dendritic cell progenitors in human blood. J Exp Med. 1994;180:83–93. doi: 10.1084/jem.180.1.83. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 34.Granelli-Piperno A, Delgado E, Finkel V, Paxton W, Steinman RM. Immature dendritic cells selectively replicate macrophagetropic (M-tropic) human immunodeficiency virus type 1, while mature cells efficiently transmit both M- and T-tropic virus to T cells. J Virol. 1998;72:2733–2737. doi: 10.1128/jvi.72.4.2733-2737.1998. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 35.Cameron P, Pope M, Granelli-Piperno A, Steinman RM. Dendritic cells and the replication of HIV-1. J Leukoc Biol. 1996;59:158–171. doi: 10.1002/jlb.59.2.158. [DOI] [PubMed] [Google Scholar]
  • 36.Frank I, Kacani L, Stoiber H, et al. Human immunodeficiency virus type 1 derived from cocultures of immature dendritic cells with autologous T cells carries T-cell-specific molecules on its surface and is highly infections. J Virol. 1999;73:3449–3454. doi: 10.1128/jvi.73.4.3449-3454.1999. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 37.Ganesh L, Leung K, Lore K, et al. Infection of specific dendritic cells by CCR5-tropic human immunodeficiency virus type 1 promotes cell-mediated transmission of virus resistant to broadly neutralizing antibodies. J Virol. 2004;78:11980–11987. doi: 10.1128/JVI.78.21.11980-11987.2004. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 38.Nair MPN, Mahajan SD, Schwartz SA, et al. Cocaine modulates dendritic cell-specific C type intercellular adhesion molecule-3-grabbing nonintegrin expression by dendritic cells in HIV-1 patients. J Immunol. 2005;174:6617–6626. doi: 10.4049/jimmunol.174.11.6617. [DOI] [PubMed] [Google Scholar]

Articles from The AAPS Journal are provided here courtesy of American Association of Pharmaceutical Scientists

RESOURCES