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Dual role of alpha-defensin-1 in anti-HIV-1 innate immunity.

Abstract
Alpha-defensins are abundant antimicrobial peptides in polymorphonuclear leukocytes and play an important role in innate immunity. We have previously shown that alpha-defensin-1 can inhibit HIV-1 replication following viral entry. Here we examined the molecular mechanism(s) of alpha-defensin-1-mediated HIV-1 inhibition. Alpha-defensin-1 had a direct effect on HIV-1 virions at a low MOI in the absence of serum. The direct effect on HIV-1 virions was abolished by the presence of serum or an increase in virus particles. Studying the kinetics of the HIV life cycle revealed that alpha-defensin-1 inhibited steps following reverse transcription and integration. Analysis of PKC phosphorylation in primary CD4+ T cells in response to alpha-defensin-1 indicated that alpha-defensin-1 inhibited PKC activity. Pretreatment of infected CD4+ T cells with a PKC activator, bryostatin 1, partially reversed alpha-defensin-1-mediated HIV inhibition. Like alpha-defensin-1, the PKC isoform-selective inhibitor Go6976 blocked HIV-1 infection in a dose-dependent manner. Furthermore, kinetic studies and analysis of HIV-1 products indicated that alpha-defensin-1 and Go6976 blocked HIV-1 infection at similar stages in its life cycle, including nuclear import and transcription. Taken together, our studies demonstrate that, in the absence of serum, alpha-defensin-1 may act directly on the virus, but, in the presence of serum, its effects are on the cell, where it inhibits HIV-1 replication. At least 1 of the cellular effects associated with HIV inhibition is interference with PKC signaling in primary CD4+ T cells. Studying the complex function of alpha-defensin-1 in innate immunity against HIV has implications for prevention as well as therapeutics.
AuthorsTheresa L Chang, Jesus Vargas Jr, Armando DelPortillo, Mary E Klotman
JournalThe Journal of clinical investigation (J Clin Invest) Vol. 115 Issue 3 Pg. 765-73 (Mar 2005) ISSN: 0021-9738 [Print] United States
PMID15719067 (Publication Type: Journal Article, Research Support, U.S. Gov't, P.H.S.)
Chemical References
  • Antiviral Agents
  • CD4 Antigens
  • Carbazoles
  • Indoles
  • Isoenzymes
  • Receptors, CCR5
  • Receptors, CXCR4
  • Recombinant Proteins
  • alpha-Defensins
  • human neutrophil peptide 1
  • Go 6976
  • Protein Kinase C
Topics
  • Antiviral Agents (metabolism)
  • CD4 Antigens (immunology)
  • CD4-Positive T-Lymphocytes (immunology, virology)
  • Carbazoles (metabolism)
  • Cells, Cultured
  • HIV-1 (immunology, physiology)
  • Humans
  • Immunity, Innate (physiology)
  • Indoles (metabolism)
  • Isoenzymes (antagonists & inhibitors, metabolism)
  • Protein Kinase C (antagonists & inhibitors, metabolism)
  • Receptors, CCR5 (immunology)
  • Receptors, CXCR4 (immunology)
  • Recombinant Proteins (genetics, metabolism)
  • Serum (immunology)
  • Signal Transduction (physiology)
  • Virion (metabolism)
  • alpha-Defensins (genetics, metabolism)

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