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PMID: 15719067 Published · ppublish English Journal Article Research Support, U.S. Gov't, P.H.S.

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

The Journal of clinical investigation ·Vol. 115 ·No. 3 ·2005-03-00 ·Pages 765-73

Chang TL, Vargas J, DelPortillo A, Klotman ME

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.

MeSH Terms
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
Chemicals
Antiviral Agents CD4 Antigens Carbazoles Indoles Isoenzymes Receptors, CCR5 Receptors, CXCR4 Recombinant Proteins alpha-Defensins human neutrophil peptide 1 Go 6976 Protein Kinase C
Authors & Affiliations
4 authors, click to expand affiliations / ORCID
Chang Theresa L
Department of Medicine, Division of Infectious Diseases, Mount Sinai School of Medicine, New York, New York 10029, USA. Theresa.chang@mssm.edu
Vargas Jesus
DelPortillo Armando
Klotman Mary E
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Article Info
Journal
The Journal of clinical investigation
Abbr.
J Clin Invest
ISSN
0021-9738
DOI
10.1172/JCI21948
Email
theresa.chang@mssm.edu
Published
2005-03-00
Pages
765-73
Language
English
Region
United States
NLM ID
7802877
PMCID
PMC548697
Subset
IM
Grants
NICHD NIH HHS · P01 HD041763 · United States
NICHD NIH HHS · P01 HD41763. · United States
NIAID NIH HHS · R01 AI43698 · United States
External Links
PubMed source DOI: 10.1172/JCI21948 PMC Full Text View journal details
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