[Initial swing at elucidating MOA of alpha defensin-1: PKC a target?]
>>J. Clin. Invest. 115:765-773 (2005). doi:10.1172/JCI200521948.
Dual role of -defensin-1 in anti–HIV-1 innate immunity
Theresa L. Chang, Jesus Vargas, Jr., Armando DelPortillo and Mary E. Klotman
Department of Medicine, Division of Infectious Diseases, Mount Sinai School of Medicine, New York, New York, USA.
Address correspondence to: Theresa L. Chang, Department of Medicine, Division of Infectious Diseases, Box 1090, One Gustave L. Levy Place, New York, New York 10029, USA. Phone: (212) 241-6806; Fax: (212) 534-3240; E-mail: Theresa.chang@mssm.edu.
Received for publication April 22, 2004, and accepted in revised form January 4, 2005.
-Defensins are abundant antimicrobial peptides in polymorphonuclear leukocytes and play an important role in innate immunity. We have previously shown that -defensin-1 can inhibit HIV-1 replication following viral entry. Here we examined the molecular mechanism(s) of -defensin-1–mediated HIV-1 inhibition. -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 -defensin-1 inhibited steps following reverse transcription and integration. Analysis of PKC phosphorylation in primary CD4+ T cells in response to -defensin-1 indicated that -defensin-1 inhibited PKC activity. Pretreatment of infected CD4+ T cells with a PKC activator, bryostatin 1, partially reversed -defensin-1–mediated HIV inhibition. Like -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 -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, -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 -defensin-1 in innate immunity against HIV has implications for prevention as well as therapeutics.<<
Cheers, Tuck |
