Dual role of α-defensin-1 in anti–HIV-1 innate immunity

Abstract

α-Defensins are abundant antimicrobial peptides in polymorphonuclear leukocytes and play an important role in innate immunity. We have previously shown that α-defensin-1 can inhibit HIV-1 replication following viral entry. Here we examined the molecular mechanism(s) of α-defensin-1-mediated HIV-1 inhibition. α-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 α-defensin-1 inhibited steps following reverse transcription and integration. Analysis of PKC phosphorylation in primary CD4 + T cells in response to α-defensin-1 indicated that α-defensin-1 inhibited PKC activity. Pretreatment of infected CD4 + T cells with a PKC activator, bryostatin 1, partially reversed α-defensin-1-mediated HIV inhibition. Like α-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 α-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, α-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 α-defensin-1 in innate immunity against HIV has implications for prevention as well as therapeutics.

Anti herpes simplex virus activity of lactoferrin/lactoferricin – an example of antiviral activity of antimicrobial protein/peptide

“…Similar ability to reduce cell-to-cell spread has been reported for a-helical interferon [184]. Although still controversial, it has been suggested that a-defensin-1 is the soluble CD8 + T-cell antiviral factor with potent activity against HIV [185]. Similar immune activating properties are also hypothesized for Lfcin and other cationic peptides.…”

Human β-defensins

“…Whereas the former report indicated that hBD-2 and hBD-3 downregulate the HIV-1 coreceptor CXCR4 in PBMC and T lymphocytes, suggesting inhibition of the X4 virus by β-defensins at the viral entry step [139], authors of the latter did not observe receptor down-regulation by hBD-2, and suggested instead that a post-entry, intracellular signaling event is responsible for the inhibition of HIV-1 replication [138]. The idea of intracellular signaling involvement is reminiscent of studies on inhibition of HIV replication by related human neutrophil α-defensins [141,142]. Despite the differences in the interpretation of inhibition at the cellular level, β-defensins can directly inactivate HIV-1 virions [138,139].…”

Defensins in innate immunity

“…Due to their lectin-like properties, HNP1-3 can bind with relatively high affinity to HIV viral gp120 and CD4 receptors . Meanwhile, as a non-competitive inhibitor of protein kinase C (PKC), HNP1 may have a potential role against HIV-1 via interfering with PKC signaling pathways and blocking nuclear import and transcription of the HIV-1 genome (Chang et al 2005). The anti-HIV activities of HBDs remain unclear; however, studies have demonstrated that that HBD2 and HBD3 expression was significantly upregulated in both HIV-positive and HIV-negative men who have sex with men (Kreuter et al 2009).…”