Human respiratory syncytial virus (RSV) constitutes a highly pathogenic virus that infects lung epithelial cells to cause a wide spectrum of respiratory diseases. Our recent studies have revealed the existence of an interferon-␣/␤-independent, innate antiviral response against RSV that was dependent on activation of NF-B. We demonstrated that NF-B inducing pro-inflammatory cytokines like tumor necrosis factor-␣ (TNF) confers potent antiviral function against RSV in an NF-B-dependent fashion, independent of interferon-␣/␤. During our efforts to study this pathway, we identified HBD2 (human ␤-defensin-2), a soluble secreted cationic protein as an antiviral factor induced during NF-B-dependent innate antiviral activity in human lung epithelial cells. Our results demonstrated that HBD2 is induced by TNF and RSV in an NF-B-dependent manner. Induction of HBD2 in infected cells was mediated by the paracrine/autocrine action of TNF produced upon RSV infection. HBD2 plays a critical role during host defense, because purified HBD2 drastically inhibited RSV infection. We also show that the antiviral mechanism of HBD2 involves blocking of viral cellular entry possibly because of destabilization/disintegration of the viral envelope. The important role of HBD2 in the innate response was also evident from loss of antiviral activity of TNF upon HBD2 silencing by short interfering RNA. The in vivo physiological relevance of HBD2 in host defense was apparent from induction of murine ␤-defensin-4 (murine counterpart of HBD2) in lung tissues of RSV-infected mice. Thus, HBD2 functions as an antiviral molecule during NF-B-dependent innate antiviral immunity mediated by the autocrine/paracrine action of TNF.Nonsegmented negative strand RNA viruses (superfamily Mononegaviridae) constitute highly pathogenic human viruses that cause high morbidity. Human respiratory syncytial virus (RSV), 2 a nonsegmented negative strand virus, is an important human lung tropic respiratory tract pathogen causing high morbidity and mortality among infants, children, and elderly by manifesting disease states, including pneumonia, and bronchiolitis (1, 2). To date, no effective vaccine or antiviral therapy exists for RSV. Therefore, elucidation of innate immune antiviral response induced by RSV holds significant potential for development of effective antiviral therapies in the near future.The innate immune antiviral response against viruses represents an important host defense mechanism (3). Innate immunity includes the first line of defense by the host to combat virus infection before an orchestrated adaptive immune response involving immune cell priming, and antibody production is launched. Two key molecules regulating the innate antiviral function are interferon regulatory factors (IRFs) and NF-B (4). These two transcription factors are activated either individually or together in infected cells, resulting in the expression and production of interferon-␣/␤ (IFN), which are potent antiviral cytokines (5, 6). IFN produced from infected cells binds to their...

Oncolytic virotherapy is an emerging bio-therapeutic platform for cancer treatment, which is based on selective infection/killing of cancer cells by viruses. Herein we identify the human respiratory syncytial virus (RSV) as an oncolytic virus. Using prostate cancer models, we show dramatic enhancement of RSV infectivity in vitro in the androgen-independent, highly metastatic PC-3 human prostate cancer cells compared to the non-tumorigenic RWPE-1 human prostate cells. The oncolytic efficiency of RSV was established in vivo using human prostate tumor xenografts in nude mice. Intra-tumoral and intra-peritoneal injections of RSV led to a significant regression of prostate tumors. Furthermore, enhanced viral burden in PC-3 cells led to selective destruction of PC-3 cancer cells in vitro and in xenograft tumors in vivo due to apoptosis triggered by the down-regulation of NF-κB activity (and the resulting loss of anti-apoptotic function of NF-κB) in RSV-infected PC-3 cells. The intrinsic (mitochondrial) pathway constitutes the major apoptotic pathway; however, the death-receptor-dependent extrinsic pathway, mediated by the paracrine/autocrine action of tumor necrosis factor-α produced from infected cells, also partly contributed to apoptosis. Thus, the oncolytic property of RSV can potentially be exploited to develop targeted therapeutics for the clinical management of prostate tumors.

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Type I interferons (IFN), IFN-α/β constitute a critical component of innate immunity against viruses. IFN-α/β activates JAK/STAT pathway resulting in expression of various IFNstimulated antiviral proteins. While studying IFN-α/β signaling during virus infection, we identified human beta defensin-3 (HBD3) as an antiviral factor induced during IFN-α−mediated innate antiviral response in human lung epithelial cells. We showed that HBD3 is induced by IFN-α and purified HBD3 significantly inhibited vesicular stomatitis virus (VSV) infection. Further studies revealed that HBD3 confers its antiviral activity by blocking VSV cellular entry. An essential role of HBD3 during innate antiviral response was evident from loss of antiviral activity of IFN-α following HBD3 silencing by siRNA. Thus, we have identified HBD3 as an IFN-inducible antiviral factor that inhibits infection by blocking viral cellular entry.