Disease intervention strategies against respiratory syncytial virus infection

Respiratory syncytial virus (RSV) is a major cause of morbidity and some mortality in infants, young children, and the elderly worldwide. Currently, there is no effective vaccine. The antiviral drugs to control RSV infection are limited. The increasing disease burden and slow progress toward vaccine development is driving the search for new disease intervention strategies against RSV infection. RNA interference (RNAi) is a powerful tool amenable for the development of antiviral drugs. siRNAs targeting the RSV P gene (siRNA-P) have been shown to silence RSV replication both in vitro and in a BALB/c model of RSV infection. In this study, we examined the effect of siRNA-P prophylaxis on the primary and memory immune response to RSV infection in BALB/c mice. The central hypothesis of the study was siRNA-P could be used to reduce RSV replication to a level that did not cause disease pathogenesis but still allowed for robust immunity to infection. We show that mice prophylactically treated with siRNA-P to decrease but not to eliminate RSV replication exhibit reduced pulmonary inflammation and lung pathology, and produce an effective anti-RSV memory response when subsequently challenged with RSV. The results suggest that siRNA can be developed as an effective antiviral drug that can be used to reduce the viral load and parameters of pathogenesis without limiting the induction of the memory immune response. RSV surface proteins have been shown to modulate the host immune response to infection, an effect that has hindered vaccine development. The RSV G protein has been shown to contribute to the majority of immune modulation. A unique feature of the RSV G protein is that its central conserved region contains a CX3C chemokine motif, which has been shown to mimic the activities of the only known CX3C chemokine, fractalkine, and bind to the fractalkine receptor, CX3CR1, a feature that has been shown to modulate the immune response and cause disease pathogenesis in mice. In this study, we tested the hypothesis that G protein peptides and/or polypeptides could induce antibodies that blocked G protein interaction with CX3CR1. The results showed that antibodies specific for the CX3C motif had high blocking activity. These results were confirmed in mice vaccinated with G protein peptides and polypeptides where recovered antisera were tested for blocking antibodies and pulmonary disease pathogenesis was evaluated. These results suggest that vaccines can be made which induce G protein CX3CCX3CR1 blocking antibodies, and that this vaccine strategy may be useful to prevent G protein immune modulation and disease pathogenesis. INDEX WORDS: Respiratory syncytial virus, Small interfering RNA, Vaccine, Chemokine, Disease intevention DISEASE INTERVENTION STRATEGIES AGAINST RESPIRATORY SYNCYTIAL VIRUS INFECTION by WENLIANG ZHANG B.S. Ningbo University, P.R. China, 2000 MMED, Shanghai Jiaotong University, P.R. China, 2003 A Dissertation Submitted to the Graduate Faculty of the University of Georgia in Partial Fulfillment of the Requirements for the Degree DOCTOR OF PHILOSOPHY ATHENS, GEORGIA 2009 © 2009 Wenliang Zhang All Rights Reserved DISEASE INTERVENTION STRATEGIES AGAINST RESPIRATORY SYNCYTIAL VIRUS INFECTION