Since its discovery in 1998, RNA interference (RNAi) has heralded the advent of novel tools for biological research and drug dis discovery. This exciting new technology is emerging as a powerful modality for battling s om e of the most notoriously challenging viral clinical targets such as hepatitis C virus (HCV) and hum an im immunodeficiency virus (HIV). However, several critical is s ues associated with this novel technology m us t be resolved before it can progress to testing in hum an clinical trials , and these have been the target of intensive research in recent years .

RNAi: An Antiviral Defense System in Insects:

Multicellular organisms evolved sophisticated defense system s to confer protection agains t pathogens . An important characteris tic of these im m une s ys tem s is their ability to act both locally at the s ite of infection and at dis tal uninfected locations (Baulcom be, 2004; Dorner and Radbruch, 2007; Roitt et al., 2001; Voinnet, 2005). Ins ects rely on m ultiple im m une res pons es to com bat infection; one of them is RNA interference (RNAi). Here we review the current knowledge on the general m echanis m of RNAi and s um m arize what is known about the antiviral role of RNAi in the ins ect m odel Dros ophila m elanogas ter. We als o dis cus s the s trategies evolved by virus es to s uppres s the RNAi res pons e. Finally, we briefly des cribe the RNAi m echanis m in other ins ects of econom ical and/or health relevance.

RNA Silencing in Plants and the Role of Viral Suppressors:

The term RNA s ilencing refers to s everal pathways pres ent in eukaryotic organis m s that lead to the s equence s pecific elim ination or functional blocking of RNAs with hom ology to double s tranded RNAs (ds RNAs ) that have previous ly triggered the m echanis m . Bes ides playing im portant roles in developm ental control, RNA s ilencing form s part of the defence agains t virus es in plants , acting as a potent antiviral m echanis m . To es cape from the RNA s ilencing-bas ed defence, m os t plant virus es m ake us e of different s trategies , the m os t com m on relying in the action of viral proteins with the capacity to s uppres s RNA s ilencing. The characterization of thes e viral s uppres s ors is providing us eful ins ights to unders tand how RNA s ilencing works , revealing com ponents and s teps in the s ilencing pathways .

The Properties and Roles of Virus-encoded MicroRNAs:

The dis covery that virus es could encode m icro (m i)RNAs , s im ilarly to the eukaryotic organis m s they infect, has opened new pers pectives in the s tudy of hos t-virus interactions . Thes e s m all regulatory RNAs , which are critically involved in an ever-increas ing num ber of biological proces s es , have revolutionized the way we us ed to s ee gene regulation. Som e m am m alian virus es , m ainly from the herpes virus and polyom avirus fam ilies , have hijacked this m echanis m in order to help them achieve the infection of their hos t. In this chapter, we will pres ent the divers ity of known viral m iRNAs , their s pecific properties , their viral and cellular targets and the roles they play during the cours e of infection. We will s ee that m ore and m ore it appears that virally encoded m iRNAs s eem to be critically involved in every s tep of the virus life cycle.

Virus-encoded Suppressors of RNA Silencing and the Role of Cellular  miRNAs in Mammalian Antiviral Immune Responses:

Sm all RNA-directed s ilencing m echanis m s play im portant roles in the regulation of eukaryotic gene expres s ion. In plants , ins ects , nem atodes and fungi RNA s ilencing m echanis m s are als o involved in innate antiviral defence res pons es . To counter antiviral RNA s ilencing, virus es from plants , ins ects and fungi encode RNA s ilencing s uppres s ors (RSSs ). Recent s tudies s ugges t that RNA s ilencing in m am m als , or RNA interference (RNAi), is als o involved in antiviral res pons es . In particular, there is increas ing evidence that cellular regulatory m icroRNAs (m iRNAs ) have a function in res tricting virus replication in m am m alian cells . Sim ilar to plant and ins ect virus es , s everal m am m alian virus es encode RSS factors that inhibit the RNAi m echanis m . Several of thes e s uppres s ors are m ultifunctional proteins that were previous ly s hown to block innate antiviral

im m une res pons es involving the interferon (IFN) pathway. Here we s um m arize the current data on m am m alian virus -encoded RSS factors . In addition, different as pects of antiviral RNAi and the role of cellular m iRNAs in res tricting virus replication in m am m alian cells are dis cus s ed.

RNAi Gene Therapy to Control HIV-1 Infection:

RNA interference (RNAi) was dis covered as cellular gene regulation m echanis m in 1998, but s everal RNAi-bas ed applications for gene s ilencing have already m ade it into clinical trials . We will dis cus s RNAi approaches to target pathogenic hum an virus es caus ing acute or chronic infections , with a focus on pers is tent HIV-1 infection that would m os t likely require an RNAi-bas ed gene therapy. Virus es like HIV-1 are particularly difficult targets for RNAi-attack becaus e they are es cape-prone, which requires com binatorial RNAi s trategies to prevent viral es cape. The future of antiviral RNAi therapeutics is very prom is ing, but it rem ains of critical im portance to include m any controls in pre-clinical tes t m odels to unequivocally dem ons trate s equence-s pecific action of the RNAi inducers

Advances  in the Use of RNAi to Treat Chronic Hepatitis  B Virus Infection:

Chronic infection with the hepatitis B virus (HBV) occurs in approxim ately 6% of the world’s population and carriers of the virus are at ris k for com plicating hepatocellular carcinom a (HCC) and cirrhos is . Although effective vaccination is available, it is prophylactic and of little us e to individuals who are already infected with the virus . Furtherm ore, current treatm ent options have lim ited efficacy and chronic HBV infection is likely to be a s ignificant global m edical problem for m any years to com e. Silencing HBV gene expres s ion by harnes s ing RNA interference (RNAi) pres ents an attractive option for developm ent of novel and effective anti HBV agents . Num erous s tudies have reported highly s ucces s ful s uppres s ion of viral replication, which bodes well for em ploying this approach to counter HBV infection. However, des pite s ignificant and rapid progres s , further refinem ent of exis ting technologies is neces s ary before clinical application of RNAi-bas ed HBV therapies is realis ed. Im provem ent of delivery efficiency, dos e regulation, lim iting of off target effects and preventing reactivation of viral replication are s om e of the hurdles that need to be overcom e. Nevertheles s , the vas t potential of RNAi-bas ed therapeutics will continue to drive innovative res earch, and this prom is es to s urm ount the obs tacles that face this exciting field.

RNAi Applications to Defeat Respiratory Viral Infections:

Pathogenic respiratory virus es , exem plified by respiratory syncytial virus (RSV), influenza (Flu) and parainfluenza virus (PIV), are m ajor disease agents that kill m illions of hum ans worldwide. Other respiratory virus es that are also potential agents of bioterroris m include highly pathogenic avian flu virus , SARS coronavirus , and the henipavirus es . respiratory infection by RSV and PIV is the m o t prevalent caus e of pediatric hos pitalization in indus trialized Wes tern nations . In the US alone, it leads to about 100,000 adm is s ions per year at a cos t of about $300 M. The lack of a reliable vaccine or antiviral agains t thes e virus es , in part due to the high m utation rate of the viral RNA genom es , has led to the adoption of the novel RNA interference (RNAi) s trategy. This review s um m arizes s ignificant recent progres s in the developm ent of RNAi therapeutics to defeat thes e viral res piratory dis eas es



Mtech in Clinical Eng Jointly offered by Indian institute of technology Madras& Christian medical college Vellore& Sree chitra tirunal institute for medical sciences and technology Trivandrum.
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