doi:10.1038/nindia.2011.83 Published online 24 June 2011
New research suggests that the competition between a host factor (La) and a viral protein (NS3) for binding to the Hepatitis C virus (HCV) could be responsible for the molecular switch from translation to replication.
The researchers believe that since the protein-host interaction is important in the virus life cycle, it could be an important target for antiviral interventions.
HCV is a single stranded RNA virus infecting human liver cells. HCV infection leads to liver cirrhosis and hepatocellular carcinoma in many patients.
The major roadblock in the way of treating HCV infection is the genetic heterogeneity of the virus arising due to continuous mutations of the viral proteins. Simultaneous selection of the resistant viruses helps the virus escape available therapy thereby leading to loss of sustained antiviral response. This prompted the researchers to study viral physiology in further detail and investigate new anti-HCV targets.
HCV proteins are synthesized through 'internal ribosome entry site' (IRES) mediated translation of the viral genomic RNA. This is the initial obligatory step after infection. The IRES resides in the 5' untranslated region of HCV RNA where the ribosomes can directly dock in. Once viral proteins are synthesized, the viral RNA is replicated. However, the exact mechanism of switch from translation to viral RNA replication was not well understood.
The virus life cycle is aided by several host proteins as well as the viral proteins. One of the non structural proteins of HCV, the NS3 protein, plays a central role in viral polyprotein processing and RNA replication. The researchers demonstrated that the NS3 protease (NS3pro) domain alone can specifically bind to HCV-IRES RNA, predominantly in the SLIV region thereby loosing protease activity.
"More importantly, NS3 binding to the SLIV hinders the interaction of La protein resulting in inhibition of HCV-IRES translation in favour of replication," says lead resercher Saumitra Das of the Department of Microbiology and Cell Biology at Indian Institute of Science, Bangalore.