Life cycle processes of positive-strand (+)RNA viruses are broadly conserved across families, yet they employ different strategies to grow in the cell. Using a generalized dynamical model for intracellular (+)RNA virus growth, we decipher these life cycle determinants and their dependencies for several viruses and parse the effects of viral mutations, drugs and host cell permissivity. We show that poliovirus employs rapid replication and virus assembly, whereas the Japanese encephalitis virus leverages its higher rate of translation and efficient cellular reorganization compared to the hepatitis C virus. Stochastic simulations demonstrate infection extinction if all seeding (inoculating) viral RNA degrade before establishing robust replication critical for infection. The probability of this productive cellular infection, ‘cellular infectivity’, is affected by virus–host processes and defined by early life cycle events and viral seeding. An increase in cytoplasmic RNA degradation and delay in vesicular compartment formation reduces infectivity, more so when combined. Synergy among these parameters in limiting (+)RNA virus infection as predicted by our model suggests new avenues for inhibiting infections by targeting the early life cycle bottlenecks.
Positive strand (+)RNA viruses are the most common and clinically important human pathogens. Their life cycle processes are broadly conserved across many virus families but they employ different life cycle strategies for their growth in the cell. Upon RNA genome release into the cytoplasm post cellular entry, viral translation generates structural and non-structural proteins that induce intracellular remodelling, forming membrane compartments that foster viral replication leading to virus particle formation. We present a generalized dynamical model for intracellular (+)ssRNA virus growth that accounts for these critical steps. Our model can capture experimental growth dynamics for several RNA viruses as well as parse the effect of viral mutations and host cell permissivity. We show that Poliovirus (PV) employs rapid replication and virus assembly whereas Japanese Encephalitis virus leverages its higher rate of translation and efficient host membrane reorganization for enhanced viral dynamics compared to Hepatitis C virus. Since the slow membrane reorganization represents a crucial bottleneck for replication, stochastic simulations demonstrate that an infection event, even with multiple viral genomes, can go to extinction if all seeding viral RNA degrade before establishing robust viral replication. We estimate this probability of productive cellular infection, termed ‘Cellular Infectivity (Φ)’ using stochastic simulations. Φ varies for a virus-host pair with initial virus seeding and life cycle perturbations like increase in cytoplasmic RNA degradation and delay in compartment formation can reduce infectivity. Extent of synergy among these parameters while seemingly diverse for viruses is defined by Φ. Therefore, our model suggests new avenues for inhibition of viral infections by targeting early life cycle bottlenecks.
Japanese encephalitis virus (JEV), a neurotropic flavivirus, is the leading cause of viral encephalitis in endemic regions of Asia. Although the mechanisms modulating JEV virulence and neuroinvasiveness are poorly understood, several acquired mutations in the live attenuated vaccine strain (SA14-14-2) point towards translation regulation as a key strategy. Using ribosome profiling, we identify multiple mechanisms including frameshifting, tRNA dysregulation and alternate translation initiation sites that regulate viral protein synthesis. A significant fraction (~ 40%) of ribosomes undergo frameshifting on NS1 coding sequence leading to early termination, translation of NS1′ protein and modulation of viral protein stoichiometry. Separately, a tRNA subset (glutamate, serine, leucine and histidine) was found to be associated in high levels with the ribosomes upon JEV infection. We also report a previously uncharacterised translational initiation event from an upstream UUG initiation codon in JEV 5′ UTR. A silent mutation at this start site in the vaccine strain has been shown to abrogate neuroinvasiveness suggesting the potential role of translation from this region. Together, our study sheds light on distinct mechanisms that modulate JEV translation with likely consequences for viral pathogenesis.
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