How do viruses evict close relatives, and why?

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Virus diseases quickly spread among host individuals because viruses are able to multiply exponentially in each of the successive hosts they invade. The fast multiplication inevitably introduces high numbers of errors in virus genetic blueprints (genomes). Left unchecked, these errors would render most of the multiplied viruses defective, thus arresting the spread of virus diseases. Conversely, natural selection favors viruses that have the capacity to control error proliferation. Once better understood, such error mitigation mechanisms could become targets of virus disease control and management. Previous research unveiled a simple, elegant mechanism used by a plant virus that minimizes multiplication errors. This mechanism operates by excluding the virus genomes produced in any given cells from additional rounds of multiplication, thereby preventing the piling-up of multiple errors in single genomes. The goals of the research are to gain a deeper understanding of this mechanism, and to determine whether this error-purging strategy is mechanistically conserved among similar viruses. Discoveries are expected to ignite intense interest in novel preventive, therapeutic, and management strategies that abolish error purging by viruses, leading to more effective control of viral diseases, which will benefit society at large. The conscious decision to enlist both graduate and undergraduate students, especially those of under-represented backgrounds, to accomplish the research contributes to the societal goal of educating high quality future scientists through integration of teaching and research. Viruses block re-infection of their host cells by closely related viruses through superinfection exclusion (SIE). SIE is strongest when the primary and superinfecting viruses are identical. How this highly specific self-rejection is achieved, and why it is conserved among diverse viruses, are key questions of this research. Use of the the plant-infecting turnip crinkle virus (TCV) allowed the discovery that p28, one of the TCV replication proteins, facilitates replication of the primary TCV, but represses replication of nearly identical superinfectors through SIE. TCV p28 was further found to coalesce into large intracellular inclusions that trapped new p28 molecules translated from superinfector genomes. Together these findings prompted the idea that the "intended" target of SIE is progenies of the primary virus because, at the time of superinfector intrusion, these progenies would far outnumber the nearly indistinguishable superinfector. This project aims to test two inter-connected hypotheses: (1) a repressive state of p28 exerts SIE in TCV-infected cells by intercepting freshly translated p28 molecules in a prion-like manner; (2) The primary function of SIE, at least for RNA viruses like TCV, is to exclude progeny genomes from re-replication, thereby minimizing random replication errors in any given progeny genomes. These hypotheses will be addressed in four objectives: (i) determine the structural characteristics of TCV p28 in vivo and in vitro; (ii) identify and characterize SIE-defective TCV mutants; (iii) characterize SIE determinants encoded by two viruses of the family Potyviridae; and (iv) determine the molecular mechanism of SIE in these Potyviridae viruses. This project strives to identify motivated students from low-income, rural families through close collaborations with a community college, and recruit them as undergraduate and graduate participants of the underlying research.This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.