Superinfection exclusion, a phenomenon in which a preexisting
viral infection prevents a
secondary infection with the same or a closely related virus, has been described for various viruses, including important pathogens of humans, animals, and plants. The phenomenon was initially used to test the relatedness of plant viruses. Subsequently, purposeful
infection with a mild isolate has been implemented as a protective measure against virus isolates that cause severe disease. In the medical and veterinary fields,
superinfection exclusion was found to interfere with repeated applications of virus-based
vaccines to individuals with
persistent infections and with the introduction of multicomponent
vaccines. In spite of its significance, our understanding of this phenomenon is surprisingly incomplete. Recently, it was demonstrated that
superinfection exclusion of Citrus tristeza virus (CTV), a positive-sense
RNA closterovirus, occurs only between isolates of the same strain, but not between isolates of different strains of the virus. In this study, I show that
superinfection exclusion by CTV requires production of a specific
viral protein, the p33
protein. Lack of the functional p33
protein completely eliminated the ability of the virus to exclude
superinfection by the same or a closely related virus. Remarkably, the
protein appeared to function only in a homology-dependent manner. A cognate
protein from a heterologous strain failed to confer the exclusion, suggesting the existence of precise interactions of the p33
protein with other factors involved in this complex phenomenon.