Plants limit virus replication via cell-intrinsic restriction factors (CIRFs). Several of these antiviral factors have been identified for tombusviruses in Saccharomyces cerevisiae (a surrogate model host) using high-throughput screens with genomic libraries. Among the recognized CIRFs the centromeric histone CENH3 stood out due to its distinctive function and high connectivity with other restriction and pro-viral factors in a protein-protein interaction network. CENH3 is essential for the definition of chromosomal centromeric regions and chromosome segregation. Experiments with a yeast mutant and silencing or overexpression of the plant homolog CENH3 in Nicotiana benthamiana suggested a significant effect of this protein over the viral replication. Despite the fact that histones are components of nucleosomes, we found new RNA binding function for CENH3 with the viral RNA. We characterized this interaction using in vitro experiments with cell free replication assays developed for TBSV. CENH3 has been found to localize in non-centromeric regions of chromosomes, interestingly within genes previously characterized as pro-viral host factors for TBSV, influencing their transcription. We are currently investigating how downregulation or inactivation of CENH3 affects transcription of these genes and consequently the viral replication. Altogether, our findings open up an opportunity for developing broad and long-lasting resistance against plant viruses. This discovery is also quite relevant for other plant pathogens, due to their dependence on their hosts during infection.