The ability to efficiently spread within a plant allows the virus to establish productive infection and increases its chances for the dissemination to new host plants. Although the majority of plant viruses are capable of infecting most types of cells within their hosts, some viruses exhibit apparent restriction to particular tissues upon their host invasion. Such case is exemplified by several groups of phloem-limited viruses, among which are RNA viruses belonging to the family Closteroviridae. The factors and processes that control phloem restriction of these viruses as well as the evolutionary reason of viral phloem limitation are not well understood. In our recent study, we showed that p33 protein of Citrus tristeza closterovirus (CTV) affects viral pathogenicity by modulating a host immune response. During virus infection, p33 triggers the accumulation of reactive oxygen species (ROS) and plant cell death. Deletion of the p33 gene from the CTV genome resulted in a significant decrease in ROS upon virus infection in tobacco and citrus, while positively impacted virus accumulation and spread. As we observed, the p33 deletion mutant was able to spread beyond phloem and enter xylem cells, which resulted in the abnormal vascular tissue differentiation leading to a significant enhancement of the stem pitting syndrome. Based on these observations, we hypothesized that the plant recognizes p33 and activates the host immune response to restrict CTV into the phloem tissue and minimize the disease.