Abstract
BackgroundEpstein-Barr virus is a human herpesvirus that infects a majority of the human population. Primary infection of Epstein-Barr virus (EBV) causes the syndrome infectious mononucleosis. This virus is also associated with several cancers, including Burkitt’s lymphoma, post-transplant lymphoproliferative disorder and nasopharyngeal carcinoma. As all herpesvirus family members, EBV initially replicates lytically to produce abundant virus particles, then enters a latent state to remain within the host indefinitely.MethodsThrough a genetic screen in Drosophila, we determined that reduction of Drosophila Tor activity altered EBV immediate-early protein function. To further investigate this finding, we inhibited mTOR in EBV-positive cells and investigated subsequent changes to lytic replication via Western blotting, flow cytometry, and quantitative PCR. The student T-test was used to evaluate significance.ResultsmTOR, the human homolog of Drosophila Tor, is an important protein at the center of a major signaling pathway that controls many aspects of cell biology. As the EBV immediate-early genes are responsible for EBV lytic replication, we examined the effect of inhibition of mTORC1 on EBV lytic replication in human EBV-positive cell lines. We determined that treatment of cells with rapamycin, which is an inhibitor of mTORC1 activity, led to a reduction in the ability of B cell lines to undergo lytic replication. In contrast, EBV-positive epithelial cell lines underwent higher levels of lytic replication when treated with rapamycin.ConclusionsOverall, the responses of EBV-positive cell lines vary when treated with mTOR inhibitors, and this may be important when considering such inhibitors as anti-cancer therapeutic agents.
Highlights
Epstein-Barr virus is a human herpesvirus that infects a majority of the human population
In a Drosophila model system, we identified Tor as a modifier of Z and R activities. Translating this finding to the context of lytically-replicating Epstein-Barr virus (EBV), we found that mTORC1 inhibition via rapamycin treatment yielded different effects in B cell versus epithelial cell lines
We discovered that modulation of mTOR activity alters EBV lytic replication, beginning with a genetic screen in Drosophila that demonstrated that loss of Tor enhanced Z activity, and suppressed R activity, in Drosophila tissues (Figure 1)
Summary
Epstein-Barr virus is a human herpesvirus that infects a majority of the human population. Epstein-Barr virus (EBV) is a human herpesvirus which has infected a large majority of the world’s human population This virus infects epithelial cells of the nasopharynx, where it replicates in a lytic or productive manner, as well as B lymphocytes, where the virus enters a latent state [1]. EBV is associated with a plethora of diseases, including infectious mononucleosis, lymphomas (Burkitt’s lymphoma, Hodgkins lymphoma, post-transplant lymphoproliferative disorder), epithelial-based cancers (including nasopharyngeal carcinoma), multiple sclerosis, and the rare but deadly X-linked lymphoproliferative syndrome [2]. The prevalence of this virus, along with its potential for serious disease, necessitate the study of means to inhibit lytic replication, as well as treatments to kill EBVpositive cancer cells. The late genes are expressed to provide the virion structural elements [1]
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