Anushah Mirza

Introduction. Cytomegalovirus (CMV) is from the family of beta-herpesvirus and is transmitted through bodily fluids.^1,2 CMV can cause a broad range of serious disease like end organ failure.³ CMV is a latent virus whose reactivation is triggered by IL-6 and extracellular signal-regulated kinase (ERK)- mitogen activated protein kinase signaling.⁴ Immunocompromised patients may have lack of/delayed recovery of CMV-specific CD4+ and CD8+ lymphocytes leading to CMV disease.⁵ Antiviral prophylaxis is ineffective in treating these patients since it targets the late stage of infection.⁵ Bromodomain protein targeting has been suggested as a therapeutic target in these patients.⁶ Methods. CD14+ monocytes were latently infected with GFP tagged CMV.⁷ Differential phosphoproteomics was used in cells that both support or do not support IL-6 induced viral reactivation in the latently infected cells. Next, hematopoietic cell kinase (HCK) activity was inhibited to prove that HCK is required for HCMV reactivation.⁸ Then, monocytes were incubated with HDACis and BRDis over the occurs of 4 days, and the level of CMV IE induction was assessed.⁶ Finally, it was tested if HDACis and I-BETs had an effect on T cell functionality by monitoring interferon-γ secretion using total peripheral blood mononuclear cells (PBMCs) in quantitative anti–IFN-γFluorospot assays.⁸ Results. In the latent stage of CMV, CD 14+ monocytes show high levels of expression of UL 138 mRNA, low levels of lytic transcripts IE and UL99, while in the lytic stage the opposite was true.⁷ The selective reactivation of the CMV virus is dependent on activation of viral gene expression in dendritic cells by IL-6 and concomitant SFK and ERK signaling.⁸ I-BETs release transcriptional activator complex P-TEFB and other recruits promotes causing transcription of CMV lytic genes.⁶ BET proteins are connected to regulation of HCMV latency and reactivation. I-BETs release transcriptional activator complex P-TEFB and other recruits promotes causing transcription of CMV lytic genes. This happens while restricting viral DNA replication and full CMV reactivating allowing cytotoxic immune targeting of latently infected cells.⁶ Conclusion. Treatment of cytomegalovirus latently infected CD14+ monocytes with histone deacetylase inhibitors (HDACis) that target a variety of epigenetic markers in an in vitro model have the ability to induce immediate early gene expression such that cells could then be targeted by T cells. By using I-BETs, CMV morbidity in post-transplant patients can be curbed by using a shock and kill method of causing expression of latent HCMV cells and inducing their purging by cytotoxic T cells. ⁶

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