Human cytomegalovirus (HCMV), the largest known human herpesvirus, is a major cause of disease in individuals whose immune systems are compromised or immature and is the commonest infective cause of congenital damage to the central nervous system. Similarly, it can also be life-threatening in the context of organ or bone marrow transplant or advanced HIV infection.
Unlike many other viruses, HCMV is never cleared after primary infection but persists for the lifetime of the host. In part, this is due to the profound ability of HCMV to avoid the host’s immune response.
However, this lifelong viral persistence is also underpinned by a biological property of all herpesviruses; the ability to undergo latent infection where viral genomes are carried silently in the absence of detection of infectious virions. It is now clear that that reactivation of virus from these latent pools is also a major cause of congenital infection as well as causing much of the HCMV-mediated disease observed in immunocompromised transplant patients and patients with AIDS.
Our work has shown one major site of viral latency in vivo to be in cells of the myeloid lineage: undifferentiated myeloid cells such as monocytes and their CD34+ bone marrow progenitors carry the virus latently but differentiation of these cells to mature dendritic cells (DCs) or macrophages results in reactivation of a productive virus infection. Our work has also shown that this regulation of latency and reactivation results from epigenetic regulation of the viral genome through post-translational modifications of histones associated with key regulatory viral genes. Understanding the intracellular mechanisms which regulate viral latency and reactivation will be important for a complete understanding of the pathogenesis of HCMV infection.
CD34+ progenitor cells will differentiate to become macrophages and DCs and, as these are key immune-regulatory cells of the host, understanding how HCMV perturbs their normal function during latency and reactivation is also crucial to our understanding of this human pathogen. We are, therefore, presently using transcriptome and proteome analyses to address what key components of myeloid cell biology are perturbed during HCMV infection. We have already shown that a novel class of viral genes encoding microRNAs (miRNAs) are expressed during latent infection and that latent infection also perturbs the normal balance of cellular miRNAs. How this regulates viral and cellular gene expression during latency is under investigation.
Upon reactivation of HCMV, numerous viral genes can target normal cellular control mechanisms to ensure efficient productive infection: these include cell cycle, cellular transcription, cell signalling and apoptosis. We are also interested in the mechanism by which specific viral genes interdict in these normal cellular control mechanisms and how the virus interacts with the cell to “hijack” cellular functions to optimise them for virus production. Recently, we have identified a novel pro-life viral gene expressed during HCMV infection which, intriguingly, we have identified as a non-coding RNA. We are presently identifying how it’s interaction with the cell mitochondria prevents untimely cell death and whether this could be used as a novel therapeutic for diseases involving lack of mitochondrial function.
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