Abstract
The successful establishment and maintenance of human cytomegalovirus (HCMV) latency is dependent on the expression of a subset of viral genes. Whilst the exact spectrum and functions of these genes are far from clear, inroads have been made for protein-coding genes. In contrast, little is known about the expression of non-coding RNAs. Here we show that HCMV encoded miRNAs are expressed de novo during latent infection of primary myeloid cells. Furthermore, we demonstrate that miR-UL148D, one of the most highly expressed viral miRNAs during latent infection, directly targets the cellular receptor ACVR1B of the activin signalling axis. Consistent with this, we observed upregulation of ACVR1B expression during latent infection with a miR-UL148D deletion virus (ΔmiR-UL148D). Importantly, we observed that monocytes latently infected with ΔmiR-UL148D are more responsive to activin A stimulation, as demonstrated by their increased secretion of IL-6. Collectively, our data indicates miR-UL148D inhibits ACVR1B expression in latently infected cells to limit proinflammatory cytokine secretion, perhaps as an immune evasion strategy or to postpone cytokine-induced reactivation until conditions are more favourable. This is the first demonstration of an HCMV miRNA function during latency in primary myeloid cells, implicating that small RNA species may contribute significantly to latent infection.
Highlights
It is well established that lytic reactivation from latency can be triggered by differentiation of latently infected myeloid cells to dendritic cells or macrophages which results in the production of infectious virions
Whilst low levels of IE72 transcript have been observed using extremely sensitive RT-PCR in some studies[18,19], the comparatively high levels of latency-associated transcripts compared to IE72 transcripts, which is in stark contrast to the relative super-abundance of IE72 transcription observed during lytic infection, is still consistent with a latent infection in undifferentiated myeloid cells
We further show that one of these, miR-UL148D, targets cellular ACVR1B, a receptor of the activin signalling axis which has a number of functions in cellular processes but, importantly for human cytomegalovirus (HCMV) biology, is known to promote monocyte differentiation to dendritic cells (DCs)
Summary
It is well established that lytic reactivation from latency can be triggered by differentiation of latently infected myeloid cells to dendritic cells or macrophages which results in the production of infectious virions. As non-coding RNAs are capable of concurrently modulating the expression of multiple targets[23,26,27,28] and altering gene expression at a global level, these RNAs are non-immunogenic molecules which, if expressed during latency, will not arouse detection of the latently infected cells by the immune system This is a important consideration during latency as the majority of the HCMV-encoded immune evasion genes are likely not expressed during this part of viral life cycle. Studies of HCMV miRNAs during latency have been restricted to analyses in the latent/quiescently infected THP-1 myelomonocytic cell line model[24,25,26] as well as one recent analysis in monocytes of HCMV seropostive donors[26] In this analysis[26], there appeared to be little consistency between the small number of donors tested and the viral miRNAs detected
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
