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Review
. 2015 Jun;204(3):421-9.
doi: 10.1007/s00430-015-0401-6. Epub 2015 Mar 14.

Sleepless latency of human cytomegalovirus

Emma Poole  1 , John Sinclair
Affiliations
Review

Sleepless latency of human cytomegalovirus

Emma Poole et al. Med Microbiol Immunol. 2015 Jun.

Abstract

As with all human herpesviruses, human cytomegalovirus (HCMV) persists for the lifetime of the host by establishing a latent infection, which is broken by periodic reactivation events. One site of HCMV latency is in the progenitor cells of the myeloid lineage such as CD34+ cells and their CD14+ derivatives. The development of experimental techniques to isolate and culture these primary cells in vitro is enabling detailed analysis of the events that occur during virus latency and reactivation. Ex vivo differentiation of latently infected primary myeloid cells to dendritic cells and macrophages results in the reactivation of latent virus and provides model systems in which to analyse the viral and cellular functions involved in latent carriage and reactivation. Such analyses have shown that, in contrast to primary lytic infection or reactivation which is characterised by a regulated cascade of expression of all viral genes, latent infection is associated with a much more restricted viral transcription programme with expression of only a small number of viral genes. Additionally, concomitant changes in the expression of cellular miRNAs and cellular proteins occur, and this includes changes in the expression of a number of secreted cellular proteins and intracellular anti-apoptotic proteins, which all have profound effects on the latently infected cells. In this review, we concentrate on the effects of one of the latency-associated viral proteins, LAcmvIL-10, and describe how it causes a decrease in the cellular miRNA, hsa-miR-92a, and a concomitant upregulation of the GATA2 myeloid transcription factor, which, in turn, drives the expression of cellular IL-10. Taken together, we argue that HCMV latency, rather than a period of viral quiescence, is associated with the virally driven manipulation of host cell functions, perhaps every bit as complex as lytic infection. A full understanding of these changes in cellular and viral gene expression during latent infection could have far-reaching implications for therapeutic intervention.

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Figures

Fig. 1
Fig. 1
Manipulation of host cell functions during latent HCMV infection, perhaps every bit as complex as lytic infection. Infection of cells results in a wide range of changes to the infected cell. During lytic infection (a), there are reported changes to the modulation of cell metabolism, transcription, translation, cell cycle, cell signalling as well as the inhibition of immune surveillance, cell stress, and cell death [–25]. Similarly, during latent infection (b), there are reported changes to the manipulation of host cell transcription and cell signalling and, again, the inhibition of host immune surveillance, cell stress, and cell death [, , –36]
Fig. 2
Fig. 2
A number of pro- and anti-apoptotic factors in the FAS signalling pathway are altered during HCMV latency. Either CD34+ cells were uninfected or HCMV latency was established for 10 days, and the cells were harvested for protein analysis (a–d). Relative levels of proteins involved in FAS-mediated and IL-10 signalling were analysed by apoptosis array (R&D systems) (a) and highlighted are Aa (Bcl2), Ab (p53 phospho-serine-15), and Ac (HSP70). Alternatively, cells were harvested for Western blot analysis of total and phosphorylated STAT3 (antibodies from cell signalling) relative to actin loading control (antibody from Abcam) (b) and quantified by densitometry. Data are represented as fold change during latency from representative Western blots (c). The data are summarised in context with the literature in (d). Extrinsic FAS-mediated apoptosis involves FADD, caspase 8, pro-caspase 3, and caspase 3 and leads to apoptosis [81, 82]. Intrinsic mitochondrial-mediated apoptosis involves Bax, Bid, voltage-dependent anion channel (VDAC), cytochrome C (cyt c), pro-caspase 9, and the apoptome [83, 84]. Additionally, anti-apoptotic IL-10 signalling can involve STAT3 phosphorylation, Bcl2, and HSP70 [59, 61, 62]. These anti-apoptotic factors are all positively regulated during HCMV latency. Finally, the two isoforms of virally induced IL-10, cmvIL-10 and LAcmvIL-10, are shown in (e), where grey boxes represent exons. LAcmvIL-10 is generated from alternative splicing, which does not express exon 3
Fig. 3
Fig. 3
Myeloid transcription factor GATA2 plays multiple roles during HCMV latency. Following the establishment of latency in CD34+ cells for 10 days, there is an induction of cellular hsa-miRNA-92a via LAcmvIL-10 [31, 79]. This leads to a direct upregulation of the cellular transcription factor GATA2 [34]. GATA2 can drive the transcription of the latency-associated viral products LUNA and UL144 [34, 85] as well as driving transcription of the cellular cytokine gene IL-10 [31]. Whether other mechanisms for the upregulation of GATA2 during HCMV latency are also induced is not yet known. IL-10 serves to create an immune suppressive environment [32] as well as to lead to pro-life signalling to the latently infected cell [31]. IL-10 leads to STAT3 phosphorylation and signals to anti-apoptotic factors Bcl2 and HSP70 (see Fig. 2)
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