The Establishment of HCMV Latency

One of the critical steps for establishing latency is likely to include the silencing of the viral MIEP: such control of viral major IE gene expression is a credible mechanism by which all subsequent viral lytic gene expression will be regulated (Fig. 2). Thus, what regulates the MIEP? The MIEP appears to be regulated by multiple cellular transcription factors and higher-order chromatin structure during both lytic (Meier and Stinski 1996; Nevels et al. 2004; Ioudinkova et al. 2006; Reeves et al. 2006) and latent infection (Sinclair and Sissons 2006). Promoter transfection assays have identified a number of factors that repress the MIEP: including YY1 (ying yang 1) (Liu et al. 1994), ERF (ets-2 repressor factor) (Bain et al. 2003) and Gfi-1 (growth factor independent-1) (Zweidler-Mckay et al. 1996). These factors are expressed at high levels in nonpermissive cells and, interestingly, ERF and YY1 are known to interact with chromatin-modifying enzymes (Thomas and Seto 1999; Wright et al. 2005). Consistent with this, during both experimental and natural latency, the transcriptionally inactive MIEP is associated with markers of repressed chromatin, such as Heterochromatin protein 1 (HP1), and is responsive to the histone deacetylase inhibitor Trichostatin A (TS A) providing a model for silencing of the MIEP during experimental (Meier 2001; Murphy et al. 2002; Reeves et al. 2005a) and natural latency (Reeves et al. 2005b). Interestingly, during experimental latency in GM-Ps, cellular factors associated with the formation of repressive chromatin (i.e. AML-1b) are known to be upregulated (Slobedman et al. 2004). Therefore, such cellular responses to latent infection, coupled with a cellular environment already high in levels of repressors of the MIEP, may be critical determinants for the establishment and maintenance of latent carriage of viral genomes.

Fig. 2 The establishment of HCMV latency is promoted by chromatin structure. Following infection (a), HCMV infects the cells of the bone marrow (b) and establishes a latent infection of the CD34+ cells resident therein (c). High levels of cellular transcriptional repressors such as ERF and YY1 (d) repress the MIEP. As well as transcription factor binding, histone proteins are recruited to the MIEP which become targets for histone deacetylases and histone methyltransferases that are recruited by YY1 and ERF (e). These methylated histones become targets for the recruitment of HP-1, which augments repression and the establishment of latency (f). Whether any viral products expressed during latency that are important for the repression of the MIEP in this model is, to date, unknown

Fig. 2 The establishment of HCMV latency is promoted by chromatin structure. Following infection (a), HCMV infects the cells of the bone marrow (b) and establishes a latent infection of the CD34+ cells resident therein (c). High levels of cellular transcriptional repressors such as ERF and YY1 (d) repress the MIEP. As well as transcription factor binding, histone proteins are recruited to the MIEP which become targets for histone deacetylases and histone methyltransferases that are recruited by YY1 and ERF (e). These methylated histones become targets for the recruitment of HP-1, which augments repression and the establishment of latency (f). Whether any viral products expressed during latency that are important for the repression of the MIEP in this model is, to date, unknown

To date, there is a good consensus that HCMV infects CD34+ haematopoietic stem cells and establishes a latent infection in them. Whilst this is demonstrably true, it has also been suggested that subsets of CD34+ cells may show susceptibility for HCMV productive infection. A study by Goodrum et al. (2004) that analysed differential outcomes of HCMV infection in sorted populations of haematopoietic CD34+ stem cells concluded that infection of one subset of CD34+ cells (CD34+ but CD38") established the hallmarks of a latent infection (Goodrum et al. 2004), i.e. no detectable virus production but the ability to reactivate upon cellular differentiation. In contrast, other CD34+ cell subpopulations were fully productive for HCMV infection, whilst more mature CD34+ stem cell subpopulations appeared to undergo abortive infection and failed to maintain latent viral genomes. This suggests that the outcome of infection of different CD34+ stem cell subpopulations could depend on the exact phenotype of each stem cell subpopulation. Indeed, there is increasing evidence of early lineage commitment in the haematopoietic stem cell compartment such that a dendritic cell fate, although not irreversible (O'Garra and Trinchieri 2004), is thought to be determined at earlier stages of progenitor cell development (Olweus et al. 1997; Monji et al. 2002). Taken together, these observations could support the hypothesis that HCMV infection of CD34+ stem cells, resulting in latent viral carriage, is restricted to certain subpopulations of CD34+ stem cells. These cells are restricted to specific myeloid cell fates and this mechanism may explain why the carriage of HCMV genomes occurs in some but not all cell types of the myeloid lineage.

Alternatively, infection of CD34+ stem cells could, in itself, promote lineage commitment of the latently infected cell to specific myeloid cell types. Although there is no direct evidence for this, differences in the cellular transcriptome of experimentally latently infected GM-Ps compared with uninfected GM-Ps suggest that such changes in cellular gene expression upon latent infection could, hypo-thetically, promote lineage commitment of these myeloid progenitor cells (Slobedman et al. 2004). Thus, whether viral genome carriage in only certain myeloid cells is a consequence of HCMV initially infecting specific CD34+ subpopulations which are already committed to different lineages or is due to the latent infection itself, promoting lineage commitment to specific myeloid cell types, is unclear, but both are plausible.

It is clear that a critical determinant of whether the outcome of an infection is productive or latent is dependent on the regulation of IE gene expression: if repression of the MIEP prevails, latency will probably be established (Sinclair and Sissons 1996). However, whether this also involves expression of other specific viral genes is not clear. As stated previously, experimental latency models have identified a wide range of viral transcripts which appear to be expressed during latency. However, many of these are not exclusive to latent infection (Lunetta and Wiedeman 2000; Bego et al. 2005; Goodrum et al. 2007) and their expression has not been confirmed in natural latency (Beisser et al. 2001; Goodrum et al. 2002; Cheung et al. 2006). Consequently, they may simply represent noise from abortive or productive infection in certain subpopulations of progenitor cell types or they may represent a class of viral gene products required to establish latent infection (see Sect. 4, above).

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