Latency is operationally defined as the persistence of the viral genome in the absence of viral lytic gene expression, but importantly, with the capacity of the virus to re-enter its lytic life cycle. The ease and rapidity with which HCMV reactivates in vivo, causing severe disease, is in stark contrast to the ability to reactivate in vitro.
Observations from both experimentally and naturally latent cells suggest that the cellular environment is a key factor in HCMV reactivation: changes in the cellular environment result in the induction of viral lytic gene expression and, hence, virus reactivation (Fig. 3+. A number of functions associated with virus infection are known to augment viral IE gene expression. Virus binding on the surface of the cell results in significant changes to the cellular environment by targeting a number of
Fig. 3 Reactivation may be promoted by pro-inflammatory signals and is differentiation dependent. CD34+ cells carry the HCMV genome in a latent form (A), maintained by a repressive chromatin structure around the MIEP (B). Exposure of CD34+ cells to growth factors and/or inflammatory cytokines promotes myeloid differentiation to mature macrophages and dendritic cells (C). Differentiation is concomitant with changes in the levels of specific cellular transcription factors and co-factors. These changes promote the reactivation of HCMV immediate-early gene expression, which is consistent with changes in the chromatin structure of the MIEP from a repressed to an active conformation (D). Whether this change is totally regulated by cellular factors or requires a viral product remains unknown
Fig. 3 Reactivation may be promoted by pro-inflammatory signals and is differentiation dependent. CD34+ cells carry the HCMV genome in a latent form (A), maintained by a repressive chromatin structure around the MIEP (B). Exposure of CD34+ cells to growth factors and/or inflammatory cytokines promotes myeloid differentiation to mature macrophages and dendritic cells (C). Differentiation is concomitant with changes in the levels of specific cellular transcription factors and co-factors. These changes promote the reactivation of HCMV immediate-early gene expression, which is consistent with changes in the chromatin structure of the MIEP from a repressed to an active conformation (D). Whether this change is totally regulated by cellular factors or requires a viral product remains unknown signaling pathways (Fortunato et al. 2000; Simmen et al. 2001; Johnson and Hegde 2002; see the chapters by A. Yurochko and M.K. Isaacson et al., this volume). Viral tegument proteins are also delivered to the cell which can target cellular functions (Everett 2006; see the chapter by G. Maul, this volume). Finally, some of these viral tegument proteins delivered by the virion particle are known to transactivate gene expression to promote high levels of viral IE transcription (Liu and Stinski 1992; Bresnahan and Shenk 2000; Schierling et al. 2004; see the chapter by R; Kaletja, this volume). However, none of these are likely to be involved in reactivation from latency as no virions will be present in the apparent absence of these events during latency; the switch from a latent to a reactivating phenotype requires a latency breaking step. Whether this is a virally encoded latent function or is a consequence of changes to the cellular environment is presently under intense investigation in a number of laboratories.
In our laboratory, we have shown that reactivation of viral gene expression and productive infection in natural (Reeves et al. 2005b) or experimental latency (Murphy et al. 2002; Reeves et al. 2005a) is associated with differentiation of CD34+ cells to a DC phenotype. Histone acetylation at the MIEP facilitates an open chromatin conformation which is permissive for MIEP transcription (Reeves et al. 2005b). Consequently, the implication is that normal changes in cellular transcrip-tional regulators which occur upon terminal differentiation of myeloid cells could be enough to trigger reactivation of virus IE gene expression.
The likelihood that reactivation from latency occurs in the absence of virally encoded transactivators of IE gene expression implies that the viral genome senses reactivation signals from cellular mediators. The first report of reactivation in vitro from myeloid cells involved the stimulation of monocytes with cytokines derived from allogeneically stimulated T cells (Soderberg-Naucler et al. 1997), including TNF-alpha, interferon-gamma, interleukins and GM-CSF (Soderberg-Naucler et al. 2001). Pro-inflammatory factors or induction of myeloid cell differentiation have been responsible for promoting reactivation of viral major IE gene expression. This scenario may have strong clinical relevance, considering the known association of virus reactivation and CMV disease with transplantation (Sissons et al. 2002). Attempts to further characterise the role of the cytokines have, so far, proved inconclusive and await further study.
Besides the basic regulation of viral IE expression, it is also clear that the interplay between the host immune system and reactivating virus has a profound role in HCMV reactivation in vivo (Sissons et al. 2002; Peggs and Mackinnon 2004). Possibly, HCMV reactivation is a sporadic event, occurring infrequently when certain inflammatory conditions are encountered locally in the host. Alternatively, it could be a more common event, occurring whenever latently infected myeloid cells naturally differentiate. In both cases, any reactivation and virus dissemination, which could result in severe disease, is efficiently controlled by a robust immune response. This may be the reason for the unprecedented number of memory T cells that recognise lytic HCMV antigens from healthy carriers in vivo (Riddell et al. 1991; McLaughlin-Taylor et al. 1994; Wills et al. 1996; Sylwester et al. 2005). Both scenarios are possible and it is likely that that the exact mechanism could lay some where between these two extremes; either could account for the success of this virus as an opportunistic pathogen.
In contrast, during transplantation and likely accompanying immune suppression, the cytokine storm induced by transplantation could drive virus reactivation which is uncontrollable in the absence of a good cytotoxic T cell (CTL) response. However, studies to address these types of questions are extremely difficult, requiring analyses with naturally, latently infected cells and homologous or nonhomolo-gous CTLs. Given the frequency of HCMV DNA-positive cells, this would be a challenging exercise. It is becoming increasingly clear that conducting these and other analyses pertinent to HCMV latency will require a system for enriching for HCMV-positive cells in cell populations from naturally infected individuals.
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