Latency Carriage and Reactivation of HCMV in the Cells of the Myeloid Lineage

Some of the first instructive observations regarding HCMV latency came from clinical studies. Although it was extremely difficult to detect infectious virus in the blood of normal healthy individuals, it was evident that blood transfusions from healthy seropositive donors often resulted in the transmission of HCMV to blood donor recipients (Adler 1983). However, the incidence of this transmission was significantly reduced if leukocyte-depleted blood products were used (Yeager et al. 1981; Tolpin et al.

1985; Gilbert et al. 1989), which strongly suggested that viral transmission was cell-based and not mediated by free virus. Consequently, one of the cellular sites of latency was believed to be in the peripheral blood compartment.

We now know that the latent load of HCMV in healthy carriers is around 1 genome-positive cell per 10,000 peripheral blood mononuclear cells (PBMCs) (Slobedman and Mocarski 1999), clearly below the detection limits of Northern, Southern and Western analyses. However, the use of a highly-sensitive PCR approach finally permitted the analysis of HCMV latency in vivo and defined the myeloid lineage as an important site of HCMV latency (Fig. 1). An experimental approach that isolated different fractions of cells from the blood of healthy seropositives showed that carriage of HCMV DNA occurred predominantly in the leukocyte fraction of peripheral blood - particularly in the CD14+ monocyte population (Fig. 1a). HCMV was not found in the lymphocyte fraction or the polymorphonuclear cells (Fig. 1b) (Bevan et al. 1991; Taylor-Wiedeman et al. 1991, 1993; Stanier et al. 1992). Monocytes, however, represent a short-lived continually renewable population of cells that arise from haematopoietic cell precursors (CD34+ cells) present in the bone marrow (Metcalf 1989). These cells were also shown to be HCMV genomepositive, suggesting that the bone marrow represents one latent reservoir of virus (Mendelson et al. 1996; Sindre et al. 1996). Although CD34+ cells are sites of latency for HCMV and are a common precursor of both lymphoid and myeloid cells, the carriage of virus appears to be restricted to cells of the monocyte/myeloid lineage by, as yet, undefined mechanisms (for review see Sinclair and Sissons 2006).

Fig. 1 HCMV latency is established in bone marrow progenitors and is carried in the myeloid lineage. During natural latency, HCMV DNA can be detected in bone marrow progenitor cells that give rise multiple lineages. However, the carriage of viral genomes is detected in the myeloid lineage (a) and not the lymphoid lineage (b). A third endothelial lineage (c) has been proposed, but not proven (?), which may also provide another site of HCMV latency in aortic, and not venous, endothelial cells

Fig. 1 HCMV latency is established in bone marrow progenitors and is carried in the myeloid lineage. During natural latency, HCMV DNA can be detected in bone marrow progenitor cells that give rise multiple lineages. However, the carriage of viral genomes is detected in the myeloid lineage (a) and not the lymphoid lineage (b). A third endothelial lineage (c) has been proposed, but not proven (?), which may also provide another site of HCMV latency in aortic, and not venous, endothelial cells

One major difference between viral latency and reactivation is characteristically defined by the absence of lytic gene transcription during latent carriage of virus. Although transcripts arising from the major IE region of HCMV have been detected during latency (Kondo and Mocarski 1995; Kondo et al. 1996) (see Sect. 4 below), the major IE transcripts IE72 or IE86 are not expressed in naturally latent CD34+ cells or monocytes (Taylor-Wiedeman et al. 1994; Mendelson et al. 1996). Indeed, it is only upon terminal differentiation of these cells to mature macrophage or dendritic cell phenotypes that viral lytic gene expression is observed, which, under certain conditions, can result in complete reactivation and release of infectious virus (Taylor-Wiedeman et al. 1994; Soderberg-Naucler et al. 1997; Soderberg-Naucler et al. 2001; Reeves et al. 2005b). However, attempts to dissect the mechanisms of HCMV latency and reactivation have been hampered by the frequency of seropositive cells in vivo and a lack of a robust tissue culture model which allows a more thorough, large-scale analysis of natural latency.

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