Cytomegalovirus remains latent in a common precursor of dendritic and myeloid cells

Abstract

Hematopoietic cells and their progenitors play important roles in human cytomegalovirus latency and reactivation. Latent infection has been evaluated in defined populations of myeloid-lineage-committed progenitor cells coexpressing CD33 and CD15 or CD33 and CD14 along with the dendritic cell markers CD1a and CD10. These CD33 ؉ cell populations were found to support latency and expression of viral latencyassociated transcripts and to undergo reactivation of productive viral replication when differentiated in the presence of human fibroblasts. Reactivation was also observed when myeloid cells were carried in the presence of fibroblast-conditioned medium or medium supplemented with certain cytokines (interferon ␥, tumor necrosis factor ␣, interleukin 4, or granulocytemacrophage colony-simulating factor), suggesting that cell differentiation pathways act as determinants of reactivation. More primitive CD34؉ hematopoietic cells were also found to be susceptible to viral infection and latency was maintained as these cells differentiated into CD33 ؉ -lineage-committed populations. Between 0.01% and 0.001% of CD33 ؉ CD14 ؉ or CD33 ؉ CD15 ؉ bone marrow mononuclear cells isolated from naturally infected individuals were found to express latent transcripts. Thus, cytomegalovirus is carried within a small percentage of myeloid and dendritic cell progenitors in the healthy seropositive host. Virus reactivation may be triggered by factors associated with the inflammatory response.

Viral Interleukin-10 Expressed by Human Cytomegalovirus during the Latent Phase of Infection Modulates Latently Infected Myeloid Cell Differentiation

“…HCMV establishes and maintains a lifelong latent infection in primitive myeloid lineage cells (14,22,27,48,53,58). Following terminal cell differentiation of these cells into myeloid dendritic cells (DCs) and macrophages, latent virus has the ability to reactivate, resulting in the production of new, infectious virions and often severe disease in immunocompromised individuals (11,14,28,37,49,50,59,63).…”

“…HCMV establishes and maintains a lifelong latent infection in primitive myeloid lineage cells (14,22,27,48,53,58). Following terminal cell differentiation of these cells into myeloid dendritic cells (DCs) and macrophages, latent virus has the ability to reactivate, resulting in the production of new, infectious virions and often severe disease in immunocompromised individuals (11,14,28,37,49,50,59,63). Only a subset of viral genes are transcriptionally active during latency (2,8,12,13,17,23,34,47), including HCMV UL111A, a gene that encodes homologs of the potent immunomodulatory cytokine human interleukin-10 (hIL-10).…”

Antibody Repertoire Development in Fetal and Neonatal Piglets: XIX. Undiversified B Cells with Hydrophobic HCDR3s Preferentially Proliferate in the Porcine Reproductive and Respiratory Syndrome

“…Many viral pathogens have evolved mechanisms to down-regulate MHC class I presentation of viral Ags. Some produce mimic FcRs and others alter cytokine profiles (1)(2)(3). A few viruses elaborate T cell superantigens (SAgs) 3 that expand T cell subpopulations independent of virus specificity that can result in cytokine shock and cause clonal deletion (4,5).…”

Interplay between human cytomegalovirus and dendritic cells in T cell activation

“…Moreover, some viruses such as HIV and human cytomegalovirus (HCMV) use the C-type lectin receptor DC-SIGN on dendritic cells as a vector to ensure their transmission to other cells either in the periphery or in lymph nodes [1,2]. Direct arguments that DCs are real targets for HCMV in vivo are suggested, for instance, by the ability of the virus to infect hematopoietic progenitor cells [3] and by the presence of viral DNA in puriWed DCs from viremic renal transplant patients as well as from healthy virus carriers [4,5]. HCMV is a latent herpesvirus, which can be considered as a spearhead in exploiting co-existence with the host to develop numerous immunoevasion mechanisms, and virus-encoded immunoevasins have been described that impair many of dendritic cells functions including antigen presentation to CD4+ and CD8+ T cells [6].…”