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Cytomegalovirus remains latent in a common precursor of dendritic and myeloid cells
G Hahn1, R Jores, E S Mocarski
1Department of Microbiology and Immunology, Stanford University School of Medicine, Stanford, CA 94305-5124, USA.
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 latency-associated 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 gamma, tumor necrosis factor alpha, interleukin 4, or granulocyte-macrophage 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.
Insights
Human cytomegalovirus (HCMV) establishes latency in myeloid and dendritic cell progenitors. Reactivation of HCMV may be triggered by inflammatory factors and cell differentiation.
Area of Science:
- Immunology
- Virology
- Hematology
Background:
- Hematopoietic cells and their progenitors are crucial for human cytomegalovirus (HCMV) latency and reactivation.
- Latent HCMV infection has been investigated in specific myeloid-lineage progenitor cell populations.
Purpose of the Study:
- To evaluate HCMV latency and reactivation in myeloid and dendritic cell progenitors.
- To identify factors influencing HCMV reactivation from latency.
Main Methods:
- Analysis of CD33+ progenitor cells coexpressing CD15 or CD14, and dendritic cell markers (CD1a, CD10).
- Assessment of viral latency-associated transcripts.
- Induction of reactivation using human fibroblasts, fibroblast-conditioned medium, or cytokines (IFN-γ, TNF-α, IL-4, GM-CSF).
- Infection and latency studies in CD34+ hematopoietic stem cells.
Main Results:
- Defined CD33+ myeloid progenitor populations support HCMV latency and express viral latency-associated transcripts.
- Reactivation of productive HCMV replication occurs upon differentiation with fibroblasts or exposure to conditioned medium/cytokines.
- Primitive CD34+ hematopoietic cells are susceptible to HCMV infection, maintaining latency during differentiation.
- Latent transcripts are found in 0.001%-0.01% of CD33+ CD14+ or CD33+ CD15+ bone marrow cells from infected individuals.
Conclusions:
- HCMV resides in a small fraction of myeloid and dendritic cell progenitors in healthy seropositive individuals.
- Cell differentiation pathways are key determinants of HCMV reactivation.
- Factors associated with the inflammatory response may trigger HCMV reactivation from latency.