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Human cytomegalovirus infection of the monocyte/macrophage lineage in bone marrow
E J Minton1, C Tysoe, J H Sinclair
1Department of Medicine, University of Cambridge Clinical School, United Kingdom.
Abstract:
Peripheral blood monocytes (PBM) are one site of persistence of human cytomegalovirus (HCMV) in healthy carriers. However, because PBM circulate only briefly before entering the tissues and are difficult to infect with HCMV, it has been suggested that they may acquire HCMV during development in the bone marrow. Consistent with this, we show evidence that bone marrow progenitors from healthy HCMV carriers contain endogenous HCMV DNA as detected by PCR. We also show that bone marrow precursors are readily infected by clinical isolates of HCMV in vitro but that no viral gene expression occurs until these cells become differentiated. In contrast, incubation of these cells at any developmental stage with the laboratory strain AD169 resulted in few cells expressing viral immediate-early genes, and this correlated with a lack of entry of AD169 virus. These observations are consistent with bone marrow progenitors acting as a reservoir for HCMV and transmitting the viral genome to PBM, in the absence of lytic-gene expression, until they leave the circulation and undergo tissue-specific differentiation to macrophages.
Insights
Bone marrow progenitors may harbor human cytomegalovirus (HCMV) DNA in healthy carriers. These cells can transmit the HCMV genome to peripheral blood monocytes (PBM) without active viral gene expression.
Area of Science:
- Virology
- Immunology
- Hematology
Background:
- Peripheral blood monocytes (PBM) are a known reservoir for human cytomegalovirus (HCMV) in healthy individuals.
- The brief circulation time and resistance of PBM to HCMV infection suggest an alternative origin for viral persistence.
Purpose of the Study:
- To investigate the role of bone marrow progenitors as a potential reservoir for HCMV.
- To understand the mechanism of HCMV acquisition and persistence in hematopoietic cells.
Main Methods:
- Detection of endogenous HCMV DNA in bone marrow progenitors using Polymerase Chain Reaction (PCR).
- In vitro infection of bone marrow precursors with clinical HCMV isolates and the laboratory strain AD169.
- Analysis of viral gene expression and viral entry in differentiated and undifferentiated bone marrow cells.
Main Results:
- Endogenous HCMV DNA was detected in bone marrow progenitors from healthy HCMV carriers.
- Clinical HCMV isolates readily infected bone marrow precursors, but viral gene expression was delayed until differentiation.
- The laboratory strain AD169 showed limited entry and immediate-early gene expression in these cells.
Conclusions:
- Bone marrow progenitors serve as a reservoir for HCMV, containing the viral genome.
- HCMV is transmitted to PBM from bone marrow progenitors without lytic gene expression during circulation.
- Tissue-specific differentiation into macrophages facilitates subsequent viral reactivation or progression.