Impact of bone marrow hematopoiesis failure on T-cell generation during pathogenic simian immunodeficiency virus
Hugues Thiebot1, Bruno Vaslin, Sonia Derdouch
1CEA, Laboratoire d'Immuno-Pathologie Expérimentale, Service de Neurovirologie, Centre de Recherches du Service de Santé des Armées, Ecole Pratique des Hautes Etudes, Institut Paris-Sud sur les Cytokines, Université Paris XI, France.
Abstract:
Experimental infection of macaques with pathogenic strains of simian immunodeficiency virus (SIV) represents one of the most relevant animal models for studying HIV pathogenesis. In this study, we demonstrated a significant decrease in the generation of CD4+ T cells from bone marrow (BM) CD34+ progenitors in macaques infected with SIVmac251. This decrease appears to result from changes in the clonogenic potential of BM progenitors of both the myeloid and lymphoid lineages. We also demonstrated a significant decrease in the numbers of the most immature long-term culture-initiating cells (LTC-ICs). Hematopoietic failure occurred as early as primary infection, in the absence of CD34+ BM cell infection and was not related to plasma viral load. No major change was observed in the phenotype of BM CD34+ cells from infected macaques, including apoptosis markers such as annexin V staining and BcL-2 expression, but a significantly higher that normal proportion of cells were in the G0/G1 phase. This is the first demonstration that failure of BM hematopoiesis results in impaired T-cell production, which may contribute to the disruption of T-lymphocyte homeostasis characteristic of pathogenic lentiviral infections in primates.
Insights
Simian immunodeficiency virus (SIV) infection impairs T-cell production in macaques by affecting bone marrow (BM) progenitors. This hematopoietic failure, observed early in infection, contributes to T-lymphocyte imbalance in primates.
Area of Science:
- Primate immunology
- Hematopoiesis research
- Virology
Background:
- Simian immunodeficiency virus (SIV) infection in macaques is a key model for human immunodeficiency virus (HIV) pathogenesis.
- Understanding the mechanisms of T-lymphocyte depletion is crucial for developing effective therapies.
Purpose of the Study:
- To investigate the impact of SIVmac251 infection on T-cell generation from bone marrow (BM) progenitors in macaques.
- To identify the underlying causes of hematopoietic dysfunction during SIV infection.
Main Methods:
- Analysis of CD4+ T cell generation from BM CD34+ progenitors in SIV-infected macaques.
- Assessment of progenitor cell clonogenic potential and long-term culture-initiating cells (LTC-ICs).
- Evaluation of BM CD34+ cell phenotype, including apoptosis markers and cell cycle phase.
Main Results:
- SIVmac251 infection significantly reduced CD4+ T cell generation from BM CD34+ progenitors.
- A decrease in myeloid and lymphoid progenitor clonogenic potential and LTC-ICs was observed.
- Hematopoietic failure occurred early, independent of CD34+ cell infection or plasma viral load, with progenitors arrested in G0/G1 phase.
Conclusions:
- SIV infection causes hematopoietic failure in the bone marrow, impairing T-cell production.
- This BM dysfunction contributes to the T-lymphocyte imbalance seen in pathogenic lentiviral infections.
- The findings highlight a novel mechanism contributing to immune dysregulation in primate lentiviral infections.
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