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CCAAT/enhancer binding protein (C/EBP) sites are required for HIV-1 replication in primary macrophages but not CD4(+)
1Department of Microbiology, Columbia University, College of Physicians and Surgeons, 701 West 168th Street, New York, NY 10032, USA.
Abstract:
The importance of CCAAT/enhancer binding proteins (C/EBPs) and binding sites for HIV-1 replication in primary macrophages, T cell lines and primary CD4(+) T cells was examined. When lines overexpressing the C/EBP dominant-negative protein LIP were infected with HIV-1, replication occurred in Jurkat T cells but not in U937 promonocytes, demonstrating a requirement for C/EBP activators by HIV-1 only in promonocytes. Primary macrophages did not support the replication of HIV-1 harboring mutant C/EBP binding sites in the long terminal repeat but Jurkat, H9 and primary CD4(+) T cells supported replication of wild-type and mutant HIV-1 equally well. Thus the requirement for C/EBP sites is also confined to monocyte/macrophages. The requirement for C/EBP proteins and sites identifies the first uniquely macrophage-specific regulatory mechanism for HIV-1 replication.
Insights
CCAAT/enhancer binding proteins (C/EBPs) are crucial for HIV-1 replication in macrophages. This study reveals C/EBP binding sites are uniquely required for HIV-1 replication in monocyte/macrophages, not T cells.
Area of Science:
- Virology
- Immunology
- Molecular Biology
Background:
- CCAAT/enhancer binding proteins (C/EBPs) are transcription factors involved in cellular differentiation and function.
- HIV-1 replication is a complex process influenced by host cell factors and viral regulatory elements.
Purpose of the Study:
- To investigate the role of C/EBPs and their binding sites in HIV-1 replication across different cell types.
- To identify cell-type-specific regulatory mechanisms governing HIV-1 replication.
Main Methods:
- Overexpression of a dominant-negative C/EBP protein (LIP) in various cell lines and primary cells.
- Infection with wild-type and mutant HIV-1 strains harboring modified C/EBP binding sites in the long terminal repeat.
- Analysis of viral replication in promonocytes, T cell lines, and primary T cells and macrophages.
Main Results:
- HIV-1 replication was dependent on C/EBP activators in U937 promonocytes but not in Jurkat T cells.
- Primary macrophages failed to support HIV-1 replication with mutations in C/EBP binding sites, unlike T cell lines.
- The requirement for C/EBP binding sites was specific to monocyte/macrophage lineage cells.
Conclusions:
- C/EBP proteins and their binding sites are essential for HIV-1 replication in macrophages.
- This identifies a novel, macrophage-specific regulatory mechanism for HIV-1 replication.
- Understanding these host-pathogen interactions could inform therapeutic strategies targeting HIV-1 persistence.