Coordinated Regulation of SIV Replication and Immune Responses in the CNS
| Autor: | Ming Li, Janice E. Clements, Christopher M. Bartizal, Patrick M. Tarwater, Kenneth W. Witwer, Angela K. Brice, M. Christine Zink, Suzanne E. Queen, Lucio Gama, Joseph L. Mankowski, David R. Graham, John J. Varrone |
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| Jazyk: | angličtina |
| Rok vydání: | 2009 |
| Předmět: |
Central Nervous System
Chemokine Time Factors Simian Acquired Immunodeficiency Syndrome lcsh:Medicine Virus Replication 0302 clinical medicine lcsh:Science 0303 health sciences Multidisciplinary biology Brain 3. Good health medicine.anatomical_structure Acute Disease Virology/Animal Models of Infection Cytokines RNA Viral Tumor necrosis factor alpha Simian Immunodeficiency Virus medicine.symptom Research Article Central nervous system Inflammation Virus 03 medical and health sciences Immune system medicine Animals RNA Messenger 030304 developmental biology Neurological Disorders/Infectious Diseases of the Nervous System Innate immune system CCAAT-Enhancer-Binding Protein-beta Macrophages lcsh:R Immunity Virion Endothelial Cells Immunity Innate Viral replication Gene Expression Regulation Astrocytes Immunology Immunology/Immune Response biology.protein Macaca lcsh:Q 030215 immunology |
| Zdroj: | PLoS ONE PLoS ONE, Vol 4, Iss 12, p e8129 (2009) |
| ISSN: | 1932-6203 |
| Popis: | Central nervous system (CNS) invasion during acute-stage HIV-infection has been demonstrated in a small number of individuals, but there is no evidence of neurological impairment at this stage and virus infection in brain appears to be controlled until late-stage disease. Using our reproducible SIV macaque model to examine the earliest stages of infection in the CNS, we identified immune responses that differentially regulate inflammation and virus replication in the brain compared to the peripheral blood and lymphoid tissues. SIV replication in brain macrophages and in brain of SIV-infected macaques was detected at 4 days post-inoculation (p.i.). This was accompanied by upregulation of innate immune responses, including IFNbeta, IFNbeta-induced gene MxA mRNA, and TNFalpha. Additionally, IL-10, the chemokine CCL2, and activation markers in macrophages, endothelial cells, and astrocytes were all increased in the brain at four days p.i. We observed synchronous control of virus replication, cytokine mRNA levels and inflammatory markers (MHC Class II, CD68 and GFAP) by 14 days p.i.; however, control failure was followed by development of CNS lesions in the brain. SIV infection was accompanied by induction of the dominant-negative isoform of C/EBPbeta, which regulates SIV, CCL2, and IL6 transcription, as well as inflammatory responses in macrophages and astrocytes. This synchronous response in the CNS is in part due to the effect of the C/EBPbeta on virus replication and cytokine expression in macrophage-lineage cells in contrast to CD4+ lymphocytes in peripheral blood and lymphoid tissues. Thus, we have identified a crucial period in the brain when virus replication and inflammation are controlled. As in HIV-infected individuals, though, this control is not sustained in the brain. Our results suggest that intervention with antiretroviral drugs or anti-inflammatory therapeutics with CNS penetration would sustain early control. These studies further suggest that interventions should target HIV-infected individuals with increased CCL2 levels or HIV RNA in the CNS. |
| Databáze: | OpenAIRE |
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