Chemokine Networks and Altered Leukocyte Traffic in Acute Simian Immunodeficiency Virus Infection
The project presented in Chapter 1 focuses on the establishment of an in vivo leukocyte trafficking model and on defining homeostatic T lymphocyte migration patterns by tracking fluorescein dye-labeled leukocytes. In a second project (Chapter 2), T cell trafficking parameters are examined in acute SIV infection to determine if chemokine networks and T cell migration are altered. Increased T lymphocyte homing towards the small intestine is observed in SIV-infected compared to uninfected animals, which correlates with an induction of proinflammatory chemokines in this tissue. The small intestine represents a major site of CD4 T cell depletion in acute SIV infection and the observed gut-specific T cell trafficking likely provides additional target cells for viral infection and contributes to both peripheral blood and mucosal CD4 T cell decline. The third project (Chapter 3) focuses on monocyte migration into the central nervous system in acute SIV infection and monocytes' role as 'Trojan Horse' for virus import into the brain. Migration of dye-labeled monocytes across the blood-brain barrier is unambiguously demonstrated and neuroinflammation characterized. In chapter 4, I extend upon the monocyte brain-trafficking studies and develop an in vitro SIV infection model to further evaluate the impact of SIV infection on monocyte migratory parameters and their neuroinvasive potential. These studies demonstrate dysregulation of chemokines and leukocyte migratory circuits in acute SIV infection expected to contribute to CD4 T lymphocyte decline and viral dissemination via monocytes into the brain. Such studies are expected to lead to novel drug targeting and treatment options that inhibit acute and chronic (neuro-) inflammation by targeting specific cells subsets and their migratory signals.
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Altered chemokine triggers and T lymphocyte migration
Peripheral monocyte activation and enhanced neuroinvasion
Establishment of an in vitro monocyte infection model
activation marker acute infection acute SIV infection acutely SIV-infected animals antigen brain CCL2 CCR5 CCR7 CCR9 CD3+ CD4 T cell CD4 T lymphocytes CD4+ CFSE CFSE dye-labeled CFSE+ cells CFSE+ T lymphocytes chemokine CXCL9 chemokine networks chemokine receptor chemokine receptor expression choroid plexus culture CXCL9 CXCR3 DAPI detection disease dye-labeled cells encephalitis examine Figure flow cytometry fluorescein frequency of CFSE+ gated based gut lamina propria HIV and SIV HIV/SIV human immunodeficiency virus immunodeficiency virus infection Immunol infiltrating lamina propria leukocyte leukocyte trafficking ligand lymph nodes lymphocyte trafficking macrophages monocyte migration monocyte migratory monocyte subsets monocytes nonhuman primate panel pathogenesis pathogens PBMC peripheral blood monocytes proinflammatory chemokine protein recruitment rhesus macaques rhesus monocytes secondary lymphoid tissue simian immunodeficiency virus SIV-infected group SIV-infected monocytes small intestine studies T-lymphocyte target tissue sections transcript levels triggers uninfected animals uninfected macaques viral entry viral replication Virol vitro