Neuroregulatory events follow adaptive immune-mediated elimination of HIV-1-infected macrophages: studies in a murine model of viral encephalitis.
HIV-1-specific cellular immunity serves to eliminate infected cells and disease. However, how this process specifically affects the CNS is poorly understood. To mirror the regulatory events that occur in human brain after HIV-1 infection, a murine model of viral encephalitis was used to study relationships, over time, among lymphocyte-mediated infected cell elimination, innate immune responses, and neuropathology. Nonobese diabetic SCID mice were reconstituted with human PBL and a focal encephalitis induced by intracranial injection of autologous HIV-1-infected, monocyte-derived macrophages (MDM). On days 7, 14, and 21 after MDM injection into the basal ganglia, the numbers of human lymphocytes and mouse monocytes, virus-infected MDM, glial (astrocyte and microglial) responses, cytokines, inducible NO (iNOS), neurotrophic factors, and neuronal Ags were determined in brain by immunohistochemistry, real-time PCR, and Western blot assays. Microglia activation, astrocytosis, proinflammatory cytokines, and iNOS expression accompanied the loss of neuronal Ags. This followed entry of human lymphocytes and mouse monocytes into the brain on days 7 and 14. Elimination of virus-infected human MDM, expression of IL-10, neurotropins, and a down-regulation of iNOS coincided with brain tissue restoration. Our results demonstrate that the degree of tissue damage and repair parallels the presence of infected macrophages and effectors of innate and adaptive immunity. This murine model of HIV-1 encephalitis can be useful in elucidating the role played by innate and adaptive immunity in disease progression and resolution.
Poluektova
Larisa
L
Laboratory of Neuroregeneration, Center for Neurovirology and Neurodegenerative Disorders, and Department of Pathology and Microbiology, University of Nebraska Medical Center, 958215 Nebraska Medical Center, Omaha, NE 68198-5215, USA. lpoluekt@unmc.edu
Gorantla
Santhi
S
Faraci
Jill
J
Birusingh
Kevin
K
Dou
Huanyu
H
Gendelman
Howard E
HE
D015526:AIDS Dementia Complex / Q000276:immunology; D000818:Animals; D001921:Brain / Q000166:cytology / Q000276:immunology / Q000502:physiology / Q000821:virology; D002452:Cell Count; D017690:Cell Transplantation; D016207:Cytokines / Q000096:biosynthesis; D015536:Down-Regulation; D018792:Encephalitis, Viral / Q000276:immunology*; D006133:Growth Substances / Q000096:biosynthesis; D015658:HIV Infections / Q000150:complications / Q000276:immunology*; D006801:Humans; D007109:Immunity; D017708:Leukocyte Transfusion; D008264:Macrophages / Q000637:transplantation / Q000821:virology*; D008297:Male; D051379:Mice; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D015213:Neuroimmunomodulation; D012038:Regeneration; D013997:Time Factors; D014183:Transplantation, Heterologous; D015854:Up-Regulation
D016207:Cytokines; D006133:Growth Substances