The accelerated simian immunodeficiency virus macaque model of human immunodeficiency virus-associated neurological disease: from mechanism to treatment.
Highly active antiretroviral therapy has been effective in lowering viral loads in the peripheral blood, restoring immune function and reducing the incidence of opportunistic infections and dementia in human immunodeficiency virus (HIV)-infected individuals. However, motor and cognitive deficits and peripheral neuropathy continue, with some studies reporting an increase in prevalence of nervous system disease. The authors developed an accelerated, consistent simian model of HIV infection in which pigtailed macaques are dual inoculated with a neurovirulent simian immunodeficiency virus (SIV) clone and an immunosuppressive SIV strain. Infected animals invariably develop acquired immunodeficiency syndrome (AIDS) and over 90% develop central nervous system disease as well as peripheral nervous system disease with neurodegeneration by 3 months postinoculation. This model provides outstanding opportunities to delineate the pathogenesis of infection, to study the regulation of virus gene expression, and to identify host immune responses throughout the acute, clinically silent and late stages of infection. Using this model, the authors have demonstrated that the virus enters the brain within days after inoculation, that CCL2 (monocyte chemoattractant protein [MCP]-1) plays a major role in recruiting monocytes/macrophages to the brain, and that type I interferons are critical in suppressing early virus replication and inducing viral latency. This model provides a rigorous platform for the testing of potential antiretroviral, immune reconstituting, and/or neuroprotective agents and already has been used to confirm the neuroprotective properties of minocycline, which now is being tested in clinical trials of HIV-infected individuals.
Clements
Janice E
JE
Department of Molecular and Comparative Pathobiology, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205, USA.
Mankowski
Joseph L
JL
Gama
Lucio
L
Zink
M Christine
MC
D000818:Animals; D001921:Brain / Q000821:virology; D004195:Disease Models, Animal; D005838:Genotype; D008251:Macaca / Q000821:virology*; D009422:Nervous System Diseases / Q000209:etiology* / Q000628:therapy / Q000821:virology; D016097:Simian Acquired Immunodeficiency Syndrome / Q000503:physiopathology*; D015302:Simian Immunodeficiency Virus / Q000235:genetics / Q000502:physiology*
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