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(American Journal of Pathology. 2002;161:813-822.)
© 2002 American Society for Investigative Pathology

Regular Articles

Neuropathogenesis of Lentiviral Infection in Macaques

Roles of CXCR4 and CCR5 Viruses and Interleukin-4 in Enhancing Monocyte Chemoattractant Protein-1 Production in Macrophages

Andrey Hicks*, Raghava Potula*, Yong Jun Sui*, Francois Villinger{dagger}, David Pinson*, Istvan Adany*, Zhuang Li*, Chloe Long*, Paul Cheney{ddagger}, Joanne Marcario{ddagger}, Francis Novembre§, Niklaus Mueller*, Anil Kumar*, Eugene Major, Opendra Narayan* and Shilpa Buch*

From the Departments of Microbiology, Immunology, and Molecular Genetics,* Marion Merrell Dow Laboratory of Viral Pathogenesis, and Molecular and Integrative Physiology,{ddagger} University of Kansas Medical Center, Kansas City, Kansas; the Department of Pathology and Laboratory Medicine{dagger} and Yerkees Regional Primate Research Center,§ Emory University, Atlanta, Georgia; and the Laboratory of Molecular Medicine and Neuroscience, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, Maryland

Neurological disease associated with lentiviral infection occurs mainly as a consequence of primary replication of the virus or a combination of the virus infection and replication of opportunistic pathogens in the central nervous system. Recent studies have shown that whereas the disease can be caused by CCR5 tropic viruses alone, its induction by CXCR4 (X4) tropic viruses occurred usually in association with infections caused by opportunistic pathogens and in the presence of a Th2 cytokine, interleukin (IL)-4.1,2 Further, X4-mediated neurological disease developed preferentially in rhesus compared to pig-tailed macaques. Because macrophages are the target cells for lentiviral infection in the brain and because macrophage chemoattractant protein (MCP)-1 is one of the major chemokines that is closely associated with acquired immune deficiency syndrome (AIDS) dementia, we tested for correlations between MCP-1 production and virus tropism in macrophages from the two species of macaques. The studies showed that the higher susceptibility of rhesus macaques to X4 virus-mediated encephalitis correlated with heightened production of virus and MCP-1 in cultured macrophages from this species and that these effects were further enhanced with treatment with IL-4. However, the latter effect was restricted to macrophages infected with X4 viruses. IL-4 may therefore be a basic requirement for X4 viruses to cause central nervous system disease.




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