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Journal of Virology, February 2003, p. 1727-1737, Vol. 77, No. 3
0022-538X/03/$08.00+0     DOI: 10.1128/JVI.77.3.1727-1737.2003
Copyright © 2003, American Society for Microbiology. All Rights Reserved.

Arenavirus-Mediated Liver Pathology: Acute Lymphocytic Choriomeningitis Virus Infection of Rhesus Macaques Is Characterized by High-Level Interleukin-6 Expression and Hepatocyte Proliferation

Igor S. Lukashevich,* Ilia Tikhonov, Juan D. Rodas, Juan C. Zapata, Yida Yang, Mahmoud Djavani, and Maria S. Salvato

Institute of Human Virology, University of Maryland Biotechnology Institute, Baltimore, Maryland 21201

Received 24 July 2002/ Accepted 22 October 2002

Lymphocytic choriomeningitis virus (LCMV) and Lassa virus can cause hemorrhagic fever and liver disease in primates. The WE strain of LCMV (LCMV-WE) causes a fatal Lassa fever-like disease in rhesus macaques and provides a model for arenavirus pathogenesis in humans. LCMV-WE delivered intravenously or intragastrically to rhesus macaques targets hepatocytes and induces high levels of liver enzymes, interleukin-6 (IL-6), soluble IL-6 receptor (sIL-6R), and soluble tumor necrosis factor receptors (sTNFRI and -II) in plasma during acute infection. Proinflammatory cytokines TNF-{alpha} and IL-1ß were not detected in plasma of infected animals, but increased plasma gamma interferon was noted in fatally infected animals. Immunohistochemistry of acute liver biopsies revealed that 25 to 40% of nuclei were positive for proliferation antigen Ki-67. The increases in IL-6, sIL-6R, sTNFR, and proliferation antigen that we observe are similar to the profile of incipient liver regeneration after surgical or toxic injury (N. Fausto, Am. J. Physiol. 277:G917-G921, 1999). Although IL-6 was not directly induced by virus infection in vitro, peripheral blood mononuclear cells from acutely infected monkeys produced higher levels of IL-6 upon lipopolysaccharide stimulation than did healthy controls. Our data confirm that acute infection is associated with weak inflammatory responses in tissues and initiates a program of liver regeneration in primates.

* Corresponding author. Mailing address: Institute of Human Virology, University of Maryland Biotechnology Institute, 725 West Lombard St., Baltimore, MD 21201. Phone: (410) 706-1366. Fax: (410) 706-5198. E-mail: lukashev{at}umbi.umd.edu.

Journal of Virology, February 2003, p. 1727-1737, Vol. 77, No. 3
0022-538X/03/$08.00+0     DOI: 10.1128/JVI.77.3.1727-1737.2003
Copyright © 2003, American Society for Microbiology. All Rights Reserved.



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