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Journal of Virology, January 2004, p. 841-854, Vol. 78, No. 2
0022-538X/04/$08.00+0     DOI: 10.1128/JVI.78.2.841-854.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.

Gamma Interferon-Mediated Inflammation Is Associated with Lack of Protection from Intravaginal Simian Immunodeficiency Virus SIVmac239 Challenge in Simian-Human Immunodeficiency Virus 89.6-Immunized Rhesus Macaques

Kristina Abel,1,2* Lisa La Franco-Scheuch,1,2 Tracy Rourke,2 Zhong-Min Ma,1,2 Veronique de Silva,2 Beth Fallert,3 Laurel Beckett,4 Todd A. Reinhart,3 and Christopher J. Miller1,2,5

Center for Comparative Medicine,1 California National Primate Research Center,2 Department of Pathology, Microbiology and Immunology, School of Veterinary MedicineDivision of Infectious Diseases,5 Division of Biostatistics, Department of Epidemiology and Preventive Medicine, School of Medicine, University of California—Davis, Davis, California,4 Department of Infectious Disease and Microbiology, University of Pittsburgh, Pittsburgh, Pennsylvania3

Received 8 May 2003/ Accepted 5 September 2003

Although gamma interferon (IFN-{gamma}) is a key mediator of antiviral defenses, it is also a mediator of inflammation. As inflammation can drive lentiviral replication, we sought to determine the relationship between IFN-{gamma}-related host immune responses and challenge virus replication in lymphoid tissues of simian-human immunodeficiency virus 89.6 (SHIV89.6)-vaccinated and unvaccinated rhesus macaques 6 months after challenge with simian immunodeficiency virus SIVmac239. Vaccinated-protected monkeys had low tissue viral RNA (vRNA) levels, vaccinated-unprotected animals had moderate tissue vRNA levels, and unvaccinated animals had high tissue vRNA levels. The long-term challenge outcome in vaccinated monkeys was correlated with the relative balance between SIV-specific IFN-{gamma} T-cell responses and nonspecific IFN-{gamma}-driven inflammation. Vaccinated-protected monkeys had slightly increased tissue IFN-{gamma} mRNA levels and a high frequency of IFN-{gamma}-secreting T cells responding to in vitro SIVgag peptide stimulation; thus, it is likely that they could develop effective anti-SIV cytotoxic T lymphocytes in vivo. In contrast, both high tissue IFN-{gamma} mRNA levels and strong in vitro SIV-specific IFN-{gamma} T-cell responses were detected in lymphoid tissues of vaccinated-unprotected monkeys. Unvaccinated monkeys had increased tissue IFN-{gamma} mRNA levels but weak in vitro anti-SIV IFN-{gamma} T-cell responses. In addition, in lymphoid tissues of vaccinated-unprotected and unvaccinated monkeys, the increased IFN-{gamma} mRNA levels were associated with increased Mig/CXCL9, IP-10/CXCL10, and CXCR3 mRNA levels, suggesting that increased Mig/CXCL9 and IP-10/CXCL10 expression resulted in recruitment of CXCR3+ activated T cells. Thus, IFN-{gamma}-driven inflammation promotes SIV replication in vaccinated-unprotected and unvaccinated monkeys. Unlike all unvaccinated monkeys, most monkeys vaccinated with SHIV89.6 did not develop IFN-{gamma}-driven inflammation, but they did develop effective antiviral CD8+-T-cell responses.

* Corresponding author. Mailing address: California National Primate Research Center/Center for Comparative Medicine, University of California—Davis, County Rd. 98/Hutchison Dr., Davis, CA 95616-8542. Phone: (530) 754-5673. Fax: (530) 754-4411. E-mail: kabel{at}ucdavis.edu.

Journal of Virology, January 2004, p. 841-854, Vol. 78, No. 2
0022-538X/04/$08.00+0     DOI: 10.1128/JVI.78.2.841-854.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.



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