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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

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-) 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--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- T-cell responses and nonspecific IFN--driven inflammation. Vaccinated-protected monkeys had slightly increased tissue IFN- mRNA levels and a high frequency of IFN--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- mRNA levels and strong in vitro SIV-specific IFN- T-cell responses were detected in lymphoid tissues of vaccinated-unprotected monkeys. Unvaccinated monkeys had increased tissue IFN- mRNA levels but weak in vitro anti-SIV IFN- T-cell responses. In addition, in lymphoid tissues of vaccinated-unprotected and unvaccinated monkeys, the increased IFN- 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--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--driven inflammation, but they did develop effective antiviral CD8⁺-T-cell responses.

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