title: 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.
abstract: 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.
authors.affiliation: Center for Comparative Medicine, California National Primate Research Center, University of California-Davis, Davis, California 95616, USA. kabel@ucdavis.edu
authors.forename: Kristina
authors.initials: K
authors.lastname: Abel
authors.forename: Lisa
authors.initials: L
authors.lastname: La Franco-Scheuch
authors.forename: Tracy
authors.initials: T
authors.lastname: Rourke
authors.forename: Zhong-Min
authors.initials: ZM
authors.lastname: Ma
authors.forename: Veronique
authors.initials: V
authors.lastname: De Silva
authors.forename: Beth
authors.initials: B
authors.lastname: Fallert
authors.forename: Laurel
authors.initials: L
authors.lastname: Beckett
authors.forename: Todd A
authors.initials: TA
authors.lastname: Reinhart
authors.forename: Christopher J
authors.initials: CJ
authors.lastname: Miller
mesh_terms: D016915:AIDS Vaccines / Q000008:administration & dosage*; D000282:Administration, Intravaginal; D000818:Animals; D005260:Female; D015658:HIV Infections / Q000469:parasitology; D015497:HIV-1 / Q000276:immunology; D006801:Humans; D007249:Inflammation / Q000276:immunology*; D007371:Interferon-gamma / Q000378:metabolism*; D008213:Lymphocyte Activation; D008221:Lymphoid Tissue / Q000166:cytology / Q000276:immunology / Q000821:virology; D008253:Macaca mulatta; D018449:SAIDS Vaccines / Q000008:administration & dosage*; D016097:Simian Acquired Immunodeficiency Syndrome / Q000517:prevention & control*; D015302:Simian Immunodeficiency Virus / Q000276:immunology / Q000472:pathogenicity*; D013601:T-Lymphocytes / Q000276:immunology; D014611:Vaccination
chemical_list: D016915:AIDS Vaccines; D018449:SAIDS Vaccines; D007371:Interferon-gamma