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Oregon Health and Science University, Vaccine and Gene Therapy Institute, Beaverton, OR 97006
Orthopoxviruses evade host immune responses by using a number of strategies, including decoy chemokine receptors, regulation of apoptosis, and evasion of complement-mediated lysis. Different from other poxviral subfamilies, however, orthopoxviruses are not known to evade recognition by CTL. In fact, vaccinia virus (VV) is used as a vaccine against smallpox and a vector for eliciting strong T cell responses to foreign Ags. and both human and mouse T cells are readily stimulated by VV-infected APC in vitro. Surprisingly, however, CD8+ T cells of mice infected with cowpox virus (CPV) or VV recognized APC infected with VV but not APC infected with CPV. Likewise, CD8+ T cells from vaccinated human subjects could not be activated by CPV-infected targets and CPV prevented the recognition of VV-infected APC upon coinfection. Because CD8+ T cells recognize viral peptides presented by MHC class I (MHC I), we examined surface expression, total levels, and intracellular maturation of MHC I in CPV- and VV-infected human and mouse cells. Although total levels of MHC I were unchanged, CPV reduced surface levels and inhibited the intracellular transport of MHC I early during infection. CPV did not prevent peptide loading of MHC I but completely inhibited MHC I exit from the endoplasmic reticulum. Because this inhibition was independent of viral replication, we conclude that an early gene product of CPV abrogates MHC I trafficking, thus rendering CPV-infected cells "invisible" to T cells. The absence of this immune evasion mechanism in VV likely limits virulence without compromising immunogenicity.
The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
1 This work was supported in part by National Institutes of Health Grants AI064843-01 (to K.F.), MO1RR00334 and AI063675 (to M.K.S.), and Oregon National Primate Research Center Grant RR00163 (to M.K.S. and K.F.).
2 Address correspondence and reprint requests to Dr. Mark Slifka and Dr. Klaus Früh, Oregon Health and Science University, Vaccine and Gene Therapy Institute, 505 Northwest 185th Avenue, Beaverton, OR 97006. E-mail addresses: Slifkam{at}ohsu.edu and fruehk{at}ohsu.edu
3 Abbreviations used in this paper: VAR, variola virus; Ara-C, cytosine arabinoside; BFA, brefeldin A; CPV, cowpox virus; EndoH, endoglycosidase H; ER, endoplasmic reticulum; ERAP, ER-associated protease; hpi, hours postinfection; HSPV, horsepox virus; ICCS, intracellular cytokine staining; MOI, multiplicity of infection; MPV, monkeypox virus; VV, vaccinia virus; MHC, MHC class I.
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