Inhibition of MHC class I-restricted antigen presentation by γ2-herpesviruses

Abstract

The ␥-herpesviruses, in contrast to the ␣-and ␤-herpesviruses, are not known to inhibit antigen presentation to CD8 ؉ cytotoxic T lymphocytes (CTLs) during lytic cycle replication. However, murine ␥-herpesvirus 68 causes a chronic lytic infection in CD4 ؉ T celldeficient mice despite the persistence of a substantial CTL response, suggesting that CTL evasion occurs. Here we show that, distinct from host protein synthesis shutoff, ␥-herpesvirus 68 down-regulates surface MHC class I expression on lytically infected fibroblasts and inhibits their recognition by antigen-specific CTLs. The viral K3 gene, encoding a zinc-finger-containing protein, dramatically reduced the half-life of nascent class I molecules and the level of surface MHC class I expression and was by itself sufficient to block antigen presentation. The homologous K3 and K5 genes of the related Kaposi's sarcoma-associated virus also inhibited antigen presentation and decreased cell surface expression of HLA class I antigens. Thus it appears that an immune evasion strategy shared by at least two ␥-herpesviruses allows continued lytic infection in the face of strong CTL immunity.

Glycoprotein L Disruption Reveals Two Functional Forms of the Murine Gammaherpesvirus 68 Glycoprotein H

“…MHV-68-infected cells were washed twice in phosphate-buffered saline (PBS), cultured for 30 min in cysteineand methionine-free medium with dialyzed fetal calf serum, and labeled for 6 h with 35 S-labeled cysteine-methionine (4). The cells were then cultured in normal medium for a further 18 h and virions recovered from supernatants by ultracentrifugation (20,000 ϫ g, 2 h).…”

“…Cells exposed to eGFP ϩ viruses were washed in PBS and analyzed directly for green channel fluorescence (35). For surface staining, cells were incubated (1 h, 4°C) with MHV-68 glycoprotein-specific MAbs followed by fluorescein isothiocyanate-conjugated rabbit anti-mouse IgG PAb (Dako Cytomation) or Alexa 633-conjugated or Alexa 488-conjugated goat anti-mouse PAb (Invitrogen).…”

The Dynamics of Murid Gammaherpesvirus 4 Within Wild, Sympatric Populations of Bank Voles and Wood Mice

“…In artificially infected laboratory mice, initial infection occurs in the lungs, followed by a spread to the spleen and the establishment of latent infections in B lymphocytes, lung epithelial cells, dendritic cells, and macrophages (Nash et al, 2001). The virus can also down-regulate major histocompatibility complex class I expression (Stevenson et al, 2000) and restrict inflammatory cell responses (Van Berkel et al, 2000;Stevenson and Efstathiou, 2005). Thus, infection may affect host immunocompetence, both by directly infecting cells related to immune system and influencing immune responses.…”

“…Typically, innate and adaptive immunity limit viral infection. However, approximately 10% of infected laboratory mice develop lymphoproliferative disease (Nash et al, 2001) and laboratory mice lacking some parts of the immune system can develop lymphomas (Tarakanova et al, 2005) and experience lethal infections (Ehtisham et al, 1993;Stevenson et al, 1999). Interestingly, there is some evidence that the pathogenesis of experimentally infected, laboratory-bred wood mice is different from lab mice (D. Hughes, pers.…”

Regulation of CD1d expression and function by a herpesvirus infection

“…[25][26][27]. Like other herpesvirus family members, it encodes proteins that block MHC class I expression on the cell surface (28)(29)(30)(31). These are known as modulator of immune recognition (MIR) proteins; MIR1 and MIR2 are expressed during lytic replication and are encoded by the open reading frames K3 and K5, respectively.…”