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A mouse cytomegalovirus (MCMV) gene conferring interferon (IFN) resistance was identified. This gene, M27, encodes a 79-kD protein that selectively binds and down-regulates for signal transducer and activator of transcription (STAT)-2, but it has no effect on STAT1 activation and signaling. The absence of pM27 conferred MCMV susceptibility to type I IFNs (α/β), but it had a much more dramatic effect on type II IFNs (γ) in vitro and in vivo. A comparative analysis of M27+ and M27 − MCMV revealed that the antiviral efficiency of IFN-γ was partially dependent on the synergistic action of type I IFNs that required STAT2. Moreover, STAT2 was directly activated by IFN-γ. This effect required IFN receptor expression and was independent of type I IFNs. IFN-γ induced increasing levels of tyrosine-phosphorylated STAT2 in M27− MCMV-infected cells that were essential for the antiviral potency of IFN-γ. pM27 represents a new strategy for simultaneous evasions from types I and II IFNs, and it documents an unknown biological significance for STAT2 in antiviral IFN-γ responses.

Mouse strains are either resistant or susceptible to murine cytomegalovirus (MCMV

The susceptibility of certain inbred mouse strains to murine cytomegalovirus (MCMV) is related to their inability to generate a strong natural killer (NK) cell response. We addressed here whether the MCMV susceptibility of the BALB/c strain is due to viral functions that control NK cell activation in a strain-specific manner. MCMV expresses two proteins, gp48 and gp40, that are encoded by the genes m06 and m152, respectively; they down-regulate major histocompatibility complex (MHC) class I expression at the plasma membrane. Using MCMV deletion mutants and revertants, we found that gp40 but not gp48 controls NK cell activation. Absence of gp40 improved antiviral NK cell control in BALB/c, but not C57BL/6, mice. Down-regulation of H-60, the high-affinity ligand for the NKG2D receptor, was the mechanism by which gp40 modulates NK cell activation. Thus, a single herpesvirus protein has a dual function in inhibiting both the adaptive as well as the innate immune response.

The NK cell–activating receptor NKG2D interacts with three different cellular ligands, all of which are regulated by mouse cytomegalovirus (MCMV). We set out to define the viral gene product regulating murine UL16-binding protein-like transcript (MULT)-1, a newly described NKG2D ligand. We show that MCMV infection strongly induces MULT-1 gene expression, but surface expression of this glycoprotein is nevertheless completely abolished by the virus. Screening a panel of MCMV deletion mutants defined the gene m145 as the viral regulator of MULT-1. The MCMV m145-encoded glycoprotein turned out to be necessary and sufficient to regulate MULT-1 by preventing plasma membrane residence of MULT-1. The importance of MULT-1 in NK cell regulation in vivo was confirmed by the attenuating effect of the m145 deletion that was lifted after NK cell depletion. Our findings underline the significance of escaping MULT-1/NKG2D signaling for viral survival and maintenance.

Genes that inhibit apoptosis have been described for many DNA viruses. Herpesviruses often contain even more than one gene to control cell death. Apoptosis inhibition by viral genes is postulated to contribute to viral fitness, although a formal proof is pending. To address this question, we studied the mouse cytomegalovirus

As innate immune system components, natural killer (NK) cells respond rapidly to infections and effectively control replication of pathogens, including murine cytomegalovirus (MCMV), a double-stranded DNA beta-herpesvirus. In the absence of NK cell control, MCMV infection results in early mortality due to uncontrolled viral replication. However, here we show that even in the face of initial NK cell control, there is late recrudescence of disease and mortality in immunodeficient mice due to the outgrowth of MCMV mutants that escape recognition by innate NK cells. These data suggest that viral infections in certain clinical settings also may be due to viral escape from innate immunity.

Natural killer (NK) cells are an important defense mechanism against pathogens, particularly against viruses belonging to the herpesvirus family (45, 48). NK cell receptor genes do not undergo somatic recombination and clonal specification (38), and their activation is tightly regulated by a balance of signaling through inhibitory receptors specific for major histocompatibility complex (MHC) class I proteins and activating NK cell receptors with diverse specificities (28). Some activating NK receptors are specific for viral proteins, such as the m157 protein of murine cytomegalovirus (MCMV) and the hemagglutinins of Sendai virus and influenza virus, which are recognized by Ly49H, NKp44, and NKp46, respectively (4,5,31,46). NKG2D is a type II C-lectin-like activating NK cell receptor that was first identified as a member of the NKG2 family (21) and is expressed on all NK cells, as well as on CD8ϩ T cells, ␥␦ T cells, and macrophages (6,15,17,22). NKG2D is a promiscuous receptor that can recognize a broad spectrum of cell surface ligands that are distantly related to MHC class I molecules and are up-regulated on stressed, infected, or transformed cells (11). The known NKG2D ligands on human cells are the MHC class I chain-related molecules (MICA and MICB) (6, 47) and the UL-16 binding proteins (ULBP-1, ULBP-2, and ULBP-3) (12), whereas the mouse NKG2D ligands are H60 (15, 30), retinoic acid early inducible gene 1 (RAE-1␣, -␤, -␥, -␦, and -ε isoforms) (10), and the recently identified murine UL-16 binding protein-like transcript 1 (MULT-1) (9). H60 was originally described as a minor histocompatibility antigen recognized by T cells from C57BL/6 mice in response to BALB.B splenocytes (30), and RAE-1 has been shown to play a role during embryonic development (57).Cytomegaloviruses (CMVs) possess a remarkable range of mechanisms to escape or subvert the immune response (2). Both human CMV (HCMV) and MCMV have developed mechanisms for evading the control of NK cells by interfering with the expression of NKG2D ligands (36). The HCMV protein encoded by the UL16 gene binds ULBP-1, ULBP-2, and MICB (12), preventing these ligands from being expressed on the surfaces of HCMV-infected cells (16,55). Based on their early susceptibility to MCMV infection, mouse strains can be either resistant or sensitive to this virus (18,43). In resistant mouse strains, NK cells become activated via an interaction of Ly49H, an activating NK cell receptor, with the MCMV-encoded m157 protein (3,46). In contrast, Ly49H-negative mouse strains, including most wild mice, show very low NK activities against MCMV, rendering them susceptible to this virus (42). The puzzling fact that Ly49H-negative mice, although being capable of mounting an effective NK cell response against other pathogens (54), are unable to create effective NK cell control of MCMV, has recently been explained by the MCMV-driven down-regulation of cellular ligands for the NKG2D receptor (27). MCMV gp40, a viral glycoprotein encoded by the m152 gene, apart from down-regulating MHC c...