K3-mediated evasion of CD8+ T cells aids amplification of a latent γ-herpesvirus

Abstract

The murine gamma-herpesvirus-68 (MHV-68) K3 protein, like that of the Kaposi's sarcoma associated herpesvirus, down-regulates major histocompatibility complex (MHC) class I expression. However, how this contributes to viral replication in vivo is unclear. After intranasal MHV-68 infection, K3 was transcribed both during acute lytic infection in the lung and during latency establishment in lymphoid tissue. K3-deficient viruses were not cleared more rapidly from the lung, but the number of latently infected spleen cells was reduced and the frequency of virus-specific CD8(+) cytotoxic T lymphocytes (CTLs) was increased. CTL depletion reversed the viral latency deficit. Thus, a major function of K3 appears to be CTL evasion during viral latency expansion.

Inhibition of MHC Class II Expression and Immune Responses by c-MIR

“…This idea emerged from an experiment, which was performed using genetically modified murine ␥-herpesvirus 68 (13). First, an mK3-deficient virus, which is not able to down-regulate MHC I expression efficiently, was generated.…”

Toll-like Receptors, Notch Ligands, and Cytokines Drive the Chronicity of Lung Inflammation

“…In the C57BL/6 background, IFN-g receptor 2/2 mice challenged with MuHV-68 maintained a progressive interstitial fibrosis that did not resolve, which could be the result of reactivation of latent virus causing renewed infection and a continuation of the chronicity of the fibrotic response (26). (27); M11, a Bcl-2 homolog (28); ORF4, a complement-regulatory protein (29); M3, a highly secreted chemokine-binding protein (30,31); and ORF74, a G protein-coupled receptor (vGPCR) with sequence homology to chemokine receptor CXCR2 (32). Previous studies have shown that both the chemokine-binding protein and vGPCR play a prominent role in the chronic aspect of the infectious process (30)(31)(32).…”

CD4+ T cells specific for a model latency‐associated antigen fail to control a gammaherpesvirus in vivo

“…The MHV-68 K3 protein catalyzes the destruction of MHC class I heavy chains [27,28] and TAP [29], and is expressed in latently infected germinal center B cells [30], probably as part of a viral growth program. It reduces by approximately 90% the effectiveness of antiviral CD8 + T cells [31]. MHV-68 also evades CD8 + T cells during episome maintenance.…”