Abstract
Cytomegaloviruses (CMVs) persistently and systemically infect the myeloid cells of immunocompetent hosts. Persistence implies immune evasion, and CMVs evade CD8+ T cells by inhibiting MHC class I-restricted antigen presentation. Myeloid cells can also interact with CD4+ T cells via MHC class II (MHC II). Human CMV (HCMV) attacks the MHC II presentation pathway in vitro, but what role this evasion might play in host colonization is unknown. We show that Murine CMV (MCMV) down-regulates MHC II via M78, a multi-membrane spanning viral protein that captured MHC II from the cell surface and was necessary although not sufficient for its degradation in low pH endosomes. M78-deficient MCMV down-regulated MHC I but not MHC II. After intranasal inoculation, it showed a severe defect in salivary gland colonization that was associated with increased MHC II expression on infected cells, and was significantly rescued by CD4+ T cell loss. Therefore MCMV requires CD4+ T cell evasion by M78 to colonize the salivary glands, its main site of long-term shedding.
Highlights
Herpesviruses establish persistent, productive infections, with high prevalence in most populations and significant disease burdens
We show that Murine CMV (MCMV) evades CD4+ T cells via its M78 protein, and that this helps infection to spread despite the immune response
We show that MCMV, like Human cytomegalovirus (HCMV), degrades MHC class II (MHC II)
Summary
Human cytomegalovirus is the commonest infectious cause of harm to unborn children. Vaccines have not stopped it establishing chronic, systemic infections. Murine cytomegalovirus (MCMV) provides an accessible model to understand why. We show that MCMV evades CD4+ T cells via its M78 protein, and that this helps infection to spread despite the immune response. While CD4+ T cells are important for host defence, viral evasion limits their capacity to act alone in controlling infection
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