Abstract
Cytomegaloviruses (CMVs) are host species-specific and have adapted to their respective mammalian hosts during co-evolution. Host-adaptation is reflected by “private genes” that have specialized in mediating virus-host interplay and have no sequence homologs in other CMV species, although biological convergence has led to analogous protein functions. They are mostly organized in gene families evolved by gene duplications and subsequent mutations. The host immune response to infection, both the innate and the adaptive immune response, is a driver of viral evolution, resulting in the acquisition of viral immune evasion proteins encoded by private gene families. As the analysis of the medically relevant human cytomegalovirus by clinical investigation in the infected human host cannot make use of designed virus and host mutagenesis, the mouse model based on murine cytomegalovirus (mCMV) has become a versatile animal model to study basic principles of in vivo virus-host interplay. Focusing on the immune evasion of the adaptive immune response by CD8+ T cells, we review here what is known about proteins of two private gene families of mCMV, the m02 and the m145 families, specifically the role of m04, m06, and m152 in viral antigen presentation during acute and latent infection.
Highlights
Human cytomegalovirus, the prototype member of the β-subfamily of the herpes virus family [1], is of medical relevance as it can cause lethal disease resulting from cytopathogenic organ infection in an immunologically immature or immunocompromised human host
In transplantation centers worldwide, primary or reactivated Human cytomegalovirus (hCMV) is a feared complication in transplantation patients. These include recipients of solid organ transplantation (SOT) who receive immunosuppressive prophylaxis to prevent allograft rejection as well as recipients of hematopoietic cell transplantation (HCT) who are immunocompromised by hematoablative therapy of an aggressive hematopoietic malignancy prior to HCT and, in particular in the case of unrelated or family donors, by immunosuppressive prophylaxis or therapy of graft-versus-host disease (GvHD) after HCT [8,9,10]
As we have reviewed previously, results from the mouse model of infection with murine CMV have revealed basic principles of CMV pathogenesis, immune control, and immune evasion that apply to human infection, not in molecular details but by convergence in many aspects of virus-host interaction [17]
Summary
Human cytomegalovirus (hCMV), the prototype member of the β-subfamily of the herpes virus family [1], is of medical relevance as it can cause lethal disease resulting from cytopathogenic organ infection in an immunologically immature or immunocompromised human host (for a synopsis of hCMV disease manifestations, see [2,3]). These are defined by the absence of sequence homologs in phylogenetically distant CMV species, except for some overlap between hCMV and the phylogenetically less distant non-human primate CMVs [1] It appears that duplications and mutations starting from an ancestor gene, supposedly captured from the host early in co-evolution, were the viral evolutionary response to the development of polymorphism of cellular genes involved in host immunity, such as genes encoding antigen-presenting HLA/MHC molecules. For the remaining family members (m02, m05, m07–m10, and m16) that carry YXXΦ sorting motifs, the cargos have not yet been defined It could be cargos not involved in innate or adaptive immune responses, though MHC-I molecules of H-2 haplotypes other than those binding to m04 remain candidates. This finding prompted us to suggest the acronym vRAP (viral regulator of antigen presentation) to account for both negative and positive roles of viral proteins in pMHC-I cell surface trafficking and presentation to CD8+ T cells
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