Search

Conflicting hallmarks are attributed to cytomegalovirus (CMV) infections. CMVs are viewed as being master tacticians in "immune evasion" by subverting essentially all pathways of innate and adaptive immunity. On the other hand, CMV disease is undeniably restricted to the immunologically immature or immunocompromised host, whereas an intact immune system prevents virus spread, cytopathogenic tissue infection, and thus pathological organ manifestations. Therefore, the popular term "immune evasion" is apparently incongruous with the control of CMV infections in the immunocompetent human host as well as in experimental non-human primate and rodent models. Here, we review recent work from the mouse model that resolves this obvious discrepancy for the example of the virus-specific CD8 T-cell response. Immune evasion proteins encoded by murine CMV (mCMV) interfere with the cell surface trafficking of antigenic peptide-loaded MHC class-I (pMHC-I) complexes and thereby reduce their numbers available for interaction with T-cell receptors of CD8 T cells; but this inhibition is incomplete. As a consequence, while CD8 T cells with low interaction avidity fail to receive sufficient signaling for triggering their antiviral effector function in the presence of immune evasion proteins in infected cells, a few pMHC-I complexes that escape to the cell surface are sufficient for sensitizing high-avidity CD8 T cells. It is thus proposed that the function of immune evasion proteins is to raise the avidity threshold for activation, so that in the net result, only high-avidity cells can protect. An example showing that immune evasion proteins can make the difference between life and death is the lacking control of infection in a mouse model of MHC-I histoincompatible hematopoietic cell transplantation (allogeneic-HCT). In this model, only low-avidity CD8 T cells become reconstituted by HCT and almost all infected HCT recipients die of multiple-organ CMV disease when immune evasion proteins are expressed. In contrast, lowering the avidity threshold for antigen recognition by deletion of immune evasion proteins allowed control of infection and rescued from death., (© 2022. The Author(s).)

Prostate cancer is a heterogeneous disease with a need for new prognostic biomarkers. Human leukocyte antigen (HLA) genes are highly polymorphic genes central to antigen presentation to T-cells. Two alleles, HLA-A*02:01 and HLA-A*24:02, have been associated with prognosis in patients diagnosed with de novo metastatic prostate cancer. We leveraged the next-generation sequenced cohorts CPC-GENE and TCGA-PRAD to examine HLA alleles, antiviral T-cell receptors and prostate cancer disease recurrence after prostatectomy. Carrying HLA-A*02:01 (111/229; 48% of patients) was independently associated with disease recurrence in patients with low-intermediate risk prostate cancer. HLA-A*11 (carried by 42/441; 10% of patients) was independently associated with rapid disease recurrence in patients with high-risk prostate cancer. Moreover, HLA-A*02:01 carriers in which anti-cytomegalovirus T-cell receptors (CMV-TCR) were identified in tumors (13/144; 10% of all patients in the cohort) had a higher risk of disease recurrence than CMV-TCR-negative patients. These findings suggest that HLA-type and CMV immunity may be valuable biomarkers for prostate cancer progression., (© 2022 The Authors. Molecular Oncology published by John Wiley & Sons Ltd on behalf of Federation of European Biochemical Societies.)

Cytomegaloviruses (CMVs) are controlled by innate and adaptive immune responses in an immunocompetent host while causing multiple organ diseases in an immunocompromised host. A risk group of high clinical relevance comprises transiently immunocompromised recipients of hematopoietic cell transplantation (HCT) in the "window of risk" between eradicative therapy of hematopoietic malignancies and complete reconstitution of the immune system. Cellular immunotherapy by adoptive transfer of CMV-specific CD8 T cells is an option to prevent CMV disease by controlling a primary or reactivated infection. While experimental models have revealed a viral epitope-specific antiviral function of cognate CD8 T cells, the site at which control is exerted remained unidentified. The observation that remarkably few transferred cells protect all organs may indicate an early blockade of virus dissemination from a primary site of productive infection to various target organs. Alternatively, it could indicate clonal expansion of a few transferred CD8 T cells for preventing intra-tissue virus spread after successful initial organ colonization. Our data in the mouse model of murine CMV infection provide evidence in support of the second hypothesis. We show that transferred cells vigorously proliferate to prevent virus spread, and thus viral histopathology, by confining and eventually resolving tissue infection within nodular inflammatory foci.

Cytomegaloviruses (CMVs) belong to the β-subfamily of herpesviruses. Their host-to-host transmission involves the airways. As primary infection of an immunocompetent host causes only mild feverish symptoms, human CMV (hCMV) is usually not considered in routine differential diagnostics of common airway infections. Medical relevance results from unrestricted tissue infection in an immunocompromised host. One risk group of concern are patients who receive hematopoietic cell transplantation (HCT) for immune reconstitution following hematoablative therapy of hematopoietic malignancies. In HCT patients, interstitial pneumonia is a frequent cause of death from hCMV strains that have developed resistance against antiviral drugs. Prevention of CMV pneumonia requires efficient reconstitution of antiviral CD8 T cells that infiltrate lung tissue. A role for mast cells (MC) in the immune control of lung infection by a CMV was discovered only recently in a mouse model. MC were shown to be susceptible for productive infection and to secrete the chemokine CCL-5, which recruits antiviral CD8 T cells to the lungs and thereby improves the immune control of pulmonary infection. Here, we review recent data on the mechanism of MC-CMV interaction, a field of science that is new for CMV virologists as well as for immunologists who have specialized in MC.

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.

Reactivation of latent cytomegalovirus (CMV) endangers the therapeutic success of hematopoietic cell transplantation (HCT) in tumor patients due to cytopathogenic virus spread that leads to organ manifestations of CMV disease, to interstitial pneumonia in particular. In cases of virus variants that are refractory to standard antiviral pharmacotherapy, immunotherapy by adoptive cell transfer (ACT) of virus-specific CD8 + T cells is the last resort to bridge the "protection gap" between hematoablative conditioning for HCT and endogenous reconstitution of antiviral immunity. We have used the well-established mouse model of CD8 + T-cell immunotherapy by ACT in a setting of experimental HCT and murine CMV (mCMV) infection to pursue the concept of improving the efficacy of ACT by therapeutic vaccination (TherVac) post-HCT. TherVac aims at restimulation and expansion of limited numbers of transferred antiviral CD8 + T cells within the recipient. Syngeneic HCT was performed with C57BL/6 mice as donors and recipients. Recipients were infected with recombinant mCMV (mCMV-SIINFEKL) that expresses antigenic peptide SIINFEKL presented to CD8 + T cells by the MHC class-I molecule K b . ACT was performed with transgenic OT-I CD8 + T cells expressing a T-cell receptor specific for SIINFEKL-K b . Recombinant human CMV dense bodies (DB-SIINFEKL), engineered to contain SIINFEKL within tegument protein pUL83/pp65, served for vaccination. DBs were chosen as they represent non-infectious, enveloped, and thus fusion-competent subviral particles capable of activating dendritic cells and delivering antigens directly into the cytosol for processing and presentation in the MHC class-I pathway. One set of our experiments documents the power of vaccination with DBs in protecting the immunocompetent host against a challenge infection. A further set of experiments revealed a significant improvement of antiviral control in HCT recipients by combining ACT with TherVac. In both settings, the benefit from vaccination with DBs proved to be strictly epitope-specific. The capacity to protect was lost when DBs included the peptide sequence SIINFEKA lacking immunogenicity and antigenicity due to C-terminal residue point mutation L8A, which prevents efficient proteasomal peptide processing and binding to K b . Our preclinical research data thus provide an argument for using pre-emptive TherVac to enhance antiviral protection by ACT in HCT recipients with diagnosed CMV reactivation., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Gergely, Podlech, Becker, Freitag, Krauter, Büscher, Holtappels, Plachter, Reddehase and Lemmermann.)