Latent CMV infection of Lymphatic endothelial cells is sufficient to drive CD8 T cell memory inflation.

CMV, a ubiquitous herpesvirus, elicits an extraordinarily large T cell response that is sustained or increases over time, a phenomenon termed 'memory inflation.' Remarkably, even latent, non-productive infection can drive memory inflation. Despite intense research on this phenomenon, the infected cell type(s) involved are unknown.

Walking on snow-covered Arctic sea ice to infer ice thickness.

The ice-covered Arctic Ocean constitutes a unique underwater acoustic waveguide; it is a half-channel, upward refracting environment possessing a rough upper boundary consisting of sea ice of varying thickness. The sea ice itself is an acoustic waveguide, capable of supporting the propagation of compressional and shear waves. In particular, the ice supports compressional wave resonances created by impulsive forces on the upper surface of the ice.

PD-1-specific "Blocking" antibodies that deplete PD-1 T cells present an inconvenient variable in preclinical immunotherapy experiments.

Therapeutic antibodies blocking PD-1-/PD-L1 interaction have achieved remarkable clinical success in cancer. In addition to blocking a target molecule, some isotypes of antibodies can activate complement, NK cells or phagocytes, resulting in death of the cell expressing the antibody's target. Human anti-PD-1 therapeutics use antibody isotypes designed to minimize such antibody-dependent lysis.

Vaccine-induced CD8 T cells are redirected with peptide-MHC class I-IgG antibody fusion proteins to eliminate tumor cells in vivo.

Simulating a viral infection in tumor cells is an attractive concept to eliminate tumor cells. We previously reported the molecular design and the in vitro potency of recombinant monoclonal antibodies fused to a virus-derived peptide MHC class I complex that bypass the peptide processing and MHC loading pathway and directly displays a viral peptide in an MHC class I complex on the tumor cell surface. Here, we show that a vaccination-induced single peptide-specific CD8 T cell response was sufficient to eliminate B16 melanoma tumor cells in vivo in a fully immunocompetent, syngeneic mouse tumor model when mice were treated with mouse pMHCI-IgGs fusion proteins targeting the mouse fibroblast activation protein.

Correction: Cross-presentation of a spread-defective MCMV is sufficient to prime the majority of virus-specific CD8+ T cells.

[This corrects the article DOI: 10.1371/journal.pone.

Stochastic Expansions Maintain the Clonal Stability of CD8 T Cell Populations Undergoing Memory Inflation Driven by Murine Cytomegalovirus.

CMV is an obligate and persistent intracellular pathogen that continually drives the production of highly differentiated virus-specific CD8 T cells in an Ag-dependent manner, a phenomenon known as memory inflation. Extensive proliferation is required to generate and maintain inflationary CD8 T cell populations, which are counterintuitively short-lived and typically exposed to limited amounts of Ag during the chronic phase of infection. An apparent discrepancy therefore exists between the magnitude of expansion and the requirement for ongoing immunogenic stimulation.

The impact of status and social context on health service co-design: an example from a collaborative improvement initiative in UK primary care.

Background: Increasingly, collaborative participatory methods requiring open and honest interaction between a range of stakeholders are being used to improve health service delivery. To be successful these methodologies must incorporate perspectives from a range of patients and staff. Yet, if unaccounted for, the complex relationships amongst staff groups and between patients and providers can affect the veracity and applicability of co-designed solutions.

The immune response to CMV infection and vaccination in mice, monkeys and humans: recent developments.

The immune response to CMV is characterized by extremely large T cell and antibody responses that persist for a lifetime, but do not prevent superinfection with other CMV strains. This makes generation of a vaccine against CMV very difficult, but has facilitated development of CMV-vectored vaccines, which have shown promise in mouse tumor models and in monkey models of infectious disease. The serendipitous use of a mutant rhesus CMV vector for the SIV vaccine elicited extraordinary, CD8 T cell responses restricted by MHCII and non-classical MHCI molecules which apparently provide protection against SIV.

Enzymatic synthesis of core 2 O-glycans governs the tissue-trafficking potential of memory CD8 T cells.

Trafficking of memory CD8 T cells out of the circulation is essential to provide protective immunity against intracellular pathogens in nonlymphoid tissues. However, the molecular mechanisms that dictate the trafficking potential of diverse memory CD8 T cell populations are not completely defined. We show that after infection or inflammatory challenge, central memory (T) CD8 T cells rapidly traffic into nonlymphoid tissues, whereas most effector memory cells remain in the circulation.

Adaption, implementation and evaluation of collaborative service improvements in the testing and result communication process in primary care from patient and staff perspectives: a qualitative study.

Background: Increasing numbers of blood tests are being ordered in primary care settings and the swift and accurate communication of test results is central to providing high quality care. The process of testing and result communication is complex and reliant on the coordinated actions of care providers, external groups in laboratory and hospital settings, and patients. This fragmentation leaves it vulnerable to error and the need to improve an apparently fallible system is apparent.

CMV immune evasion and manipulation of the immune system with aging.

Human cytomegalovirus (HCMV) encodes numerous proteins and microRNAs that function to evade the immune response and allow the virus to replicate and disseminate in the face of a competent innate and acquired immune system. The establishment of a latent infection by CMV, which if completely quiescent at the level of viral gene expression would represent an ultimate in immune evasion strategies, is not sufficient for lifelong persistence and dissemination of the virus. CMV needs to reactivate and replicate in a lytic cycle of infection in order to disseminate further, which occurs in the face of a fully primed secondary immune response.

Fibroblast-adapted human CMV vaccines elicit predominantly conventional CD8 T cell responses in humans.

Cytomegalovirus (CMV)-based vaccines have shown remarkable efficacy in the rhesus macaque model of acquired immune deficiency syndrome, enabling 50% of vaccinated monkeys to clear a subsequent virulent simian immunodeficiency virus challenge. The protective vaccine elicited unconventional CD8 T cell responses that were entirely restricted by MHC II or the nonclassical MHC I molecule, MHC-E. These unconventional responses were only elicited by a fibroblast-adapted rhesus CMV vector with limited tissue tropism; a repaired vector with normal tropism elicited conventional responses.

Blocking Virus Replication during Acute Murine Cytomegalovirus Infection Paradoxically Prolongs Antigen Presentation and Increases the CD8+ T Cell Response by Preventing Type I IFN-Dependent Depletion of Dendritic Cells.

Increasing amounts of pathogen replication usually lead to a proportionate increase in size and effector differentiation of the CD8 T cell response, which is attributed to increased Ag and inflammation. Using a murine CMV that is highly sensitive to the antiviral drug famciclovir to modulate virus replication, we found that increased virus replication drove increased effector CD8 T cell differentiation, as expected. Paradoxically, however, increased virus replication dramatically decreased the size of the CD8 T cell response to two immunodominant epitopes.

A Phase 1 Study of 4 Live, Recombinant Human Cytomegalovirus Towne/Toledo Chimera Vaccines in Cytomegalovirus-Seronegative Men.

Background:  Human cytomegalovirus (HCMV) infection causes disease in newborns and transplant recipients. A HCMV vaccine (Towne) protects transplant recipients.

Methods:  The genomes of Towne and the nonattenuated Toledo strain were recombined, yielding 4 Towne/Toledo chimera vaccines.

Intratumoral Infection with Murine Cytomegalovirus Synergizes with PD-L1 Blockade to Clear Melanoma Lesions and Induce Long-term Immunity.

Cytomegalovirus is an attractive cancer vaccine platform because it induces strong, functional CD8(+) T-cell responses that accumulate over time and migrate into most tissues. To explore this, we used murine cytomegalovirus expressing a modified gp100 melanoma antigen. Therapeutic vaccination by the intraperitoneal and intradermal routes induced tumor infiltrating gp100-specific CD8(+) T-cells, but provided minimal benefit for subcutaneous lesions.

Strength in Numbers: Visualizing CTL-Mediated Killing In Vivo.

Cytotoxic CD8+ T lymphocytes (CTLs) have long been believed to be extremely efficient killers. Forster and colleagues (Halle et al., 2016) used in vivo imaging to tell a different story, in which each CTL killed only 2-16 targets a day, and several CTLs per target were needed to get the job done.

Routine failures in the process for blood testing and the communication of results to patients in primary care in the UK: a qualitative exploration of patient and provider perspectives.

Background: The testing and result communication process in primary care is complex. Its successful completion relies on the coordinated efforts of a range of staff in primary care and external settings working together with patients. Despite the importance of diagnostic testing in provision of care, this complexity renders the process vulnerable in the face of increasing demand, stretched resources and a lack of supporting guidance.

Test result communication in primary care: a survey of current practice.

Background: The number of blood tests ordered in primary care continues to increase and the timely and appropriate communication of results remains essential. However, the testing and result communication process includes a number of participants in a variety of settings and is both complicated to manage and vulnerable to human error. In the UK, guidelines for the process are absent and research in this area is surprisingly scarce; so before we can begin to address potential areas of weakness there is a need to more precisely understand the strengths and weaknesses of current systems used by general practices and testing facilities.

Cytokine-Mediated Activation of NK Cells during Viral Infection.

Unlabelled: Natural killer (NK) cells provide a first line of defense against infection via the production of antiviral cytokines and direct lysis of target cells. Cytokines such as interleukin 12 (IL-12) and IL-18 are critical regulators of NK cell activation, but much remains to be learned about how cytokines interact to regulate NK cell function. Here, we have examined cytokine-mediated activation of NK cells during infection with two natural mouse pathogens, lymphocytic choriomeningitis virus (LCMV) and murine cytomegalovirus (MCMV).

Prescription coverage in indigent patients affects the use of long-acting opioids in the management of cancer pain.

Purpose: We tested the hypothesis that prescription coverage affects the prescribing of long-acting opiates to indigent inner city minority patients with cancer pain.

Materials And Methods: We conducted a chart review of 360 patients treated in the Oncology Practice at University of Medicine and Dentistry of New Jersey University Hospital, who were prescribed opiate pain medications. Half the patients were charity care or self-pay (CC/SP), without the benefit of prescription coverage, and half had Medicaid, with unlimited prescription coverage.

Cytomegalovirus-based cancer vaccines expressing TRP2 induce rejection of melanoma in mice.

Cytomegalovirus (CMV) induces strong and long-lasting immune responses, which make it an attractive candidate for a cancer vaccine vector. In this study, we tested whether a tumor antigen expressed in CMV can induce a strong anti-tumor effect. We expressed an unmodified melanoma antigen, mouse tyrosinase-related protein 2 (TRP2), in mouse cytomegalovirus (MCMV).

Competition for antigen at the level of the APC is a major determinant of immunodominance during memory inflation in murine cytomegalovirus infection.

The unique ability of CMV to drive the expansion of virus-specific T cell populations during the course of a lifelong, persistent infection has generated interest in the virus as a potential vaccine strategy. When designing CMV-based vaccine vectors to direct immune responses against HIV or tumor Ags, it becomes important to understand how and why certain CMV-specific populations are chosen to inflate over time. To investigate this, we designed recombinant murine CMVs (MCMVs) encoding a SIINFEKL-enhanced GFP fusion protein under the control of endogenous immediate early promoters.

Uncovering phantom shocks in cardiac patients with an implantable cardioverter defibrillator.

Background: Implantable cardioverter defibrillator recipients sometimes report "phantom shocks" (PSs), defined as a reported shock lacking objective evidence. The aim of this study was to describe the subjective experience of PSs and their psychosocial correlates using a mixed methods approach.

Methods: PS participants were matched on sex and age with individuals who received objective shocks only (OSO).