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Invited Speakers


Sunday, 7 April, 15:45-16:30

Tiziana Lazzarotto Keynote
Tiziana Lazzarotto
University of Bologna, Italy
Biography
Twenty Years of Study on the Pathogenesis and the Diagnosis of Congenital CMV Infection

Human cytomegalovirus (CMV) is the leading cause of congenital infections worldwide due to intrauterine infection, with a global incidence of 0.7% of live births. Furthermore, it is the most common nongenetic cause of childhood hearing loss in the post-rubella era and a significant cause of neurodevelopmental delay.

Understanding the pathogenesis of infection from the mother via the placenta to the neonate is crucial if we are to produce new interventions and provide supportive mechanisms to improve the outcome of congenitally infected children. In recent years, our understanding of the complex interaction between the placenta and CMV and how it relates to congenital infection has improved significantly. The observations show that CMV particularly infects amniotic membranes and impairs cytotrophoblast-induced lymphangiogenesis and vascular remodeling in the placenta and arrests the proper development of human trophoblast progenitor cells, thus interfering with the earliest stages in the growth of new villi. This results in increased hypoxia which ultimately contributes to restriction in fetal growth. Immunohistochemical and virological studies of placental tissues suggest that a severe placental infection is associated with diffuse villitis and necrosis, consistent with functional impairment and possible consequent hypoxic cerebral damage.

Although the diagnosis of congenital CMV infection is still complex, major goals have been achieved in recent years including: more reliable IgM tests for screening pregnant women whose pre-pregnancy serological status for CMV is unknown; tests to determine the avidity index of anti-CMV IgG, allowing the diagnosis of a primary CMV infection; innovative and reliable molecular tests to detect and quantify the CMV-DNA in maternal body fluids and in amniotic fluid.

We demonstrated that a fully standardized diagnostic algorithm lessens the anxiety felt by pregnant women largely due to concerns about mismanagement. Infact, a correct interpretation of serological and virological tests followed by appropriate counselling by an expert physician is an effective tool in reducing the number of unnecessary pregnancy terminations by over 70%.




Sunday, 7 April, 16:30-17:00

Kristen Spytek Kristen Spytek, President and CEO
National CMV Foundation
Biography

Sunday, 7 April, 16:30-17:00

Sara Doutre Sara Doutre, Director
National CMV Foundation
Biography

Monday, 8 April, 8:00-8:30

Marisa Mussi-Pinhata Keynote
Marisa Mussi-Pinhata
Ribeirão Preto Medical School, University of São Paulo, Brazil
Biography
Natural History of Congenital CMV Infection

An overview of the epidemiology of congenital CMV infection will be presented focusing on the known consequences of the infection in children born in a high CMV seroprevalence population.




Sunday, 8 April, 10:15-10:40

Soren Gantt Keynote
Soren Gantt
The University of British Columbia, Canada
Biography
Spots, Spit and Sawbucks: Operational and Cost-effectiveness Considerations of Newborn CMV Screening


Monday, 8 April, 13:20-13:45

Albert Park Keynote
Albert Park
University of Utah Health, United States
Biography
The Pathogenesis of CMV-Related Hearing Loss

Sensorineural hearing loss is the most common sequelae from congenital cytomegalovirus (cCMV) infection, and yet, its pathogenesis is incompletely understood. This presentation will summarize the work of others and of our lab to better understand the host immune response underlying CMV induced SNHL. Specific focus will be made on viral entry and targeted cells, the presence of outer hair cell loss despite a lack of direct infection, and the important role of excessive reactive oxygen species.




Monday, 8 April, 13:45-14:10

Eva Karltorp Keynote
Eva Karltorp
Karolinska Institutet, Sweden
Biography
Vestibular dysfunction due to congenital CMV Infection – More Common Than We Thought?

Is the full burden of disabilities due to congenital CMV (cCMV) infection yet known?

Even if the virus was observed already 1881 and isolated 1956, most children born with the infection today are still not diagnosed. Thus only the children with the most severe and obvious disabilities will be identified and not enough knowledge about the children with less severe infection will be retrieved.

Vestibular dysfunction caused by cCMV infection is not videly known and needs to be added to the previous list of known disabilities due to cCMV infection. Probably other symptoms and disabilities will be added in the near future.

This presentation will try to cover what we know about vestibular disorders among cCMV infected children so far. The first publication showing vestibular disability in children with cCMV infection was published 1983 (Pappas) and since then a few more have been written (Strauss -85, Huygen-96, Ahlfors -99, Zagolski -08, Inoue -13, Karltorp -14, Barnard -15 & Maes/De Kegel -17). Even so, the general knowledge about the vestibular disorders due to cCMV is sparse.

In 2014, a long term follow up of 26 severe hearing impaired children due to cCMV showed that the vast majority of the children also had vestibular dysfunction (Karltorp). The results of the children’s vestibular dysfunction in daily life will be described in this presentation and also the ways in which one can test vestibular function in infants and young children.

 




Monday, 8 April, 15:40-16:05

Min-Hua Luo Keynote
Min-Hua Luo
Wuhan Institute of Virology, CAS, China
Biography
Congenital CMV Infection: From Human Neural Progenitor Cell Model to Embryo Mouse Brain Model

Congenital human cytomegalovirus (HCMV) infection is the leading cause of fetal brain development disorders. Virus-susceptible cells are located in the subventricular zone where neural progenitor/stem cells (NPCs) is the major cell type. NPCs is fundamental for fetal brain development: (1) proliferation of NPCs controlling neural cell numbers; (2) differentiation of NPCs controlling the numbers and function of neural cells, including mature neurons and glia; (3) migration of differentiated neural cells controlling brain structure; and (4) synapse and network formation among mature neurons and glia controlling the structural and functional brain connectome. Thus, NPCs has been applied as a clinically associated model for investigation of the underlying mechanisms. Our work has shown HCMV affects proliferation of NPCs and perturbs neural cell fate, including premature differentiation of neural progenitor cells (NPCs); NPC marker molecules (SOX2, DCX) and Notch signal pathway (Notch1/Jag1, Hes1) are clearly regulated by HCMV infection, and HCMV-IE1 plays an important role in the regulation. There are limitations in NPCs cell model: hard to demonstrate the migration of neural cells, and formation of brain structure and function. Therefore embryonic mouse brain infection model was established, which demonstrating virus infection and disease progress. a congenitally infected mouse model to elucidate the mechanisms of cytomegalovirus infection and fetal brain development disorders, and (2) created bacterial artificial chromosomes (BACs), including HCMV-, MCMV-, HSV-1- and VZV-BAC to identify the viral factors involved in neuropathy and make the viral pathogenesis be visible




Tuesday, 9 April, 8:00-9:00

Domenico Tortorella Panel Presentation
Domenico Tortorella
Icahn School of Medicine at Mount Sinai, New York
Biography
Prevention


Tuesday, 9 April, 8:00-9:00

Don Diamond Panel Presentation
Don Diamond
City of Hope, United States
Biography
Prevention


Tuesday, 9 April, 8:00-9:00

Karen Fowler Panel Presentation
Karen Fowler
University of Alabama - Birmingham, United States
Biography
Prevention


Tuesday, 9 April, 8:00-9:00

Paul Griffiths Panel Presentation - Moderator
Paul Griffiths
University College London, United Kingdom
Biography
Moderator


Tuesday, 9 April, 8:00-9:00

Stanley Plotkin Panel Presentation
Stanley Plotkin
University of Pennsylvania, United States
Biography
Prevention


Tuesday, 9 April, 10:30-10:55

Mark Prichard Keynote
Mark Prichard
University of Alabama - Birmingham, United States
Biography
New Drugs for the Therapy and Prophylaxis of CMV Infections

The recent approval of letermovir marks a new era of therapy for human cytomegalovirus (HCMV) infections, particularly for the prevention of HCMV disease in hematopoietic stem cell transplant recipients. For almost 30 years ganciclovir has been the therapy of choice for these infections and by today’s standards this drug exhibits only modest antiviral activity that is often insufficient to completely suppress viral replication, and drives the selection of drug-resistant variants that continue to replicate and contribute to disease. While ganciclovir remains the therapy of choice, additional drugs that inhibit novel molecular targets, such as letermovir, will be required as highly effective combination therapies are developed not only for the treatment of immunocompromised hosts, but also for congenitally infected infants. Sustained efforts, largely in the biotech industry and academia, have identified additional highly active lead compounds that have progressed into clinical studies with varying levels of success and at least two have the potential to be approved in the near future. Some of the new drugs in the pipeline inhibit new molecular targets, remain effective against isolates that have developed resistance to existing therapies, and promise to augment existing therapeutic regimens. Existing drugs will also be discussed and some of the more promising candidates will be reviewed with an emphasis on those progressing through clinical studies. The in vitro and in vivo antiviral activity, spectrum of antiviral activity, and mechanism of action of new compounds will be reviewed to provide an update on potential new therapies for HCMV infections that have progressed significantly in recent years.




Tuesday, 9 April, 13:55-14:20

Camille Kotton Keynote
Camille Kotton
Harvard Medical School, United States
Biography
An Overview of CMV in the Immunocompromised Host:  Impact, Prevention, and Antiviral Treatments
CMV is one of the most significant pathogens for organ and bone marrow transplant patients, and can have a significant impact on morbidity and mortality. It can also affect other immunocompromised patients. With optimal prevention, using antiviral prophylaxis, monitoring, immunoglobulins, and possibly vaccines in the future, the risk of disease can be significantly mitigated. We are in an era of growing antiviral therapeutic options, useful for both prevention and treatment. Resistant/ refractory CMV infection now has multiple alternative therapies. This overview will detail state-of-the-art therapies and diagnostics in this vulnerable population.


Wednesday, 10 April, 8:00-8:25

Stipan Jonjic Keynote
Stipan Jonjic
University of Rijeka, Faculty of Medicine, Croatia
Biography
NK cells are major players in brain inflammation and pathology in congenital CMV infection

Strict species specificity of human CMV (HCMV) precludes studies of congenital HCMV infection in animals.  Since newborn mice are developmentally comparable to human fetus at the end of second trimester, infection of newborn mice with murine CMV (MCMV) is a well-established model of congenital CMV infection that has already contributed greatly to our understanding of pathogenesis and immunobiology of CMV infection in the brain. Previous studies have shown that inflammatory response in brain of MCMV infected newborn mice is associated with activation of resident microglia, which secrete proinflammatory mediators and attract  innate immune cells and T cells in sequential manner. However, the extent to which either viral infection or the immune response itself underlie the occurrence of developmental abnormalities, remains largely unknown. Recently, we have shown that brain-infiltrating NK cells act as major source of IFN-γ, which in turn drives the microglia activation and neurodevelopmental delays in infected newborn mice. In this talk I will present dynamics of NK cells in early inflammatory response in brain of MCMV infected newborn mice and their contribution to pathogenesis in developing brain.




Wednesday, 10 April, 8:25-8:50

Arnaud Marchant Keynote
Arnaud Marchant
Institute for Medical Immunology, Université libre de Bruxelles, Belgium
Biography
Adaptive immunity to CMV: revisiting the role of antibodies


Wednesday, 10 April, 10:05-10:30

Carolyn Coyne Keynote
Carolyn Coyne
University of Pittsburgh, United States
Biography
Antiviral signaling at the maternal-fetal interface


Wednesday, 10 April, 10:30-10:55

Dana Wolf Keynote
Dana Wolf
Hadassah University Hospital, Israel
Biography
Human Cytomegalovirus Transmission and Local Immunity at the Maternal-fetal Interface


Wednesday, 10 April, 13:00-13:25

Felicia Goodrum Keynote
Felicia Goodrum
University of Arizona, United States
Biography
Mechanisms of CMV latency and reactivation

Herpesviruses persist indefinitely in their host through complex and poorly defined interactions that mediate a life-long infection. The virus-host interactions important to latency of human cytomegalovirus (HCMV), as well as the very nature of the latent infection, is a centerpiece of our research. HCMV coordinates the expression of four viral genes from a genetic locus that plays an important role in dictating patterns of infection in cell types including CD34+ hematopoietic progenitor cells and endothelial cells. Two viral genes encoded within this locus, UL135 and UL138, have opposing roles in regulating viral replication. UL135 promotes reactivation from latency and virus replication in hematopoietic progenitor cells, in part, by overcoming replication-suppressive effects of UL138. UL135 and UL138 oppose one another by targeting the host factor, epidermal growth factor receptor (EGFR), but with opposite effects. pUL135 promotes the trafficking and turnover of EGFR from the cell surface, whereas pUL138 preserves surface expression of EGFR. UL135 mediates the turnover of EGFR through its interaction with host adapter proteins, Abi-1 and CIN85, known to regulate the turnover of EGFR through their interaction with the Cbl E3 ubiquitin ligase. In turn, EGFR signaling contributes to latency, in part by impacting gene expression from the UL133-UL138 locus to drive latency. In addition to these virus-host interactions mediating the switch between latent and replicative states, we have identified novel promoter elements in the major immediate early transcription unit that re-initiate HCMV gene expression for reactivation. These promoter elements are impacted by UL133-UL138 gene expression and shift long-held paradigms surrounding the de-repression of HCMV gene expression for reactivation. Defining the virus-host interactions and mechanisms regulating HCMV latency and reactivation is important to developing strategies to control HCMV disease.




Wednesday, 10 April, 13:25-13:40

Andrew Davison Keynote
Andrew Davison
University of Glasgow, United Kingdom
Biography
Natural HCMV Genomics

Understanding HCMV evolution, epidemiology and pathogenesis depends on being able to analyse the genomes of viral strains present in clinical material without first having to isolate and passage them in cell culture. There are several ways to do this, and the most productive so far has involved target enrichment by hybridisation to RNA bait libraries. In a collaborative study, we analysed 207 high-throughput sequencing datasets generated in this way directly from clinical samples, in the process determining the sequences of 91 HCMV strains. We focused on four important features of the HCMV genome, namely hypervariation, multiple-strain infection, recombination and natural mutation. Our main findings were that (i) it is vital to monitor the quality and characteristics of sequencing libraries in conducting investigations of HCMV diversity, particularly within an individual host, (ii) variation in single-strain infections is very much less than that in multiple-strain infections, (iii) recombination has figured large in HCMV evolution, but some strains have apparently been transmitted for thousands of years without recombining further, and (iv) HCMV mutants carrying non-functional genes (pseudogenes) have been circulating and recombining for long periods and can cause congenital infection and the resulting clinical sequelae. Target capture coupled with high-throughput sequencing thus offers a powerful means of studying natural HCMV genomics, as long as the data are scrutinised carefully and interpreted in the context of the characteristics of the virus.




Wednesday, 10 April, 15:10-15:35

Daniele Lilleri Keynote
Daniele Lilleri
Fondazione IRCCS Policlinico San Matteo, Italy
Biography
Maternal Immune Correlates of Protection from human Cytomegalovirus Transmission to the Fetus


Wednesday, 10 April, 16:20-16:45

Charles Cook Keynote
Charles Cook
BIDMC / Harvard Medical School, United States
Biography
CMV Reactivation in Immunocompetent Hosts
Cytomegalovirus is a known pathogen in immunosuppressed patients that has recently been recognized to reactivate in immune competent hosts during critical illness. The causes and consequences of such reactivation events will be discussed. In addition, the impact that previous CMV infection has on host responses to bacterial sepsis will also be reviewed.


Thursday, 11 April, 8:00-8:25

Andrew Yurochko Keynote
Andrew Yurochko
LSU Health Sciences Center Shreveport, United States
Biography
Infected Monocytes and their Role in Viral Dissemination and Persistence

HCMV-infected monocytes play key roles in hematogenous dissemination and life-long persistence of the virus in the human host. Our laboratory has shown that HCMV manipulates the biology of infected monocytes through a distinct and unique receptor-ligand engagement initiated during viral binding that then continues during the ensuing intracellular trafficking of the virion. Functionally, HCMV receptor-ligand engagement in monocytes promotes virion entry and nuclear translocation of the viral genome, and the changes needed for dissemination of infected monocytes to organ tissue. We have data that direct viral engagement of the epidermal growth factor receptor (EGFR) and beta1- and beta3-integrins through glycoprotein B (gB) and the pentameric gH/gL/UL128-131 complex, respectively, drives these important functional changes. More specifically, our work identifies that binding of viral glycoproteins to their cognate receptors creates a cell type specific signalsome that is responsible for the distinct phospho-proteomic and transcriptomic signatures seen in infected monocytes. Dissection of how EGFR and integrin engagement and intracellular signaling promotes infection has identified a delayed intracellular trafficking pattern in monocytes not seen in other infected cell types, and the biological changes needed for viral dissemination and persistence (i.e. pathogenic motility, enhanced survival and differentiation of monocytes into long-lived macrophages).  Together, we argue that viral receptor-ligand engagement is the molecular convergence point where the evolutionary important aspects of viral entry are linked to the biological triggers needed for dissemination and persistence and, ultimately, to HCMV-mediated acute and chronic diseases.




Thursday, 11 April, 8:25-8:50

Mark Wills Keynote
Mark Wills
University of Cambridge, United Kingdom
Biography
Immune modulation by HCMV latently infected cells; can these cells be targeted and cleared by the immune system?

HCMV is not cleared by the immune response following primary infection but persists for the life-time of the host, in part due to the establishment of latency in cells of the myeloid lineage, for example CD34+ progenitor cells and their CD14+ monocyte derivatives. During HCMV latency, the viral transcription programme is limited compared to lytic infection, however a number of well-established viral genes are expressed eg US28, UL138, UL111a, as well as viral microRNAs. In this talk I will discuss our recent work investigating HCMV driven modulation of the latent cell secretome and recognition of latently infected cells by both CD4+ and CD8+ T cells and NK cells.

We have shown that HCMV can manipulate the secretion of cellular proteins from latently infected CD34+ and CD14+ cells, producing TGFb and cIL-10 which have an immunosuppressive effect on T cell function. In addition, CXCL10 secretion by monocytes causes migration of activated CD4 and CD8+ T cells as well as NK cells. Interaction with the activated T cells leads to reactivation of HCMV whilst suppressing T cell effector function.

We have also investigated if T cells are generated against proteins expressed during latency.  The majority of individuals tested had T cells specific for at least one virus protein expressed during latency. However, unlike T cell responses to classical lytic HCMV proteins which are dominated by IFNg producing cells, these T cells often make IL-10 and TGFb and suppress anti-viral T cell responses. Neutralizing these cytokines enhances anti-viral effector functions.

Finally, I will discuss the treatment of latently infected cells with histone deacetylase inhibitors (HDACi), in order to induce lytic virus gene expression from latent genomes, but not full virus reactivation, thus making these cells targets for the immune system.




Thursday, 11 April, 11:15-12:00

Jay Nelson Keynote
Jay Nelson
Oregon Health & Science University, United States
Biography
Human Cytomegalovirus Regulation of Epidermal Growth Factor Receptor Signaling in Latency and Disease