7:00-17:30
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Registration and Information Desk
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7:30-11:30
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Speaker Check-In
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8:00-8:30
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Welcome and Opening Remarks
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8:30-9:10
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Keynote 1
Presenter:
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Keynote
Ileana Cristea Princeton University, United States
Biography
Ileana Cristea is a Professor in the Department of Molecular Biology at Princeton University. Her laboratory focuses on characterizing mechanisms of cellular defense against viruses, as well as mechanisms used by viruses to manipulate these critical cellular processes. Towards these goals, she has promoted the integration of virology with proteomics and bioinformatics. She has developed methods for studying virus-host protein interactions in space and time during the progression of an infection, which have allowed her group to bridge developments in mass spectrometry to important findings in virology. For example, her laboratory has contributed to the emergence of the research field of nuclear DNA sensing in immune response, and has discovered sirtuins as broad-spectrum antiviral factors. Dr. Cristea is the President of US HUPO and chairs the Infectious Disease initiative of the Human Proteome World Organization. She has taught the summer Proteomics Course at Cold Spring Harbor Laboratory for over ten years, and is Senior Editor for mSystems, Associate Editor for Journal of Proteome Research, and on the Editorial Boards of Molecular Systems Biology and Molecular Cellular Proteomics. She was recognized with the Bordoli Prize from the British Mass Spectrometry Society (2001), NIDA Avant-Garde Director Pioneer Award for HIV/AIDS Research (2008), Human Frontiers Science Program Young Investigator Award (2009), Early Career Award in Mass Spectrometry from the American Chemical Society (2011), the American Society for Mass Spectrometry Research Award (2012), the Molecular Cellular Proteomics Lectureship (2013), the Mallinckrodt Scholar Award (2015), and the Discovery Award in Proteomic Sciences at HUPO (2017).
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Dynamic Organelle Shape and Function during Infection with Herpesviruses
Changes in cellular composition and organization are a core component of infections with herpesviruses. The tight link between the shape of a cellular organelle and its function is exploited by viruses during infections as mechanisms acquired to either support virus replication or inhibit host defense responses. Here, we investigate dynamic organelle alterations by integrating microscopy structural analysis, quantitative proteomics and lipidomics, and the development of mathematical modeling and computational platforms for data analysis. These hybrid approaches allowed us to uncover finely-tuned temporal alterations in organelle shape that are used to either activate or inhibit specific organelle functions at different stages of infection. One example is our finding that human cytomegalovirus (HCMV) and herpes simplex virus (HSV-1) induce peroxisome biogenesis and unique morphological changes to support viral replication. Infection triggers peroxisome growth and fission, leading to increased peroxisome numbers and irregular disc-like structures. This change in peroxisome shape leads to increased plasmalogen production, supporting secondary envelopment during virus assembly. Another example is our discovery of a lamin acetylation event that helps to maintain the integrity of the nuclear periphery, thereby inhibiting the formation of virus-induced lamin infoldings and virus capsid egress. Our studies also point to alterations in organelle shape that are connected to changes in protein interactions and protein movements between organelles. We present our efforts to globally characterize the formation and dissociation of protein interactions during the progression of HCMV infection. Finally, we report the development of a computational platform that allows the users to visualize protein interactions that are dynamic in space and time, and to integrate information of subcellular localization, functional annotations, and protein abundances.
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9:10-9:35
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Symposium 1A: Bernard Roizman Lecture
Presenter:
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Symposium
Richard Longnecker Northwestern University, United States
Biography
Dr. Longnecker is the Dan and Bertha Spear Research Professor in the Department of Microbiology-Immunology at the Northwestern Feinberg School of Medicine (FSM) where he studies the pathobiology of the human herpesviruses herpes simplex virus (HSV) and Epstein-Barr virus (EBV). He received his PhD in Virology at the University of Chicago where he began his studies on herpes simplex virus (HSV). Following postdoctoral training at Harvard Medical School studying Epstein-Barr virus (EBV), he joined the faculty at Northwestern Feinberg School of Medicine where he continues to study HSV and EBV. His laboratory focuses on the host-pathogen relationship of Epstein-Barr virus (EBV) and herpes simplex virus (HSV) as well as the fundamental processes these viruses use to infect target tissues in humans.
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Age-Dependent Differences in the Innate Interferon Response Contribute to Mortality in Newborn HSV Encephalitis
Newborn herpes simplex virus (HSV) is life-threatening infection in 1 in 3,200 births in the U.S. Unlike adult infections, which are typically asymptomatic, over 50% of neonatal HSV infections result in disseminated disease and encephalitis. This difference may be due to age-dependent differences in the host immune response. Studies in humans and mice show a critical role for IFN signaling in controlling HSV infection. To investigate if age-dependent differences in IFN signaling contributes to increased mortality in newborn disease, wild-type (WT) and IFN α/β receptor knock-out (IFNARKO) 7-day-old (P7) and adult mice were intracranially infected with HSV-1. While WT adult mice were highly resistant to infection in an IFNAR-dependent manner, the type I IFN response prolonged survival but did not affect overall mortality in the newborn mice This difference in susceptibility correlated with age-dependent differences with lower levels of IFNAR and PKR in the brain of P7 mice, which increased to adult levels during the first weeks of life. These differences did not reflect a global downregulation of the IFN response in newborns as levels of TLR3 and STAT1 were modestly higher in newborns. These findings suggest that increased susceptibility to HSV-1 infection of the CNS in newborns is associated with decreased IFN signaling. We found similar results when WT and IFNARKO P7 mice were infected intraperitoneally (i.p.) with HSV-1 to model disseminated disease. We also found that unlike the adult brain, the newborn choroid plexus (CP) was susceptible early in HSV-1 infection. Interestingly, we found deletion of IFNAR resulted in susceptibility of the CP to infection in the adult brain suggesting that the CP in an interferon dependent manner may be the gateway for HSV-1 spread to the brain and neurologic morbidity that follows.
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9:35-10:00
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Symposium 1B
Presenter:
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Richard Stanton Cardiff University, United Kingdom
Biography
I was awarded my PhD by the University of Wales College of Medicine (2004) and following 6 years as a post-doctoral researcher, I was appointed Lecturer in Microbiology at Cardiff University, followed by Senior Lecturer in 2014 and then Reader in 2018. Following my PhD on the Function of HHV-6 IE Genes, HCMV became the focus of my research. My first work on HCMV revealed that despite its inherent heterogeneity, the hypervariable gene UL146 was genetically stable following transmission in renal transplant patients. I then developed a BAC-based high-throughput Adenovirus expression system (the AdZ vector) to permit rapid insertion of genes by recombineering. Although of much wider utility, the vector was developed specifically to enable cloning of the HCMV canonical genes, and ultimately permitted the generation of an Adenovirus vector bank of all HCMV genes, for functional screening of the entire genome. HCMV research is complicated by the rapid selection of mutants in cultured virus. To address this issue, in collaboration with Gavin Wilkinson and Andrew Davison (Glasgow), the genome of clinical HCMV strains were characterised and we ultimately generated a BAC clone of a HCMV genome (Merlin) that accurately matched the virus found in the original clinical sample. Merlin was designated the 1st International Diagnostic Standard for HCMV, against which all diagnostic assays are now calibrated. It has also proven an invaluable reagent to study virus pathogenicity. Using this resource, my research has gone on to reveal that wildtype HCMV spreads primarily by direct the cell-cell transmission, in a manner that is highly resistant to neutralising antibodies, as well as innate and intrinsic immune defenses. A collaboration with Michael Weekes (Cambridge), enabled us to use leading-edge quantitative proteomics to analyse HCMV infection in unprecedented detail. By combining molecular biology with a genetically intact HCMV strain and high end proteomics, novel mechanisms by which immune cells recognise pathogen infected cells have been revealed, and multiple viral genes that systematically manipulate the surface of the infected cell to prevent recognition by both NK and T-cells have been identified.
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Insight into HCMV Biology Revealed by Genetically Intact Virus Strains
Wild-type HCMV strains are not readily propagated in vitro. HCMV mutants are rapidly selected during isolation in fibroblasts, reproducibly affecting gene RL13, the UL128 locus (genes UL128, UL130 and UL131A) and often the UL/b′region. As a result, the virus becomes less cell associated, altered in tropism and less pathogenic. This problem is not restricted to high-passage strains, as even low-passage strains can harbour biologically significant mutations. Cloning and manipulation of the HCMV genome as a bacterial artificial chromosome (BAC) offers a means of working with stable, genetically defined strains. We generated a BAC clone of stain Merlin, and repaired the sequence back to the sequence found in the original clinical sample. Stable propagation of phenotypically wild-type virus could only be achieved by placing both RL13 and UL128L under conditional expression. This system remains the only way of performing experiments in vitro, using a clonal strain expressing the complete wildtype HCMV proteome, and has revealed numerous novel insights into the biology of HCMV. This includes the way that the virus grows, the mechanisms and consequences of direct cell-cell spread, the way cell-free virus enters cells, and the way infected cells interact with multiple components of the immune system. In turn, understanding these areas of biology informs on ways of potentially developing more effective therapeutics.
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10:00-10:30
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Oral Abstracts
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10:30-11:00
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Refreshment Break
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11:00-12:30 - Concurrent Session
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Concurrent Session 1C: Genomics & Evolution
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Concurrent Session 1A: Virus- Host Interactions
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Concurrent Session 1B: Structure, Assembly & Entry
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12:30-13:30
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Lunch
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13:30-14:10
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Keynote 2: Genomics & Evolution
Presenter:
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Keynote
Moriah Szpara Penn State, United States
Biography
Moriah Szpara is an Associate Professor in the Department of Biochemistry and Molecular Biology and the Huck Institutes for the Life Sciences, at the Pennsylvania State University (PSU). Szpara is part of the Center for Infectious Disease Dynamics (CIDD) at Penn State, and organizes the Virology@PSU network. Szpara received her Ph.D. in Molecular and Cell Biology from the University of California Berkeley, with a focus on the transcriptional programs underlying neuronal development. As a postdoctoral fellow at Princeton University, Szpara trained with Dr. Lynn Enquist in the area of neurotropic herpesviruses, and initiated her research on viral comparative genomics in the Lewis-Sigler Institute for Integrative Genomics.
The Szpara lab at Penn State is focused on dissecting viral genetic contributions to virulence, the contributions of viral diversity in clinical and field settings, and the molecular interactions of herpes simplex virus (HSV) with host neurons. The Szpara lab uses approaches that range from genomics and bioinformatics analyses of viral genetic variation, to human neuronal cell responses to infection. The Szpara lab has also produced open-source software packages to facilitate herpesvirus genome assembly and comparison, including VirAmp (http://viramp.com) and VirGA (http:// virga.readthedocs.org/). More information on the labs research can be found at: http://szparalab.psu.edu/.
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The individual human scale of herpes simplex virus infection: how a persistent infection lifestyle impacts viral genomic diversity and evolution
The genetic diversity that enables herpesvirus evolution comes from single nucleotide substitutions, recombination events, and tandem repeat length fluctuations, as well as fitness-based competition among these variants. In our past and ongoing research, we have characterized how genetic variants in alphaherpesvirus genome populations impact the phenotypes observed in controlled laboratory conditions, using both cell culture and animal models. Now we are exploring how the same properties of viral genetic diversity and evolutionary selective pressures play out in natural human infections. Unlike the beta- and gammaherpesviruses where both latent and lytic sites of infection are accessible in living humans, the relative inaccessibility of neuronal sites of latency for alphaherpesviruses leads us to focus on surface shedding of reactivated virus. The goal of our research is to combine the insights from human, cell-culture, and animal-based studies to shed new light on how viral genetic diversity impacts the outcomes of lifelong persistent alphaherpesvirus infections in humans.
We utilize highly sensitive oligonucleotide enrichment methods to detect herpes simplex virus (HSV) genomes in clinical shedding episodes, in combination with ultra-deep sequencing to capture the diversity of alleles in each viral population. These approaches enable us to construct not only a viral consensus genome for each sample, but also a profile of the minor allelic variants that are present. We can then compare how the viral population shifts during a time-series of longitudinal samples from a single patient, or how this diversity is impacted during transmission. These data provide our first insights into HSV-1 and HSV-2 viral populations in new primary genital infections, neonatal infections, and host-to-host transmission events. Viral genetic variants observed in human infections can then be brought back into controlled cell-culture conditions and animal models, to explore the molecular functions of these variants and their impacts on viral fitness.
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14:10-14:35
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Symposium 2A: Genomics & Evolution
Presenter:
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Symposium
Kenneth Kaye Harvard University, United States
Biography
Ken Kaye is in the Departments of Medicine at Brigham and Womens Hospital and Harvard Medical School. He received his AB in Biology at Harvard College and MD at Harvard Medical School. Ken worked in the laboratory of Bernie Fields on reovirus as an undergraduate and medical student. For his postdoctoral work, Ken investigated Epstein-Barr virus working with Elliott Kieff. Kens laboratory investigates Kaposis sarcoma herpesvirus (KSHV) latency. His work has focused on the latency-associated nuclear antigen (LANA), which has homologs in other gamma-2 herpesviruses, including murine gammaherpesvirus 68 (MHV68).
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Cross-species conservation of episome maintenance between KSHV and MHV68 LANA allows for in vivo investigation of kLANA
The gamma-2 herpesviruses infect a broad range of mammalian species ranging from rodents to primates. Kaposi’s sarcoma-associated herpesvirus (KSHV) is the only gamma-2 herpesvirus that infects humans. Infection with KSHV is predominantly latent. During latency, the viral genome circularizes by fusing at its terminal repeat elements and persists as a multicopy, extrachromosomal episome. Only a small subset of viral genes are expressed in latent infection, including the latency-associated nuclear antigen (LANA). All gamma-2 herpesviruses encode LANA homologs. KSHV LANA mediates episome persistence by tethering episomal viral genomes to mitotic chromosomes to segregate virus genomes to progeny nuclei. N-terminal LANA attaches to chromosomes by binding histones H2A/H2B on the surface of the nucleosome. C-terminal LANA binds mitotic chromosomes and also contains a DNA binding domain (DBD) that recognizes specific sequence in KSHV terminal repeat (TR) DNA.
Murine gamma-2 herpesvirus 68 (MHV68) provides a robust small animal model for gammaherpesvirus investigation. mLANA acts on MHV68 mTR sequence to mediate episome persistence, analogous to KSHV kLANA. kLANA and mLANA differ substantially in size and kTR and mTR show little sequence conservation. Despite these differences and more than 60 million years of evolutionary divergence, kLANA and mLANA act reciprocally on TR DNA to mediate episome persistence. Further, kLANA rescues mLANA deficient MHV68, allowing chimeric virus to establish latent infection in vivo. These results provide a tractable model for investigation of kLANA in vivo.
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14:35-15:00
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Symposium 2B: Genomics & Evolution
Presenter:
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Symposium
Lars Dölken University of Wuerzburg, Germany
Biography
Lars Dölken received his MD from the University of Greifswald, Germany, in 2005. During his postdoctoral training at the Max von Pettenkofer Institute in Munich until 2011, he also became a registered specialist in Microbiology, Virology and Infection Biology. For his work, he received the Robert Koch Post-doctoral Award in 2011. Supported by an MRC Clinical Scientist Fellowship, he moved to the University of Cambridge, UK. In 2015, he took over the chair of virology at the Julius-Maximilians-University of Würzburg, Germany, where he also became affiliated with the newly founded Helmholtz Institute for RNA-based Infection Research (HIRI) in 2018. In 2016 he was awarded with an ERC consolidator award of the European Union to work on RNA-based regulation in herpes simplex virus infection.
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Systems biology analysis of HSV-1 host cell manipulation
Lytic herpes simplex virus 1 infection (HSV-1) is a paradigm for virus-induced host shut-off exerted at RNA level. Immediately upon virus entry, the virion host shut-off (vhs) endonuclease, delivered by the incoming virus particles, rapidly starts cleaving actively translated cellular and viral mRNAs. To abrogate its endonuclease activity, vhs is subsequently escorted to the nucleus by the viral VP16 and VP22 proteins. With the advent of lytic viral gene expression, the viral infected cell polypeptide 27 (ICP27) is expressed and interferes with cellular RNA metabolism while facilitating viral gene expression at multiple levels. Moreover, the viral immediate early protein ICP22 interferes with positive transcription elongation factor b (P-TEFb), thereby modulating the phosphorylation of the RNA polymerase II C-terminal domain. Finally, HSV-1 targets cellular RNA polymerase for proteasomal degradation late in infection. My lab aims to elucidate the molecular mechanism, regulatory network and functional role of the cellular processes governing RNA synthesis, processing, export and stability. These are extensively coupled by large multifunctional protein complexes, which HSV-1 elaborately interferes with. We employ a systems biology approach to decipher the complex molecular regulatory mechanisms and assess their importance for productive HSV-1 infection.
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15:00-15:30
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Refreshment Break
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15:30-16:10
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Spotlight - Vaccine A
Presenter:
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Spotlight
Scott Schmid Centers for Disease Control and Prevention, United States
Biography
Dr. Schmid received his PhD in microbiology at the University of Tennessee, working under Barry Rouse. He evaluated cytokine and cellular requirements for CTL responses to HSV-1 in mice. He was a post-doctoral fellow and research associate at Yale University with Nancy Ruddle. There, he demonstrated that lymphotoxin induces apoptosis in target cells, causing DNA fragmentation comparable to that observed for the CTL lethal hit. Dr. Schmid joined CDC in 1986 and serves as the team leader for herpesviruses, comprising efforts on VZV, congenital CMV, and HHV-8. In 1998 he established the National VZV Laboratory as a reference diagnostic laboratory to help monitor varicella vaccine impact, to confirm VZV vaccine adverse events, to evaluate outbreaks, and to confirm severe varicella disease. The laboratory also performs 18 herpesvirus diagnostics including realtime PCR for all 9 human herpesviruses. He has also played a key role in characterizing genomic variation in VZV (collaboration with UCL and VA San Diego), resulting in 1200+ complete VZV genome sequences from samples obtained from cases of herpes zoster. Currently he is comparing functional aspects of the humoral immune responses to Zostavax and Shingrix shingles vaccines. He serves on the editorial boards for J Clin Virol and Arch Virol.
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The Checkered History of Alphaherpesvirus Vaccines: Successes, Failures, and Possible Solutions
Successful vaccines have been licensed and approved for varicella and zoster, and several veterinary alphaherpesvirus vaccines are available, albeit most of them have important limitations. Despite the development of numerous candidate vaccines for herpes simples virus using a variety of vaccination strategies, none has yet had demonstrable efficacy in large clinical trials. A number of factors might explain this difficulty, including differences between VZV and HSV in disease presentation, reactivation frequency, etc. It recently became possible to compare the immunological responses to two licensed herpes zoster vaccines on a much more granular level than has generally been attempted for vaccine studies. The two vaccines have pronounced differences in efficacy for the prevention of herpes zoster, both in the cell-mediated and humoral immune responses. These differences would not have been detected using the more traditional approach of evaluating only IgG titers and T cell proliferation. These studies demonstrated that large numbers are not required to detect substantial differences in the immunological response; thus the excuse that more detailed assessments of the immune response during the developmental phases of candidate vaccines is no longer true. As such, it may make sense to compare the immune response to candidate vaccines with the response to wild type natural infection in the earliest stages, before making the decision to proceed to large clinical trials.
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16:10-16:35
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Spotlight - Vaccine B
Presenter:
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Symposium
Bill Britt The University of Alabama at Birmingham, Birmingham, Alabama
Biography
Studying congenital cytomegalovirus (CMV) infection which is the most common cause of hearing loss and neurodevelopmental abnormalities globally, Dr. Britt leads a team that has made fundamental contributions to current understanding of virus structure and assembly as well as in the antigenicity and immunogenicity of viral proteins that in some cases were selected for vaccine development. As senior leader of investigators at UAB who have focused their efforts on this perinatal infection, he has translated laboratory findings into strategies to define key aspects of the natural history of congenital CMV infection. Specifically, he has made important contributions to the study of this perinatal infection, including the paradigm shifting demonstration that normal seroimmune women can be reinfected with new strains of CMV. More recently his studies have focused on the neuropathogenesis of human CMV infections, including the use of patient cohorts and informative animal models to translate basic immunological and virological findings in these models into new therapies. As a result of longstanding contributions to both basic and clinical studies of cytomegaloviruses, he is considered one of the worlds leading herpesvirologists. His studies have been recognized by investigators worldwide and he currently leads multi-investigator studies with scientists from Brazil, Germany, Croatia, and in several centers in the US. His work has been supported by a variety of sources, including NIH P30 and R01 grants. He has contributed more than 200 articles to the scientific literature and authored or co-authored over 50 chapters in basic science textbooks, monographs, and textbooks of Medicine and Pediatrics.
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Vaccines to Limit CMV Infection and Disease: Progress and Hurdles
There has been considerable effort in the development of vaccines to limit infection and disease associated with congenital HCMV (cCMV) infections and HCMV infections in transplant recipients. A number of different approaches ranging from attenuated replication competent viruses to adjuvanted subunit vaccines have been tested in different populations. Although less than definitive, findings from some trials have resulted in continued interest in the development of vaccines by investigators from both academia and pharma. These efforts are to be applauded as several HCMV vaccine platforms have failed in clinical trials and the efficacy of passive immunotherapy with HCMV-immune globulin remains unproven. Similarly, studies in non-human primates have provided only limited support for conventional approaches of HCMV vaccine development. A major hurdle that continues to hinder HCMV vaccine development has been the identification of correlates of protective immunity that can prevent intrauterine transmission and limit disease in pregnant women with HCMV infection. The limitations in our current understanding of immune correlates of protective immunity in pregnant women is perhaps best illustrated by observations in the natural history of cCMV in infants born to women with HCMV immunity prior to conception. In contrast, HCMV specific T cell immunity appears to be correlated with outcomes transplant recipients, although anti-HCMV antibodies also modify the outcomes of HCMV infections in these patients. In spite of limitations in current knowledge of HCMV vaccine design and testing, findings from studies in animal models and from vaccine trials argue that our understanding of immune responses associated with protection for HCMV infection and disease has increased significantly and together, point to adaptive immune responses that could be targeted for vaccine development.
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16:35-17:00
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Spotlight - Vaccine C
Presenter:
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Spotlight
Nandini Sen Stanford University, United States
Biography
Dr. Sen is a Senior Research Scientist at the Dept. of Medicine, Stanford University, California. Her passion for microbial pathogenesis led her to pursue doctoral research on the molecular evolution of diarrheagenic Vibrio species from Kolkata University, India. As a post-doctoral fellow, Nandini worked on Hepatitis B replication mechanisms with Dr. John Tavis at St. Louis University, St. Louis. Subsequently, Dr. Sen moved to Stonybrook University where she studied host immune responses to Hantavirus infection in Dr. Erich Mackows laboratory. Since 2008, Nandini has worked at Stanford University with Dr. Ann Arvin to decipher how Varicella Zoster Virus (VZV) successfully negotiates host immune responses. In investigating the role and regulation of the Type I and II interferon responses, her work has demonstrated how VZV interferes with the IRF family of transcription factors to block antiviral responses, while activating the STAT family proteins, viz. STAT3, to support viral replication. She has helmed projects on single-cell analysis of VZV-infected cells using mass cytometry to understand the molecular basis of VZV lymphotropism that involves extensive viral remodeling of T cells. Dr. Sen is fascinated by signaling networks, especially the complexities of host antiviral signal heterogeneity and cross-talk across functionally diverse single-cell continuums in the host. Apart from interrogating viruses, Nandini is also deeply passionate about promoting STEM education among underprivileged children.
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Varicella Zoster Virus: Master-tuner of Immune Checks and Balances
Varicella zoster virus (VZV) is a lymphotropic alpha-herpesvirus that causes varicella (primary infection) and zoster (reactivation) in human hosts. The ability of VZV to hitch-hike onto tonsil T cells and repurpose them toward skin trafficking involves a sophisticated remodeling mechanism that was revealed by single cell analysis of T cells using mass cytometry. Simultaneous measurements of 25 intracellular and cell surface proteins in VZV-infected, bystander, and mock-infected T cells revealed specific induction of cell signaling pathways within VZV-infected cells and corresponding alterations in their surface architecture to mimic skin-tropic T cells. Upon reaching the skin, VZV triggers an interferon (IFN) response and viral infection at this site manifests itself in the formation of skin lesions that progresses against this innate barrier. VZV encodes powerful strategies to overcome the host IFN response; VZV-IE62 blocks IFN induction by inhibiting the phosphorylation of interferon response factor 3 (IRF3), a key transcription factor mediating IFN induction. More recently, we found that VZV blocks the amplification of IFN signaling by modulating IRF9, another host factor vital for this response. While type I IFNs (IFNa/b) delay the onset of VZV infection, the effects are reversible; in contrat, VZV fails to overcome the antiviral response in cells exposed to Type II IFN (IFNg). The antiviral action of IFNg was dependent on IRF1 since IRF1 gene knockout released the irreversible inhibitory effect of IFNg on VZV infection.
A fascinating theme that emerges from these studies is that by differentially targeting specific IRF and STAT transcription factors, VZV shapes the host IFN-mediated antiviral and inflammatory outcomes to favor its own pathogenesis. How VZV navigates and delicately evades innate immune checks and balances via transcriptional and post-translational regulation of multiple host cell genes and proteins in discrete cellular contexts will be discussed.
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17:00-17:25
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Spotlight - Vaccine D
Presenter:
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Spotlight
Cliona Rooney Baylor College of Medicine, United States
Biography
Dr Rooney received her PhD in Immunology from Cambridge University in 1981. She then pursued postdoctoral fellowships in virology and immunovirology with a focus on Epstein-Barr virus (EBV) at the University of Birmingham and at Yale. She joined the faculty at the St Marys Branch of the Ludwig Institute in 1998 and then returned to the US in 1998 when she joined the faculty first of St Jude Childrens Research Hospital in Memphis Tennessee, and then at Baylor College of Medicine in Houston, where she is now a full Professor and Director of the Translational Research Laboratories of the Center for Cell and Gene Therapy, and Co-Director of the graduate program in Translational Biology and Molecular Medicine Medicine. Since 1992, she has exploited her training in viral immunology for the treatment of virus-associated diseases and malignancies. She first developed clinical protocols for the prevention and treatment of EBV-associated lymphomas that occur after HSCT then extended this successful therapy to other viral infections of stem cell transplant recipients and to EBV-positive malignancies that occur in immunocompetent individuals. She has a particular interest in strategies that render T cells genetically resistant to inhibition by the tumor microenvironment, such as a dominant-negative TGF-beta receptor and a constitutively active IL-7 receptor. To add a safety switch for genetically enhanced T-cells, she developed the inducible caspase 9-based suicide gene that was inducible by dimerization and that has proved successful in clinical trials. To overcome the lack of in vivo proliferation of T-cells expressing chimeric antigen receptors (CARs) for tumor antigens, I have evaluated the use of virus-specific T cells (VSTs) as hosts, so that CAR-VST activation and expansion can be induced by endogenous viruses, viral vaccines or oncolytic viruses.
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Herpesviruses to enhance the anti-tumor activity of CAR T-cells
Despite their great success for the treatment of hematological malignancies, T-cells modified with chimeric antigen receptors (CARs) have produced few complete responses in solid tumors. Solid tumor lack the proinflammatory cytokines and ligands required for T-cell activation, expansion and sustained function, and instead express multiple inhibitory ligands. Most virus infections, by contrast, are rapidly recognized by innate immune responses that create an appropriate environment for T cell activation, expansion and persistence that is sustained until the infection is resolved. We have attempted to hijack this immunogenicity of viruses for the treatment of solid tumors, by introducing CARs into virus-specific T-cells (VSTs) and using CAR-VSTs in a setting of herpesvirus reactivation (EBV) or vaccination (VZV). We show first that EBV reactivation in the setting of hematopoietic stem transplantation (HSCT) can drive the expansion of CD19.CAR-modified EBV-specific T-cells (EBVSTs) in HSCT recipients, and second that GD2.CAR-modified VZV-specific T-cells (VZVSTs) not only expand in response to VZV vaccination, but reactivate endogenous patient T-cells specific for non-viral tumor antigens (antigen spreading in patients with osteosarcoma, leading to long term tumor control.
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17:30-19:00
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Poster Session 1 & Reception
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