Carrie B. Coleman, Ph.D.
Epstein Barr virus (EBV) is an oncogenic human gamma-herpesvirus associated with a substancial number of malignancies. EBV is classified into two strains, EBV Type-1 (EBV-1) and EBV Type-2 (EBV-2), based on genetic variations. Both EBV types are prevalent in equatorial Africa and in the HIV+ population worldwode, groups at high risk for EBV-associated malignancies. Importantly, both EBV-1 and EBV-2 have been shown to be associated with EBV+ lymphomas occurring in these populations. Despite the apparent pathogenciity of EBV-2, the majority of studies addressing mechansims of EBV latency establishment and persistene, as well as requirements for EBV-associated lymphoma development, have focused on EBV-1. The lack of EBV-2 specific studies is significant as these viruses exhibit fundamental differences suggesting distinct mechanisms to establish latency and persist.
Specify, EBV-1 is known to persist int he human population by establishing a latent infection in B cells. However, our recent findings have demonstrated that EBV-2 has a unique tropism for T cells, infecting both B and T cells. This has been observed in culture, in healthy Kenyan infants, and in a EBV-2 mouse model, strongly suggesting that infection of T cells is a natural part of the EBV-2 life-cycle. Thus, shifting our view of EBV biology, introducing a new paradign of EBV-2 cellular tripism, and uncovering the potential role of T cells in EBV-2 latency establishment, persistence and lymphomagenesis. The broad research interest of the lab is to understand EBV-2 biology, specifically elucidating the significance of EBV-2 infection of T cells and the origins of EBV-2 associated lymphomas in populations at high risk for these malignancies.
Terje Dokland, Ph.D.
Structure and assembly of viruses and viral proteins: The research in my lab is focused on the structures of viruses and viral proteins, and the macromolecular assembly processes that gives rise to functional virions. One project is on the role of “helper” bacteriophages in the mobilization of pathogenicity islands (SaPIs) in Staphylococcus aureus. SaPIs lack genes encoding structural gene products, but are packaged into viral particles using proteins encoded by the helper. In many cases the capsids formed are smaller than those normally assembled by the virus itself. We are interested in the regulation of this size determination process, which we study with a combination of structural and biochemical techniques, including cryo-EM and X-ray crystallography. Other projects focus on the bacteriophage P2/P4 system and on the agricultural pathogen PRRSV, an RNA virus belonging to the arterivirus family that infects pigs.
Ilya Frolov, Ph.D.
My research is focused on dissecting the molecular mechanisms of alphavirus replication and interaction with host cells. In this direction, we are studying the RNA promoter elements and the mechanism of formation of alphavirus replication complexes, define functions and interactions of their cellular and viral components. Another direction of our research is aimed at understanding the mechanism of Venezuelan equine encephalitis virus particle assembly and RNA encapsidation. These data are being used for development of new vaccine candidates against alphavirus infections.
Elena Frolova, Ph.D.
Our research interests are geared towards expanding our understanding of alphavirus pathogenesis at the molecular and cellular levels. Alphaviruses are circulating in the Central, South and North Americas and cause periodic, extensive equine epizootics and epidemics of encephalitis with frequent lethal outcomes and neurological sequelae in humans. The main objective of out lab is to investigate the functions of virus-specific nonstructural and structural proteins in virus replication and inhibition of the cellular antiviral response. Our studies have demonstrated that geographically isolated New World alphaviruses, such as Venezuelan equine encephalitis virus and Old World alphaviruses, such as Sindbis and chikungunya viruses, have developed fundamental differences in their mechanisms for downregulating cellular transcription and translation, which represent the main means of alphavirus inactivation of antiviral genes. The detailed characterization of these mechanisms provides a strong basis for the rational design of recombinant alphaviruses with programmed, irreversibly attenuated, cell-restricted phenotypes. These genetically modified aphaviruses can, subsequently, be safely used for vaccine development. Other projects in the lab are aimed at the production and purification of alphavirus nonstructural proteins, characterization of their enzymatic activities and design of assays for screening small molecule libraries in order to identify new antiviral drugs.
J. Victor Garcia-Martinez, Ph.D.
Throughout evolution, humans have been challenged by viral pathogens new to the species. For the most part, our immune system mounts an adequate response that protects us from the fatal consequences of infection. However, in some instances viruses can circumvent the immune system and cause fatal diseases such as cancer (EBV, KSHV, HCV), hemorrhagic fever (Ebola virus), AIDS (HIV) and now COVID-19 (SARS-CoV-2). Understanding the host pathogen relationship at a molecular level provides rational approaches to therapy and vaccine development. In addition, it also provides a better understanding of human biology and immunology. We are interested in how human viruses cause human cancer, how HIV causes AIDS, how SARS-CoV-2 causes COVD-19 and why the immune system is not able to control viral infections. Our working hypothesis is that specific viral genes are the key determinants of viral pathogenesis and are responsible for disease progression. To evaluate the role of these genes in disease progression, we have developed in vitro and in vivo models that recapitulate specific aspects of viral infection. Our emphasis has been placed on xenograft animal models where human specific pathogens can be studied and where novel therapeutic interventions can be evaluated. For example, lymphotropic viruses are responsible for a vast number of human cancers. Unfortunately, their study has been severely limited due to fact that the majority of these viruses do not infect other mammals. Thus, the lack of animal models susceptible to infection by these human viruses has severely limited our ability to develop novel treatments and effective vaccines. Our laboratory has established novel animal models that recapitulate key aspect of infection by human-specific viruses such as CMV, Zika, RSV, EBV, HIV, HHV-8, dengue virus and SARS-CoV-2. We are currently using these systems to evaluate novel interventions to treat and/or prevent the devastating diseases caused by these agents
Todd Green, Ph.D.
Dr. Green’s lab uses structural techniques to study proteins from negative-stranded RNA viruses that are involved in polynucleotide synthesis. In order to gain a better understanding of the replication cycle of this class of viruses, my lab is studying the molecular structure of vesicular stomatitis virus (VSV), a prototype of this group. Using state-of-the-art techniques, such as x-ray crystallography and cryo-electron microscopy, we have observed atomic-level snapshots of how the viral capsid protein encapsidates and protects the genomic RNA, how this template is accessed by the viral polymerase co-factors, and how the capsid structure is affected by specific RNA sequences. Moving forward, we continue to investigate the mechanisms of viral transcription and replication by structural and biochemical techniques. Better understanding of these processes will yield new avenues for future therapeutic design against this group of viruses.
Masa Kamata, Ph.D.
The major research foci of our laboratory are understanding a) how viruses or malignant cells establish and maintain prolonged infections or uncontrolled cell division, respectively, in patients under host immune pressure and b) how the host immune system can be mobilized to fight infection or cancer. To this end, we have worked to establish effective strategies using humanized mouse and non-human primate models; our aim is to develop a treatment capable of achieving a state wherein the host immune system decreases levels of virus or cancer in patients to the point where further treatment is not necessary. Our recent efforts using immunotherapeutic strategies have provided potential tools for controlling HIV-1 load as well as aggressive cancers that metastasize to the brain. These studies provide fundamental insight into the basis of host-virus and host- malignant cell interactions and ultimately identify clinically relevant therapeutic targets to augment immune responses and restore antiviral or anticancer immunity in patients.
Elliot Lefkowitz, Ph.D.
My research interests are directed at contributing to the understanding of microbial genomics and evolution by developing and utilizing computational tools and bioinformatics techniques to mine sequence and other data for significant patterns characteristic of function and/or evolution. This work has included the development of new algorithms for the detection of viral regulatory motifs; tools for the identification of viral genes; the development and utilization of High Performance and Grid Computing tools for bioinformatics analysis; and the development and use of tools for analyzing patterns of viral evolution. I have also been involved in the development of databases, web applications, and analysis tools for the sequencing and annotation of several complete bacterial and viral genomes. This includes development of the Viral Bioinformatics Resource Center, one of the original NIH-sponsored Bioinformatics Resource Centers (BRCs) for Biodefense and Emerging or Re-Emerging Infectious Diseases. My work includes research on the genomics and evolutionary history of large DNA viruses as well as several different RNA virus species including Human papillomavirus, Hepatitis C virus and Dengue virus.
Ongoing research projects in my group are focused on the analysis of, and the development of tools to support the analysis of the genomics and evolution of the large DNA viruses in the family Poxviridae. Poxviruses are highly successful pathogens, known to infect a variety of hosts. The family Poxviridae includes variola virus, the causative agent of smallpox, which has been eradicated as a public health threat but could potentially reemerge as a bioterrorist threat. The risk scenario includes other animal poxviruses as well as genetically engineered or synthetically derived poxviruses. Past research on orthologous viral gene sets has defined some of the evolutionary relationships between members of the Poxviridae family. But it has not been clear how variation between family members arose in the past—an important issue in understanding how these viruses may vary and possibly produce future threats. Therefore the goal of our research has been to better understand the viral genotypic-phenotypic relationships that result in wide differences in host range and pathogenicity, as well as the evolutionary mechanisms involved in genome variation. Our work has included a comprehensive analysis of all proteins encoded by viruses of the family Poxviridae, to assess the evolutionary history of genes likely acquired through horizontal gene transfer. This effort has allowed us to predict and date the patterns of host gene acquisition throughout the evolutionary history of this virus family, and helps us to better understand the molecular mechanisms of survival and pathogenesis employed by viruses of this family at different stages of their evolution.
Nicholas Lennemann, Ph.D.
Our research is focused on the interactions between viruses and the secretory pathway to better understand how viruses hijack and manipulate the host cell. Positive-strand RNA viruses (e.g. enteroviruses, flaviviruses, and coronaviruses) are responsible for severe disease manifestations worldwide. Interestingly, replication of all positive-strand RNA viruses induces dramatic rearrangements of intracellular membranes to form replication organelles, which allow for the concentration of viral and host factors required for replication. Enteroviruses, flaviviruses, and coronaviruses target the secretory pathway to form these structures. This pathway consists of many cellular processes that are exploited by viruses during infection, including protein/lipid trafficking, protein glycosylation, and autophagy, which requires trafficking of vesicle-sequestered cargo destined for degradation during cellular stress, such as virus infection. The coordinated movement of lipids and proteins between organelles is regulated by a vast number of host proteins, which can be manipulated by viruses to facilitate infection. The roles of a large number of host proteins that regulate these processes in mammals have been inferred from characterization of orthologs in yeast. However, many of these proteins remain poorly characterized in mammalian cells and it is unclear whether they have roles during viral infection. Thus, our research is focused on identifying and characterizing host secretory pathway factors that regulate positive-strand RNA virus infection, including those that facilitate autophagy/ER-phagy, membrane trafficking, and secretory organelle shaping/biogenesis.
Frances Lund, Ph.D.
One of the major research objectives in the Lund laboratory is to identify the key factors that regulate the balance between protective and pathogenic immune responses to viral infection. In one project we use the influenza infection model to evaluate how B cells and the antibodies made by B cells contribute to local pulmonary protection from reinfections with the same or different strains of the influenza virus. We use genetically modified strains of mice as well as altered influenza viruses to identify the key pathogen and immune system-derived signals that initiate the early innate as well as later adaptive B cell response to flu. We then use this information to evaluate B cell responses in humans following natural infection and vaccination with the long-term goal of designing more protective influenza vaccines. In a second project, we evaluate immune-mediated pulmonary pathology in animals infected with influenza virus. In particular, we focus on the early innate immune response and evaluate how chemokines modulate pulmonary inflammation and tissue damage. The goal of this research is to identify therapeutics that dampen the damaging lung inflammation that often accompanies infection with the most pathogenic strains of flu.
Jan Novak, Ph.D.
Dr. Novak’s research interests in Virology include studies of glycosylation of viral glycoproteins and the effect of differential glycosylation on infectivity and immunogenicity. For example, understanding the role of differential glycosylation of HIV-1 envelope glycoprotein on its multiple functions will impact development of new effective HIV vaccines.
Peter Prevelige, Ph.D.
Virus Structure and Assembly: My laboratory uses a variety of biophysical and structural approaches to approach fundament questions in virus structure and assembly. We are particularly interested in questions of form determination, for how icosahedral viruses assemble from subunits which high fidelity, or why some viral capsid such as HIV adopt different morphologies. Among the techniques that we utilize are: cryo-EM, NMR, mass spectrometry, single molecule spectroscopy, light scattering, and kinetic analysis.
Virus Based Bio-Nanotechnology: Virus particles can be viewed as nanoscale structural scaffolds precisely defined down to the atomic level. Well understood techniques of protein chemistry and molecular biology provide facile tools for the selective modification of individual amino acids. These modified viral particles can be used to display targeting ligands for biomedical imaging and delivery (theranostics) applications or alternatively as a route to well-defined nanoscale materials. Our virus based bio-nano projects utilize our detailed knowledge of the structure and assembly of the 60nm capsid of the bacteriophage P22 to address both of these classes of applications.
Jamil S. Saad, Ph.D
HIV-1 replication is strongly dependent on the cellular machinery to produce progeny virus. The discovery of cellular factors that participate in HIV replication pathways has provided new insights into the molecular basis of virus–host cell interactions. Elucidation of the molecular interactions between the host cell and HIV are important for understanding the virus replication and the subsequent cytopathogenesis in the infected cell, which will aid in the development of more efficient antiviral drugs. We are interested in the underlying structural basis by which HIV proteins interact with cellular constituents during the virus replication cycle. A major component of our research program is directed towards understanding key protein-protein and protein-membrane interactions that are critical for HIV replication. Another aspect of our research is to identify small molecule inhibitors that are able to block virus-host protein-protein complexes and ultimately serve as potential anti HIV drugs. The results generated from this research will provide new insights into these mechanisms and identify new attractive targets that will ultimately aid in rational drug design.
Angela Wahl, Ph.D.
Our research is focused on studying the mechanisms of virus transmission and pathogenesis, host pathogen interactions including the role of the microbiome in infection, the human immune response to infection, and evaluating novel agents to prevent and treat infection using precision animal models. Our work with viruses currently focuses on HIV, oncogenic viruses that cause cancer like Epstein-Barr virus, and respiratory viruses including respiratory syncytial virus and coronaviruses.
Mark R. Walter, Ph.D.
Structural biology of viral proteins that disrupt cytokine signaling: An ongoing goal of the laboratory is to design molecules that enhance or prevent cytokine signaling. One way to understand how to manipulate cytokine signals is to understand the mechanisms used by viruses to accomplish this task. Pox and herpes viruses have designed novel proteins to disrupt cytokine signaling upon infection. Structure-function studies on these molecules provide considerable insight into the mechanisms used by virus to evade the host immune system. Furthermore, these strategies might also be used to control dysregulated cytokine signaling found in autoimmune disease. See
1. Yoon et al. Epstein-Barr Virus IL-10 Engages IL-10R1 by a Two-step Mechanism Leading to Altered Signaling Properties. J. Biol. Chem. 26586-26595, 2012 and
2. Nuara et al. Structure and mechanism of IFN-γ antagonism by an orthopoxvirus IFN-γ Binding Protein P.N.A.S. 105, 1861-1866, (2008).
Design of novel vaccines against human cytomegalovirus (HCMV): Current viral vaccines elicit antibodies to viral proteins that prevent/limit entry of virus into cells of their host. To date, this strategy has not been successful in a number of viruses, including HCMV, that directly target immune cell signaling pathways to evade host immune responses. HCMV infection can cause severe hearing loss, mental disabilities, and even death in a developing fetus. Currently there is no vaccine for HCMV. To address this problem, we are using our expertise in cytokine structural biology to design novel antigens that target virally produced cytokines. To date, these antigens show efficacy in animal models of HCMV. Further testing of this strategy and evaluating molecules for possible clinical trials are now underway. See
1. Logsdon et al. Design and Analysis of Rhesus Cytomegalovirus IL-10 Mutants as a Model for Novel Vaccines against Human Cytomegalovirus. PLoS One. 6 (2011).
2. Eberhardt et al. Host Immune Responses to a Viral Immune Modulating Protein: Immunogenicity of Viral Interleukin-10 in Rhesus Cytomegalovirus-Infected Rhesus Macaques. PLoSOne 7 (2012).
Allan J. Zajac, Ph.D
I love studying cell-mediated immune responses to infections. My research program is centered upon understanding why robust and highly effective immune responses are induced by certain viral infections and vaccinations and why and how they become corrupted during persistent infections, compromising viral control. Our studies have shown that virus-specific CD8 T cells succumb to exhaustion during persistent infections, and have highlighted a vital role for CD4 T cells in supporting CD8 T cell responses. We also discovered that the CD4 T cell-derived cytokine, IL-21, is essential for sustaining cell-mediated immunity in chronically infected hosts. More recently, we demonstrated that adhesion molecule interactions influence the balance of effector and memory phenotype cells, and also regulate the deletion of virus-specific CD8 T cells during chronic infections. As our projects have advanced a common immunological theme that has emerged is the central role of cytokines, as both intrinsic regulators and predictors of the outcome of the CD8 T cell response, and also as extrinsic factors that provoke and direct their development. Consequently, our interests have evolved towards analytically deconvoluting the functional complexity of CD8 T cell responses, with a major goal of understanding how the formation of discrete cytokine-producing subsets is controlled and how they contribute to the clearance of infections and tumors. These studies are helping to define how CD8 T cell functional disparities translate to qualitative and quantitative differences in the ensuing response, forecast fate decisions, and dictate protective efficacy.