Lecture Summaries

1 Introduction and Course Overview The first meeting will consist of introductions, both of the instructors and the students. The instructors will present a general overview of the course, discuss the format, and explain the preparation that will be expected of each student each week. The instructors will also provide an overview of the course material with an introduction to general aspects of viral infection and concepts of host innate immunity.
2 Host Sensors of Viral Infection-I Induction of the anti-viral innate immune response depends on recognition of viral components by sensors present in the host. One of the key cytoplasmic viral sensors is the RNA helicase that recognizes double-stranded RNA generated during a viral infection. In this class, we will discuss the mechanism of Retinoic acid Induced Gene-1 (RIG-I) mediated viral sensing and subsequent activation of interferon (IFN) responses along with a strategy adopted by influenza virus to evade detection by this anti-viral component. From paper 1, you will learn about the role of ubiquitin in activating RIG-I that is critical for the anti-viral response, and from paper 2 we will discuss the mechanism by which influenza Non-Structural protein 1 (NS1) interacts directly with RIG-I to inhibit production of interferons.
3 Host Sensors of Viral Infection-II: The Road to IFN Production Runs through the Mitochondria The type-I interferon response constitutes one of the first lines of defense against virus infections. In the first paper you will learn that the signaling pathway for inducing IFN production after detection of virus relies on the Mitochondrial Anti-Viral Signaling protein (MAVS). In the second paper we will read about the discovery of the first viral protein known to directly target MAVS and inhibit its function by cleaving it from the mitochondrial membrane— Hepatitis C Virus Non-Structural 3–4a protein (NS3-4A) protein.
4 Secreted IFN – In the Extracellular Space, No One Can Hear You Scream Vaccinia virus (VV) is the prototypic member of the poxvirus family of cytoplasmic DNA viruses. VV and other poxviruses have evolved clever strategies to evade the anti-viral effects of IFNs. The first paper we will discuss is one of the classics describing the initial discovery of the IFN cytokine. From the second paper, you will learn how VV employs mimicry to block the anti-viral activity of IFNs by expressing a decoy receptor that binds the cytokine.
5 Vaccines: We Win, Finally. Not So Fast Successful vaccines, which prevent viral infection, generate neutralizing antibodies. Our first paper presents the most promising approach in vaccine development for dengue virus (DENV). We will discuss why vaccines against dengue virus might do more harm than good. The second paper will look at the clinical development of a neutralizing antibody to treat human Cytomegalovirus Virus (hCMV) infection, which was aborted due to lack of efficiency, followed by the discovery of a bizarre solution hCMV has employed to evade neutralizing antibodies.
6 Trip to Sanofi/Pasteur We will visit the Sanofi/Pasteur Research Institute in Cambridge, which is actively involved in developing vaccines for viruses such as influenza. This visit will allow the students to appreciate the translational aspect of the research topics that we discuss in class and see the laboratory setting in an institute dedicated to fighting against infectious diseases and the equipment and the techniques that are routinely used.
7 A New Player in the Puzzle of Filovirus Entry into Host Cells Viruses of the genera Ebola virus and Marburg virus are filoviruses that cause haemorrhagic fever in primates, with extremely high fatality rates. Studies have focused on elucidating how these viruses enter host cells, with the aim of developing therapeutics. From the first paper, you will learn about how Ebola virus utilization of host cathepsins for cellular entry permits the virus to evade immune recognition while also providing a new target for therapeutics. From paper 2, we will discuss a novel screening strategy to identify host factors required for Ebola viral infection. This method resulted in identification of NPC1 as a necessary host protein that mediates Ebola virus entry.
8 IFN Signaling: United STATs and the Rule of V IFN binding to the IFN receptor leads to stimulation of the IFN signaling pathway and subsequent creation of the antiviral state, as an endpoint of signal transduction through the Janus Kinase-Signal Transduction and Activator of Transcription (JAK-STAT) pathway. Our first paper, a classic, studies how the pathway was characterized using chemical mutagenesis. From the second paper we will look at how one virus family (paramyxovirus) has particular expertise in blocking the IFN signaling pathway and focus on the Nipah virus V protein which binds and sequesters the STAT proteins.
9 Mechanisms of Human Cytomegalovirus Infection and Restriction Little is known about the mechanism by which IFNs inhibit human Cytomegalovirus (hCMV) replication. Viperin is an interferon-inducible protein that is expressed during infection by hCMV. Despite being a protein of an anti-viral innate immune response, Viperin can enhance infection in host cells. In this class we will discuss the two distinct modes of operation of Viperin. Paper 1 describes how Viperin functions to restrict viral infection. Paper 2 describes a novel strategy that hCMV employs to coopt the function of Viperin to facilitate the infectious process.
10 HIV Restriction Factors and Mechanism of Evasion Interferon-induced genes function to inhibit viral infection at a number of steps. Tetherin is an example of an interferon-induced gene that blocks release of Human Immune-deficiency Virus (HIV) and other enveloped viruses. In this session we will discuss the opposing modes of action on Tetherin by HIV and the host cell. Paper 1 describes the mechanism through which Tetherin acts to block release of viral particles by directly tethering nascent enveloped virions to the surface of infected cells. Paper 2 describes subsequent strategies that HIV has evolved to counteract this anti-viral activity through degradation of Tetherin in the lysosomes.
11 Interferon-Induced Transmembrane (IFITM) Proteins as Restriction Factors for Influenza Virus The host expresses a number of interferon-induced genes to defend against influenza virus infection. The IFITM proteins are such a class of restriction factors that function to inhibit a number of viruses, such as influenza, dengue virus and West Nile virus. From paper 1, we will discuss a screening strategy for identification of anti-viral host proteins and the initial discovery of this family of proteins that mediate cellular innate immunity. From paper 2, you will learn about IFITM3 mutations discovered in the human population and linked to increased morbidity and mortality during influenza infection.
12 End-term final assignment

See “Assignments” for a description of what is expected. The students will receive written evaluations of their presentations from the instructor.

Discussion of final assignment. We will conclude with a general discussion to summarize what we covered in the course and address any questions that the students might have. Students are encouraged to provide feedback about any aspect of the course.

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