Medical Virology Lecture 19: Gammaherpesviruses
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Questions and Answers

What is one characteristic of the virus mentioned?

  • It always triggers a strong host immune response.
  • It produces no infected computers.
  • It is difficult to model in a laboratory. (correct)
  • It rapidly spreads through textile fibers.

    • How effective is the virus in evading host defenses?

  • It creates a visible reaction in infected individuals.
  • It has an average success rate.
  • It is particularly good at evading host immune response. (correct)
  • It relies solely on direct infections.

    • What type of cells does the virus infect?

  • Muscle cells.
  • Neurons.
  • Epithelial cells. (correct)
  • Red blood cells.

    • Which of the following statements is true regarding the virus?

    <p>It is good at evading host immune responses. (A)</p> Signup and view all the answers

    What is implied about the virus's impact on hosts?

    <p>It is difficult for the immune system to counteract. (A)</p> Signup and view all the answers

    Which virus is primarily associated with Epstein Barr virus (EBV) infections?

    <p>Kaposi’s Sarcoma Virus (A)</p> Signup and view all the answers

    What is a characteristic of Gammaherpesviruses regarding their host range?

    <p>They have a very restricted host range. (C)</p> Signup and view all the answers

    Which type of cells do Gammaherpesviruses primarily target in vitro?

    <p>Lymphoblastoid cells (D)</p> Signup and view all the answers

    What kind of infections can EBV cause besides primary infections?

    <p>Persistent infections (D)</p> Signup and view all the answers

    Which condition has been evidenced to be associated with EBV infection?

    <p>Multiple Sclerosis (C)</p> Signup and view all the answers

    What is the process by which substances pass through epithelial cells?

    <p>Transcytosis (D)</p> Signup and view all the answers

    Which of the following describes a characteristic of transcytosis?

    <p>It can be associated with viral infections. (B)</p> Signup and view all the answers

    What happens to substances during transcytosis in epithelial cells?

    <p>They pass through and are transported to the other side of the cell. (B)</p> Signup and view all the answers

    Why is transcytosis not well understood?

    <p>It involves complex cellular mechanisms. (D)</p> Signup and view all the answers

    In which situation can transcytosis occur?

    <p>When specific signals activate the process. (D)</p> Signup and view all the answers

    What happens when cells come into contact with a virus?

    <p>They secrete antibodies. (B)</p> Signup and view all the answers

    What could be a potential consequence of viral infection in epithelial cells?

    <p>Increased cell growth leading to tumors. (B)</p> Signup and view all the answers

    What occurs when naive cells are ready to become more like plasma cells?

    <p>They become reactivated. (D)</p> Signup and view all the answers

    What is a key role of the tonsils in relation to viral infections?

    <p>They may become infected with viruses. (D)</p> Signup and view all the answers

    What do infected cells do in response to a viral presence?

    <p>They produce viruses in larger amounts. (A)</p> Signup and view all the answers

    Which process occurs when stress is applied to the immune system?

    <p>It can lead to reactivation of latent infections. (A)</p> Signup and view all the answers

    What effect do larger amounts of produced viruses have on the body?

    <p>They could increase the risk of cancer. (B)</p> Signup and view all the answers

    What is a potential risk of epithelial cells becoming infected by a virus?

    <p>They could become cancerous. (C)</p> Signup and view all the answers

    What characterizes the acute phase of infectious mononucleosis (IM)?

    <p>Rapid expansion of NK cells and CD8+ T cells (A)</p> Signup and view all the answers

    Which symptom is NOT typically associated with infectious mononucleosis?

    <p>Coughing (D)</p> Signup and view all the answers

    How long can a person remain infectious before symptoms of infectious mononucleosis appear?

    <p>Up to 7 weeks (A)</p> Signup and view all the answers

    What is a common aftereffect of infectious mononucleosis recovery?

    <p>Extreme tiredness (D)</p> Signup and view all the answers

    What type of cells are primarily infected during the acute phase of IM?

    <p>Memory B cells (A)</p> Signup and view all the answers

    Which of the following does NOT indicate a strong inflammatory response?

    <p>Rapid decrease in CD8+ T cells (C)</p> Signup and view all the answers

    What can reactivation of EBV lead to?

    <p>Increased symptoms of IM (C)</p> Signup and view all the answers

    Which type of lymphocyte is primarily responsible for attacking infected B cells?

    <p>CD8+ T cells (D)</p> Signup and view all the answers

    What is a primary factor influencing susceptibility to glandular fever?

    <p>HLA type (A)</p> Signup and view all the answers

    What typically follows the acute phase of infectious mononucleosis?

    <p>Gradual improvement over weeks (B)</p> Signup and view all the answers

    What is a consequence of no viral proteins being produced in cells?

    <p>Antigen presentation is eliminated. (D)</p> Signup and view all the answers

    In the context of immune response, NK cells are distinct from which type of immune cell?

    <p>Memory B cells (A)</p> Signup and view all the answers

    What effect does EBV have on B cells in the body?

    <p>It immortalizes specific B cells. (A)</p> Signup and view all the answers

    Which of the following does NOT occur when B cells are infected by EBV?

    <p>Elimination of B cells (D)</p> Signup and view all the answers

    What happens to antigen presentation when no viral proteins are produced?

    <p>It is completely absent. (D)</p> Signup and view all the answers

    Why are immortalized cells significant in research?

    <p>They can replicate indefinitely. (B)</p> Signup and view all the answers

    Which characteristic differentiates immortalized B cells from normal B cells?

    <p>They exhibit uncontrolled growth. (B)</p> Signup and view all the answers

    During an EBV infection, which of the following immune responses would likely be impaired?

    <p>B cell differentiation (A)</p> Signup and view all the answers

    What is a direct consequence of B cells not presenting antigens?

    <p>Inhibition of T cell activation (C)</p> Signup and view all the answers

    How does the presence of EBV affect non-viral proteins in B cells?

    <p>It competitively inhibits their synthesis. (B)</p> Signup and view all the answers

    Flashcards

    Virus

    A small infectious agent that replicates inside living cells.

    Infected cells

    Cells that have been invaded by a virus.

    Host immune response

    The body's defense mechanisms against the virus.

    Modeling viruses

    Trying to understand how viruses work through study.

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    Laboratory study

    A controlled setting for researching viruses.

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    Gammaherpesviruses host range

    Gammaherpesviruses infect a limited type of host cells, primarily lymphocytes (B or T cells), but also some epithelial or fibroblastic cells in vitro.

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    EBV infection stages

    EBV infection can be primary (initial infection) or persistent (long-lasting).

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    EBV and cancer

    EBV infection is linked to some cancers, and its gene expression during latency may be involved.

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    EBV and multiple sclerosis

    Some scientific evidence suggests a correlation between EBV and multiple sclerosis.

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    KSHV (Kaposi's sarcoma virus)

    A gammaherpesvirus that causes Kaposi's sarcoma.

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    Transcytosis

    A process where substances are transported through a cell, passing through the cell membrane and then out the other side.

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    Epithelial cells

    Cells that form a protective barrier or lining on surfaces of the body, such as the skin or the inside of organs.

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    Periodically activated cells

    Cells that are only turned on or become active at certain intervals, not constantly.

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    How viruses replicate

    Viruses replicate by entering cells and using the cell's machinery to make more copies of themselves.

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    Other viral infections

    There are many different types of viruses that can cause illness.

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    Virus Infection

    When a virus comes into contact with a cell and infects it, the virus can then reproduce inside the cell and potentially spread to other cells.

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    Immune Response

    The body's defense system reacts to a viral infection by producing antibodies to fight the intruder.

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    Viral Reactivation

    A dormant virus can be reactivated and become active again, potentially causing another infection.

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    Cell Transformation

    When infected cells become more like plasma cells, they can potentially lead to cancer by becoming more prone to uncontrolled growth.

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    Mucosal Infection

    Viruses can infect cells in the mucous membranes, such as those in the nose, throat, and intestines.

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    Adenoids/Tonsils Infection

    Viruses can infect the adenoids and tonsils, located in the throat.

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    Viral Replication

    When a virus infects a cell, it replicates its genetic material and produces more virus particles.

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    EBV infected cells

    Cells infected with the Epstein-Barr virus (EBV) that are not killed by the immune system.

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    EBV latency

    A state where EBV remains dormant in the host cells without producing viral proteins, avoiding detection by the immune system.

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    EBV & Glandular Fever

    Certain HLA types make people more susceptible to developing glandular fever (infectious mononucleosis) after EBV infection.

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    EBV's impact on B cells

    EBV can transform B cells, making them immortal and capable of replicating indefinitely.

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    EBV Infection in B Cells

    EBV replicates extensively in B cells, particularly in the peripheral blood and oral cavity.

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    EBV and antigen presentation

    During latency, EBV-infected cells do not display viral antigens, making it difficult for the immune system to recognize and eliminate them.

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    EBV & Memory B Cells

    During acute glandular fever, up to 50% of resting memory B cells can be infected by EBV.

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    EBV and NK cells

    EBV-infected cells can escape detection and destruction by natural killer (NK) cells.

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    Immune Response to EBV

    A strong inflammatory response occurs during EBV infection, characterized by an increase in NK cells and CD8+ T cells, resulting in the appearance of atypical lymphocytes.

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    Memory B cells

    A type of B cells responsible for long-term immunity, they can be infected by EBV but remain different from normal memory B cells.

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    EBV and lab cells

    EBV can immortalize cells in a lab setting, allowing researchers to study its effects.

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    Glandular Fever Symptoms

    Glandular fever symptoms include high fever, severe sore throat, swollen lymph nodes, extreme tiredness, and ongoing tonsillitis. Recovery usually takes 2-3 weeks, but fatigue can persist for months.

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    EBV & Infectious Period

    People infected with EBV can be infectious for up to 7 weeks before symptoms appear.

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    EBV, different RNA molecules

    EBV produces different RNA molecules during its life cycle, indicating distinct stages of its interaction with the host.

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    EBV and viral protein production

    EBV produces viral proteins only during certain stages of its life cycle, not during latency.

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    EBV Reactivation

    EBV infection can reactivate after the initial infection, potentially causing more severe symptoms.

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    EBV's effect on cells in the body

    EBV infects specific types of cells in the body, primarily lymphocytes (B and T cells), and persists in the body.

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    EBV & Episome Replication

    EBV exists as a circular episome within the host cell, which is crucial for its replication.

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    EBV Research Challenges

    Studying EBV infection processes is challenging because of its ability to persist and reactivate.

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    Study Notes

    Herpesviruses II - Gammaherpesviruses

    • Lecture 19, Medical Virology, Level H
    • Professor Andrew Davidson, E46 Biomedical Sciences Building, [email protected]
    • Date: 19/11/24

    Overview

    • Epstein Barr virus (EBV) introduction and impact
    • EBV primary and persistent infection
    • EBV - cancer associations and potential mechanisms involved
    • EBV and multiple sclerosis
    • EBV vaccines
    • Kaposi's sarcoma virus (KSHV)

    Intended Learning Outcomes

    • Describe the uniting features of human Gammaherpesviruses.
    • Describe the epidemiology of EBV and recognize the diseases associated with EBV infection.
    • Understand how EBV causes primary and persistent infections.
    • Understand the EBV gene expression patterns in different stages of latency and their relationship to EBV-induced cancers.
    • Describe the evidence for the association of EBV infection and multiple sclerosis.
    • Describe the epidemiology and diseases caused by KSHV infection.

    Subfamily Gammaherpesvirinae

    • Gammaherpesviruses have a very restricted host range.
    • In vitro, all members infect lymphoblastoid cells and some cause infection in epithelial or fibroblastic cells.
    • Typically target B or T lymphocytes.
    • Four genera: Lymphocryptovirus, Rhadinovirus, Percavirus, and Macavirus.
      • Lymphocryptovirus: mainly infects humans and non-human primates, includes human gammaherpesvirus 4 = Epstein Barr Virus
      • Rhadinovirus: mainly infects human and non-human primates, includes human gammaherpesvirus 8 = Kaposi's Sarcoma Virus
    • dsDNA genome
      • EBV ~ 170 kbp, ~ 100 protein-coding genes, also non-coding RNAs and miRNAs (>46)
      • KSHV ~ 165 kbp, at least 80 protein-coding genes, also non-coding RNAs and miRNAs
    • In both cases, linear dsDNA in particles but found as a closed circular dsDNA in the nucleus of persistently infected cells ("episome")

    Epstein Barr Virus

    • Causes most common persistent asymptomatic virus infection in humans.
    • Ubiquitous, infects 90-95% of the human population as a lifelong persistent infection.
    • Mostly causes benign infections.
    • First human tumor virus to be discovered (1964).
    • Associated with a range of diseases
      • Infectious mononucleosis (glandular fever)
      • Human cancers (200,000/year; 1.8% of all cancer deaths)
      • Multiple sclerosis
    • Primarily found in the body as a latent infection of B cells.
    • dsDNA genome completely sequenced in 1984.

    Epidemiology

    • Transmission by saliva.
    • Globally, most people are infected by the age of 5-8.
    • EBV infection at a young age is typically asymptomatic.
    • In resource-rich environments, EBV infection is frequently delayed until adolescence or early adulthood.
    • Prevalence of infectious mononucleosis depends on the age of initial EBV infection in different countries.
    • In many cases, EBV-associated cancers are most prevalent in specific geographical areas.

    EBV Associated Diseases

    • Typically causes a subclinical persistent infection
    • Primary Infection: Infectious mononucleosis (IM) ("kissing disease", glandular fever), Chronic IM, Fatal IM
    • Fatal lymphoproliferative (B-cell) disorders in various immunosuppressive conditions (e.g., after organ transplant/AIDS): Burkitt’s lymphoma (BL), Hodgkin's and non-Hodgkin's lymphomas, Nasopharyngeal carcinoma (NPC), Gastric carcinomas, Natural killer (NK)/T cell lymphomas, Multiple sclerosis

    EBV: Structure

    • Envelope proteins
    • Outer Tegument
    • Inner Tegument
    • Major capsid protein
    • Triplex
    • Icosahedron
    • Nucleocapsid
    • Portal vertex

    EBV: dsDNA genome

    • Linear form virion
    • Circular form episome

    EBV: Primary and persistent infection

    • (detailed diagrams showing the process)
    • Transmission: Oropharynx → epithelial cells → infected naive B cells → lymphoid tissue→ mucosal lymphoid tissue →dissemination→blood→latency→infection of epithelial (other) cells

    EBV: Infection of primary target cells

    -Attachment protein gp350/220 and glycoproteins gB, gp42, and gH/gL complex are essential for EBV entry into both epithelial and B cells, targeting for neutralizing antibodies.

    Infectious mononucleosis (IM) - Glandular fever

    • As age increases to young adulthood, primary EBV infection more often causes IM.
    • Linked to host genetics.
    • High replication of EBV in B cells in periphery and the oral cavity.
    • Up to 50% of resting memory B cells may be infected in the acute phase of IM.
    • Characterized by a rapid expansion in NK cells and CD8+ T cells.
    • Strong inflammatory response and emergence of atypical lymphocytes.
    • High fever, severe sore throat, swollen glands, extreme tiredness, ongoing tonsillitis.
    • Recovery typically after 2-3 weeks, but extreme tiredness can last for months (infectious for up to 7 weeks before symptoms).

    EBV: Latency

    • In latently infected cells, the genome is maintained as a transcriptionally silent genome.
    • The genome is circularised; if the cell divides, the virus genome is replicated and each daughter cell gets a copy.
    • This is achieved by a virus protein called EBNA1, which binds to the virus genome and interacts with dividing chromatin.
    • EBNA1 is among a group of at least nine EBNA-encoded proteins produced during various stages of latency, but it is the only EBV protein expressed in all types of latency.

    Function of EBV latent proteins

    • (detailed table showing specific genes and their actions)
    • Some gene products promote cell growth, while others inhibit it.

    Function of EBV latent non-coding RNAs

    • BART miRNAs
    • BHRF1 miRNAs
    • EBV-encoded RNA 1 (EBER1) and EBER2

    Patterns of latent cycle gene expression in EBV

    • Latency III
    • Latency II
    • Latency I

    Latency patterns and cancer

    • (table linking types of cancer with latency patterns)

    Burkitt Lymphoma (BL) and EBV

    • Aggressive non-Hodgkin B-cell lymphoma (1-5%)
    • Associated with EBV, HIV, and chromosomal translocations resulting in c-myc oncogene overexpression.
    • Endemic, sporadic, and immunodeficiency types of BL.
    • Endemic BL: coincident with malaria in equatorial Africa, Brazil, New Guinea, etc.
    • Investigation led to the discovery of EBV (Burkitt, Epstein, Barr, Achong)
    • Endemic BL is nearly 100% EBV+.
    • Tumours are at a state of EBV latency.
    • Sporadic BL: 89% EBV+, accounts for 40% of pediatric lymphomas.
    • EBV proteins prevent apoptosis of cells with c-myc overexpression.
    • Treatment: intensive chemotherapy and hospitalization (60-90% long-term survival).
    • EBV was discovered in 1964.

    Burkitt lymphoma (BL) and EBV discovery

    • Epstein had previously worked on Rous Sarcoma Virus, a retrovirus that causes sarcoma in chickens

    Nasopharyngeal carcinoma (NPC)

    • Epithelial cell tumor associated with EBV latency.
    • EBV is almost always present in malignant epithelial cells.
    • Predominantly found in SE Asia and southern China.
    • Major health issue (2018: 129,000 new cases and 73,000 deaths).
    • Co-factors: environment (diet, smoking, etc.), genetic predisposition (HLA type), EBV subtypes.

    Nasopharyngeal carcinoma (NPC) Mechanism

    • Mechanism of cellular transformation is not clear.
    • Infection of epithelial cells in the laboratory does not immortalize cells or give rise to long-term persistent infection.
    • Cells lacking cyclin-dependent kinase inhibitors or overexpressing cyclin D1 can be persistently infected.
    • Therefore, cells may already contain specific mutations before EBV transformation.

    Nasopharyngeal carcinoma (NPC) - additional details

    • EBv genomes in cancer are clonal.
    • EBV infection detected in high-grade pre-invasive lesions in NPC but not in low-grade disease.
    • Suggests that EBV infection must precede clonal selection of cells.

    Association of EBV lytic replication with clinical manifestations

    • (diagram displaying the relationship between EBV lytic replication and different clinical manifestations)

    EBV and Multiple Sclerosis

    • Multiple sclerosis (MS): most common chronic inflammatory and neurodegenerative disease of the central nervous system (2.8 million people worldwide).
    • Cause of MS is complex and multifactorial: genetic susceptibility, environmental factors, lack of sun/vitamin D, smoking, obesity, etc.
    • EBV is a prime candidate and has been studied as a risk factor for MS in many epidemiological studies.
    • Difficult to establish causality – long period between disease initiation and clinical disease expression.
    • 95% of people infected with EBV do not develop MS.

    EBV and MS: Evidence

    • Epidemiological evidence
    • Immunological evidence
    • Virological evidence

    EBV Latest Evidence

    • Epidemiological evidence
    • Mechanism

    EBV Vaccines

    • Aiming to prevent/reduce the severity of infection with EBV.
    • Reduce the incidence of infectious mononucleosis and EBV-associated malignancies and autoimmune diseases.
    • Vaccines in development for 40 years: 36 preclinical and 4 clinical trials.
    • Spurred on by recent findings linking EBV and MS.
    • Vaccine development hindered by undefined correlates of immune protection, lack of an appropriate animal model, lack of knowledge regarding ideal EBV antigens for vaccination, and lack of knowledge regarding ideal vaccine delivery platform.
    • Number of new vaccines in phase I clinical trials (safety/immune response): Moderna mRNA vaccine (targets four glycoprotein antigens), NIH gp350-Ferritin nanoparticle vaccine (targets gp350).

    Kaposi's Sarcoma Virus (KSHV)

    • One of the most recently discovered human tumor viruses (1994).
    • Causative agent of all forms of Kaposi's sarcoma (KS) in combination with impaired host immunity.
    • KSHV can infect several different cell types, including endothelial, B cells, epithelial cells, dendritic cells, monocytes, and fibroblasts.
    • Latency can be established in B cells and endothelial cells.
    • KS tumors are of endothelial lineage—highly aggressive in immunosuppressed/AIDS patients.

    KSHV Epidemiology

    • (detailed information on different forms of KS, clinical presentation, risk factors, and progression)

    KSHV Seroprevalence

    • (map showing global distribution of KSHV seroprevalence)

    KSHV: Diseases

    • Kaposi's sarcoma
    • Primary effusion lymphoma (PEL)
    • Multicentric Castleman disease (MCD)
    • Treatment of KSHV related diseases

    Extra Reading

    • (list of relevant research papers and articles)

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    Herpes Viruses II Gammaherpesviruses PDF

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    Explore the complex world of Gammaherpesviruses in this quiz from Lecture 19 of Medical Virology. Learn about Epstein Barr virus (EBV), its association with various diseases, and the implications of its persistent infections. Delve into the nuances of EBV-related cancers, multiple sclerosis, and the epidemiology of Kaposi's sarcoma virus (KSHV).

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