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Virus-Host Interactions Allan Zajac, Ph.D Lab: 446 BBRB Telephone: 5-5644 email: [email protected] Text: Medical Microbiology 4th edition Pathogenesis Chapter 46 Antivirals Chapter 47 Viruses and Disease Chapter 65 Immunity to Infections Chapter 14 Vaccines Chapter 15 Virus Pathogenesis Patterns of Infections Outcomes of Infections Virus-Host Interactions Antiviral Immunity Strategies for Evading the Immune Response Control of Viral Infections Vaccines Antiviral Drugs • Multiple viruses can cause the same symptoms – Hepatitis – Common Cold • The same virus can cause multiple diseases – HSV – EBV CELL RESPONSE HOST RESPONSE Lysis of Cell Death of Organism Inclusion Body Formation/ Cell Transformation/ Cell Dysfunction Classical and Severe Disease Moderate Severity Mild Illness Viral Multiplication Without Visible Change or Incomplete Viral Maturation Infection Without Clinical Illness (Asymptomatic Infection) Exposure Without Attachment and/or Cell Entry Exposure Without Infection THE ICEBURG CONCEPT VIRUSES ARE OBLIGATE INTRACELLULAR PARASITES; THEY NEED TO INFECT PERMISSIVE HOST CELLS Routes of viral transmission Mode of Transmission Example Method of Control? Aerosol/Saliva..... Respiratory of salivary spread Influenza Virus EBV Measles Mumps Transmission difficult to control Fecal-Oral Polio Rotavirus Hepatitis A Controllable by public health measures Venereal spread HSV HIV HPV Controllable by appropriate precautions Zoonoses Insect-Human Animal-Human Animal-Insect-Human Dengue Rabies Lassa Hantavirus Yellow fever Human infection can be controlled by controlling vectors (insects) and/or by controlling animal infection. No (or rare) human to human transmission Mousepox/ Polio/ Measles Overhead ACUTE Rhinovirus Influenza Yellow Fever LATENT PERSISTENT Herpes simplex Varicella-zoster Measles-SSPE CHRONIC PERSISTENT Hepatitis B LCMV in Newborn Mice Latent infection slide show Examples of latent infection followed by periodic reactivation Example Mechanism of establishment Maintenance Stimulatory mechanism for reactivation Herpes simplex virus in sensory ganglion neurons Limited transcription and possibly replication of genome Non-replicating episome Neuronal activation or damage Epstein-Barr virus in B lymphocytes Limited transcription of viral genome Replication of viral DNA as episome Antigen activation or other stimuli of B cells Papillomavirus in basal cells of epidermis Limited transcription of viral genome Replication of viral DNA as episome Differentiation of basal cells IMMUNE RESPONSES TO VIRAL INFECTIONS Medical Microbiology pg 131-135 Innate Response……..the first line of defence Interferons Activated Macrophages Natural Killer Cells Adaptive Response…….specifically targets the infection B cells/ Antibodies CD8 T cells/ Cytotoxicity and Cytokines CD4 T cells/ Cytokines (and cytotoxicity) Neutralizing Antibodies Bind to the Influenza Virus Hemagglutinin and Block Viral Attachment Rhinovirus 14 complexed with neutralizing antibodies (blue), as solved by cryo-electron microscopy and image reconstruction courtesy of Tim Baker. Purdue University FIGURE 1: (TOP) Cryoelectron micrograph (gray) and computer enhanced image (in color) of spherical human rhinovirus 14 particles (yellow &orange) saturated with a neutralizing monoclonal antibody (blue) (mAb17 IgG2a, directed against the NIM-IA site). The particle is assembled from 12 pentameric subunits. The Fc portion of the IgG is not visible, apparently because it is too mobile to produce reinforcement in the enhancement stage. This is the first direct evidence in support of the pentamer bridging hypothesis proposed by Mosser et al. in 1989 (A morph animation illustrates corresponding density in a previous, inconclusive 3D cryoelectron microscopy dataset). Pentamer bridging by an antibody molecule is illustrated by an animated model. (BOTTOM) Each bivalent IgG molecule (red, heavy chains, purple,light chains) bridges two canyons on adjacent pentamers (yellow) of the virus shell. (The hypothesized correspondance of the IgG model to the 3D cryoelectron microscopy image reconstruction is shown by a morph animation.) Binding of IgG molecules inhibits attachment by preventing insertion of cellular receptor into the canyon. Mobility of the Fc region is indicated by blurring in the region farthest from the virus surface. Adaptive/Virus-Specific Immune Responses Effector CD8+ T cell Effector CD4+ T cell Y Non-Lytic Infection Lytic Infection Detrimental Effects of Virus-Specific Immune Responses • Immune Complex Disease • Immunopathology • Antibody Dependent Enhancement of Infection Viral strategies for evading the immune system (Text Table 14-4) •Restricted gene expression; latency •Infection of sites not readily accessible to the immune system •Antigenic variation •Downregulation of surface molecules required for T cell recognition •Interference with antiviral cytokines •Immunological tolerance Viral strategies for evading the immune system Antigenic variation Antibody escape variants (lentivirus) CTL escape variants (HIV, EBV, HBV) TCR antagonism (HIV, HBV) Influenza: A segmented negative sense RNA virus that undergoes antigenic DRIFTS and SHIFTS Two mechanisms generate variations in influenza surface antigens. Antigenic Drift: The accumulation of point mutations enventually yields a variant protein that is no longer recognized by antibody to the original antigen Antigenic Shift: May occur by reassortment of an entire ssRNA between human and animal virions infecting the same cell (only four of the eight RNA segments are illustrated) Viral strategies for evading the immune system Restricted gene expression; latency HSV and VZV (neurons) EBV (B cells) HIV (resting T cells) Infection of sites not readily accessible to the immune system HSV, VZV, measles, rubella (CNS) papillomavirus (epidermis) CMV (salivary gland) Viral strategies for evading the immune system Downregulation of surface molecules required for T cell recognition MHC class I (Adenovirus, CMV, HSV, HIV) MHC class II (CMV, HIV, measles) LFA-3, ICAM-1 (EBV); CMV protein removes class I from ER Proteasome Degraded Viral strategies for evading the immune system Interference with antiviral cytokines Adenovirus (TNF) Adenovirus, EBV, HIV (Type I IFN) EBV vIL-10 (blocks synthesis of IL-2 and IL-10) Poxviruses (encode gene products that inhibit action of many cytokines) Immunological tolerance Exhaustion or clonal deletion/anergy of virus-specific CTL during chronic virus infection (e.g. HBV) Viral strategies for evading the immune system Restricted gene expression; latency Infection of sites not readily accessible to the immune system Antigenic variation Downregulation of surface molecules required for T cell recognition Interference with antiviral cytokines Immunological tolerance HSV and VZV (neurons); EBV (B cells); HIV (resting T cells) HSV, VZV, measles, rubella (CNS); papillomavirus (epidermis); CMV (salivary gland) Antibody escape variants (lentivirus); CTL escape variants (HIV, EBV, HBV); TCR antagonism (HIV, HBV) MHC class I (Adeno, CMV, HSV, HIV); MHC class II (CMV, HIV, measles); LFA-3, ICAM-1 (EBV); Adenovirus (TNF); Adenovirus, EBV, HIV (Type I IFN); EBV vIL-10 (blocks synthesis of IL-2 and IL-10); Poxviruses (inhibit action of many cytokines) Clonal deletion/anergy of virus-specific CTL during chronic infection (e.g. HBV) Controlling Viral Infections • Public Health Measures -Sanitation -Vector Control -Behavioral Changes • Vaccines • Antiviral Drugs Vaccines • How can we prevent infectious diseases? • The goal of vaccination is to induce a long lived immune response that prevents disease • Requires adaptive/antigen-specific responses • Long lived immunological memory • Accelerated recall responses that rapidly control the infection Passive immunity involves the transfer of preformed antibodies Active immunity gives rise to long-term protection Naturally acquired vs. artificial immunity LIVE VIRAL VACCINES Are attenuated forms of the parental (virulent) virus. Infection with the attenuated (vaccine) strain does not cause disease but induces protective immunity. Therefore, the vaccinee is is immunologically protected if exposed to the virulent virus. POTENTIAL PROBLEMS WITH LIVE VIRAL VACCINES: • Risk of reversion to virulence • Storage and transportation • Unrecognized agents may contaminate cultures INACTIVATED or “KILLED” VIRUS VACCINES • Examples: • • • • Inactivated poliovirus vaccine Influenza virus vaccine Hepatitis A vaccine Rabies vaccine • Efficacy Issues: • Must ensure complete inactivation • Multiple vaccinations (boosters) may be necessary • Non-replicating agents may be less effective at eliciting immune responses SUCESSFUL VACCINATIONS: SMALLPOX ERADICATION • Virology and disease aspects – – – – No secondary hosts; only infects humans No persistent infection Subclinical infections are not spread Easily diagnosed • Immunology – Infection confers long term immunity – One stable serotype – Vaccine is cheap and stable • Social and political aspects – Severe disease with high morbidity and mortality – Eradication from developed countries demonstrated feasibility – Political willingness VACCINOLOGY • • • • Subunit Vaccines Viral Vectors DNA Vaccines Peptide Vaccines ANTIVIRAL CHEMOTHERAPY Viruses are obligate intracellular parasites. Therefore antiviral drugs must specifically target viral functions without inhibiting essential host cell processes Viral Life Cycle Slide Possible Targets for Antiviral Chemotherapy TARGET PROTOTYPE DRUG Receptor analogs/WINs Amantadine RNA-dependent RNA polymerase inhibitors AZT (zidovudine) HIV Tat inhibitors Ribavirin Interferons Protease inhibitors Attachment Uncoating Primary viral RNA synthesis in RNA viruses Reverse Transcription Regulation of RNA synthesis Processing of RNA transcripts Translation of viral mRNA Protease processing/maturation Replication of DNA viruses Replication of RNA viruses Acyclovir RNA-dependent RNA polymerase inhibitors Key Points I: • Viruses are obligate intracellular parasites – There are numerous methods and routes of transmission – They infect permissive host cells – This is defines their TROPISUM • Local vs. Systemic infections – Primary vs. Secondary Viremia • Outcomes/ Types of Infection – Acute/ latent/ chronic/ transforming Key Points II: • Immune Responses to Viruses – Innate (Interferon a/b; Macrophages; NK cells) – Adaptive (B cells/ Abs; T cells/ CD4/CD8) – Detrimental effects? • Viral Strategies for Evading the Immune Response – – – – – – “Hide” from the immune response Downregulate gene expression Antigenic variation (DRIFTS and SHIFTS) Downregulation of cell surface molecules (MHC class I) Cytokine analogues/ interference Tolerance Key Points III • Infection Control • PUBLIC HEALTH • VACCINES – Live- attenuated – Inactivated- killed – Advantages/ disadvantages • ANTIVIRAL CHEMOTHERAPY – Target a virus-specific process – Avoid cellular toxicity