Antiviral immunity Paul Zhou Institut Pasteur of Shanghai Viruses that initiate infection via the skin, eye, or genital tract Site of infection Skin Method of infection Minor breaks/cuts Virus family Hepadnaviridae Herpesviridae Papovaviridae Poxviridae Herpesviridae Rhabdoviridae Bunyaviridae Flaviviridae Reoviridae Togaviridae Flaviviridae Hepadnaviridae Herpesviridae Retroviridae Adenoviridae Picornaviridae Flaviviridae Hepadnaviridae Herpesviridae Papovaviridae Retroviridae Examples Hepatitis B Herpes simplex 1 Papillomavirus Vaccinia Herpes monkey B Rabies Rift Valley fever Yellow fever, Dengue Colorado tick fever Eastern encephalitis Hepatitis C Hepatitis B Cytomegalovirus HIV, HTLV-1 Adenovirus Enterovirus 70 Hepatitis C Hepatitis B Herpes simplex 2 Papillomavirus HIV Animal bite Vector bite Injection Conjunctiva Genital tract Contact Contact Viruses that initiate infection via the respiratory tract Localization of disease Virus family Upper respiratory tract Adenoviridae Picornaviridae Example Adenovirus Rhinoviruses, some enteroviruses Sin Nombre Coronavirus Influenza Parainfluenza, RSV Lower respiratory tract Bunyaviridae Coronaviridae Orthomyxoviridae Paramyxoviridae Generalized systemic disease without initial respiratory symptoms Arenaviridae Lassa fever Bunyaviridae Hantaan virus Herpesviridae Varicella, cytomegalovirus Papovaviridae BK and JC viruses Paramyxoviridae Mumps, measles Poxviridae Smallpox (extinct) Togaviridae Rubella Viruses that initiate infection via the alimentary tract Site of infection Virus family Examples Mouth/oropharynx Herpesviridae Herpes simplex, Epstein-Barr virus, cytomegalovirus Adenovirus 40, 41 Astrovirus Norwalk agent Rotavirus Poliovirus Hepatitis A Intestinal tract Producing enteritis Adenoviridae Astroviridae Caliciviridae Reoviridae Picornaviridae Producing generalized disease usually without enteric illness Usually symptomless Adenoviridae Picornaviridae Reoviridae Some adenoviruses Enterovirus Reovirus Relationship between initial site of viral infection and disease production Site of infection Oropharynx Local Systemic Cytomegalovirus Epstein-Barr virus Herpes simplex 1 Influenza virus RSV Rhinovirus Measles Mumps Rubella Varicella Lassa Norwalk Hepatitis A Polio Hepatitis B Hepatitis C HIV Respiratory tract Intestinal tract Rotavirus Genital tract Papilloma virus Viruses that infect circulating blood cells Cell type Monocytes Virus CMV Dengue Ebola HIV Lassa Measles Rubella Yellow fever EBV HIV Human T-cell leukemia virus I/II Human herpes 6,7 Colorado tick fever B cells T cells Erythroblasts Viral transmission Mode of transmission Aerosol/saliva respiratory or salivary spread Example Influenza virus EBV Measles Mumps Polio Hepatitis A Rotavirus HSV HPV HIV Comment Transmission is difficult to control Fecal-hand-mouth spread Controllable by public health measures Venereal spread Controllable by appropriate precautions Zoonoses Insect to human Animal to human Animal to Insect to human Dengue, Rabies Human infection can be Lassa, Hanta, controlled by controlling Yellow fever vectors (insects) and/or by controlling animal infection Innate immunity against viruses • Cells – immune cells and non-immune cells • Receptors – TRL 3, 7, and 8 and C-type lectin receptors: MMR, DEC205, Langerin, BDCA-2, and DC-SIGN • Cytokines and their mechanisms – Direct and indirect • Regulations – Positive and negative Cytokines with potential to promote innate immunity during viral infections Functions Cytokine IFN-a/b Nonadaptive cell sources Monocytes/macrophages Virus-infected immune and nonimmune cells Monocytes/macrophages NK Cells Other nonimmune cells NK Cells Monocytes, macrophages PMN’s, dendritic cells Monocytes/macrophages Other nonimmune cells Monocytes/macrophages Other nonimmune cells Monocytes/macrophages Other nonimmune cells Monocytes/macrophages Other nonimmune cells Monocytes/macrophages Other nonimmune cells Monocytes/macrophages Other nonimmune cells Antiviral XXX Immunoregulatory XXX TNF XXX XXX IFN-g IL-12 IL-1a, IL-1b IL-6 IGIF IL-15 XXX XX ? ? ? ? XXX XXX XX XX XX XX IL-10 TGF-b ? X XX X Adaptive immunity against viruses Effector system Recognition molecule Antibody Surface glycoproteins or outer capsid proteins Mechanism of viral control Neutralization of virus Opsonization of virus particles Viral glycoproteins expressed on membrane of infected cells CD4 T cells Viral peptides (15 mers) presented by MHC II ACDC and ADC of virus infected cells Downregulation of intracellular viral gene expression Viral peptide derived from any exogenous proteins (surface, internal, or nonstructural) Release of antiviral cytokines (IFN-g, TNF) Activation/recruitment of macrophages. Help for antiviral antibody production Help for CD8 CTL responses Kill viral infected cells Viral peptide which usually are derived from endogenous viral proteins Cross priming for exogenous peptide Killing of virus-infected cells Release of antiviral cytokines (IFN-g, TNF) Activation/recruitment of macrophages CD8 T cells Viral peptides (8 mers) presented by MHC I Humoral response to acute viral infection in humans Example Serum antibody (yr) . Systemic infections Dengue Yellow fever Measles Mumps Polio Hepatitis A Smallpox Vaccinia Rubella Mucosal antibody (mo) 32 75 65 12 40 25 40 15 14 Mucosal infections Coronavirus Influenza virus Respiratory syncytial virus Rotavirus 12 30 3 12 Models of long-term antibody production Mechanism Re-exposure to virus - Persistent viral infection - Immune complexes on follicular dendritic cells - Cross-reactivity to self or environmental antigens - Idiotypic networks Long lived plasma cells Comments Conventional models for maintaining humoral immunity in which short-lived plasma cells are continuously replenished by memory B cells proliferating and differentiating into plasma cells Long-lived plasma cells provide an additional mechanism for maintaining persistent antibody production Effector mechanisms of cell mediated immunity Predictive value of MHC class I allele specific motifs and binding affinity in identifying CD8 T-cell epitopes during viral infection _________________________________________________________________ Class I # of Class I Total # of motif-fitting peptides (IC50) in LCMV glycoprotein allele binders and nucleoprotein _________________________________________________________________ High Intermediate Low # of CTL epitopes during LCMV infection (% of total motif-fitting peptides) Db 26 2 (2) 3 (2) 3 (0) 4 (15) Kb 28 2 (0) 4 (2) 6 (0) 2 (7) Dd 18 0 0 3 (0) 0 (0) Kd 16 1 (0) 4 (2) 2 (0) 2 (12) _______________________________________________________________ Total 88 5 (2) 11 (6) 14 (0) 8 (9) Viruses that persist in humans Virus group DNA viruses Adenovirus CMV Site of persistence Consequences Adenoids, tonsils, lymphocytes None known Kidneys, salivary glands, Pneumonia, retinitis lymphocytes?, macrophages, stromal cells EBV Pharyngeal epithelial cells, B cells Infectious mononucleosis, Burkitt’s lymphoma, nonpharyngeal carcinoma, non-Hodgkin’s lymphoma, oral hairy leukoplakia HSV 1 and 2 Sensory ganglia neurons Cold sores, genital herpes, encephalitis, keratosis HSV 6 Lymphocytes Exantem subiturn HSV 8 PBMC, Endothelial spindle cells Kaposi sarcoma VZV Sensory ganglia neurons and/or Varicella zoster satellite cells Hepatitis B virus Hepatocytes Hepatitis, hepatocellular carcinoma Hepatitis D virus Hepatocytes Exacerbation of chronic HBV infection Virus group Site of persistence Consequences Papillomavirus Parvovirus B19 Epithelial skin cells Erythroid progenitor cells in BM Polyomavirus BK Kidney Polyomavirus JC Kidney, oligodendrocytes in CNS RNA viruses Hepatitis C virus Hepatocytes Measles virusa Neurons and others in CNS Papilloma, carcinomas Aplastic crisis in hemolytic anemia, chronic BM deficiency Hemorrhagic cystitis Progressive multifocal leukoencephalopathy Hepatitis, hepatocellular carcinomas Subacute sclerosing panencephalitis, measles -inclusion body encephalitis Progressive rubella panencephalitis, IDDM? juvenile arthritis? AIDS T-cell leukemia, tropical spastic paraparesis, polymyositis None known Rubella virusa CNS HIV HTLV-I CD4 T cells, monocytes/ macrophages, microglia T cells HTLV-II T cells Mechanisms Restricted gene expression; virus remains latent in the cell with minimal to no expression Infection of sites not readily accessible to immune system Example EBV in B cells, HIV in resting T cells HSV and VZV in latently infected neurons, HSV, VZV, measles, and rubella in CNS CMV, polyomaviruses BK and JC in the kidney EBV and CMV in the salivary gland Papillomaviruses in the epidermis CMV protein UL18 is a MHC class I homologue that inhibits NK activity. Antibody escape variants in SIV/HIV CTL escape variants in HIV, EBV, and HBVT-cell receptor antagonism by HIV and HBV variants Suppression of MHC class I molecules by adenoviruses, CMV, HSV, and HIV Decreased expression of cell adhesion molecules LFA-3 and ICAM-1 by EBV Suppression of MHC class II molecules by CMV, HIV, and measles Inhibition of NK function Antigenic variation; virus rapidly evolves and mutates antigenic sites that are critical for recognition by antibody and T cells Suppression of cell surface molecules required for T-cell recognition Interference with antigen processing and presentation HSV ICP47 protein and CMV U6 protein interfere with TAP to inhibit MHC class I antigen presentation. EBV protein EBNA-1 contains gly-ala repeats that confer resistance to proteasome mediated degradation and subsequent MHC class I presentation. CMV protein pp65 phosphorylates the CMV immediate–early protein and inhibits its processing and/or presentation Adenovirus proteins E3 and E1B protect infected cells from lysis by TNF Adenovirus VA RNA, EBV EBER RNA, and HIV TAR RNA inhibit function of interferon. EBV protein BCRF1 (a homologue of IL10) blocks synthesis of cytokines such as IL-2 and interferon gamma. Clonal deletion–anergy of virus-specific CTLs in HBV carriers, HIV(?) SSPE caused by measles Viral defense molecules that interfere with the function of antiviral cytokines and chemokines Immunologic tolerance Cell-to-cell spread by snycytia Immunopathology of viral infection • Virus-induced immune complex disease Virus-antibody complex formation in fluid can be cleared through opsonization of Fc and/or complement receptors on macrophages or activated lymphocytes Or deposited onto renal glomeruli, arteries, and choroid plexus leading to glomerulonephritis, arteritis, and choroiditis Diagnosis of virus-induced immune complex disease is based on identification of presence of immune complex) viral antigen, host Ig, and complement in the pathological sites • Virus-induced autoimmune disease Evidences: 1. Human autoimmune responses are made de novo in or are enhanced during, infection by a wide variety of DNA and RNA viruses 2. In experimental animal models, both acute and persistent virus infections can induce, accelerate or enhance autoimmune disease in high-responder mice 3. Investigation of molecular mimicry indicates that a number of etiologic agents may cause autoimmune disease Mechanisms: 1. through a mitogenic effect on lymphocyte subsets 2. through infect lymphocytes and macrophages to cause cytokine and chemokine release, which in turn modulates immune responses Molecular mimicry and epitope spread Two models Acutely cytopathic viruses - Excessive damage of infected tissues - Require a rapid control for host to survive - e.g. neurotropic poliovirus, rabies virus, smallpox virus in human and VSV in mouse Poorly or non-cytopathic viruses - Do not directly induce cellular damage - Immunopathology - HBV, HCV, possibly HIV in human and LCMV in mouse Factors influencing antigenicity and immunogenicity of the native viral surface • Accessibility to antibodies (numbers of antigenic sites, density of molecules, oligomerization, glycosylation • Structural arrangement of accessible site • Frequency of germline-encoded immunoglubulin VH and VL combinations with specificity for epitopes in the accessible sites Summary • Understanding anti-viral immunity is a key for efficient vaccine development • Virus and host immune system are co-evolved (or co-adapted) in both population and individual levels (immune control and viral evasion is a constant battle) • Immune responses to viral infection is also a double edge sword (immune control versus immunopathology) • The interaction between host immune system and individual viruses varies greatly. So far no single mechanism or a set of mechanisms can count for all viruses. Therefore, the devil is in detail!