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Persistent Infec,ons Lecture 17 Biology W3310/4310 Virology Spring 2015 Paralyze resistance with persistence –WOODY HAYES Acute vs persistent infec,ons • • • • Acute infecDon -‐ rapid and self-‐limiDng Persistent infecDon -‐ long term, life of host Stable, characterisDc for each virus family Most persistent infecDons probably begin as an acute infecDon General pa5erns of infec,on Principles of Virology, ASM Press Persistent infec,ons • Occur when primary infecDon is not cleared by immune response • • Virions, protein, genomes conDnue to be produced Viral genomes may remain aQer proteins are not detected Persistent infec,ons • • No single mechanism • Viral immune modulaDon When cytopathic effects are absent and host defenses are reduced, persistent infecDon is likely Persistent human infec,ons ** * * * ** * * Principles of Virology, ASM Press The cytotoxic T lymphocyte response Principles of Virology, ASM Press Modula,on of MHC I proteins Principles of Virology, ASM Press CTL escape mutants • • Herpes simplex virus HepaDDs C virus Changes may also affect proteasomal processing Fields Virology, Wolters Kluwer Principles of Virology, ASM Press Killing ac,vated T cells • When CTL engages an infected cell, the CTL may die instead of the target • An example of viral defense HIV, CMV induce FasL on cell surface Principles of Virology, ASM Press Reduced immune surveillance • • Cells and organs differ in degrees of immune defense • Could be damaged by fluid accumulaDon, swelling, and ionic imbalances of inflammaDon • Persistent infecDons of these Dssues are common CNS, vitreous humor of eye, areas of lymphoid drainage devoid of iniDators and effectors of immune response (eye, high FasL) Infec,on of immune cells • • Many viruses infect cells of the immune system HIV infecDon of CD4 T cells, monocytes, macrophages, dendriDc cells Go to: m.socraDve.com room number: virus Which of the following are features of persistent infec,ons? 1. 2. 3. 4. 5. They last the lifeDme of the host Viral immune modulaDon is involved Immune cells may be infected They may occur in areas of reduced immune surveillance All of the above 1 Measles virus • • • • • • Paramyxoviridae No known animal reservoir One of most contagious human viruses 158,000 deaths globally in 2011 -‐ preventable Lifelong immunity aQer infecDon Causes systemic immunosuppression Principles of Virology, ASM Press SSPE • Subacute sclerosing panencephaliDs, a progressive, degeneraDve encephaliDs • • • AQer measles, 1/million contract SSPE • Genomes spread between synapDcally connected neurons 6-‐8 yr incubaDon Viral nucleoprotein parDcles detected in brain, but no infecDons virus produced Principles of Virology, ASM Press Polyomavirus * * * * * Fields Virology, Wolters Kluwer Polyomavirus persistence • • • • • • Infected for life Variety of organs -‐ kidney, intesDne, respiratory tract 100,000 parDcles/ml in urine Unknown mechanisms of persistence Progressive MulDfocal Leukoencephalopathy (PML) TWiV #250 -‐ Wookie viruses twiv.tv/2013/09/15/ twiv-‐250-‐wookie-‐viruses/ Hepa,,s B virus • Transmiged by exposure to blood (childbirth, transfusion, sex, drug use, nosocomial) • • Main target is hepatocyte 95% of adults, 5-‐10% newborns resolve acute infecDon Hepa,,s B virus • • ~350 million worldwide have chronic HBV Hepatocellular carcinoma Fields Virology, Wolters Kluwer Chronic HBV • • • Virus is not cytopathic for hepatocytes • HCC develops aQer 20-‐30 yr of chronic (oQen asymptomaDc) infecDon CTL kill infected hepatocytes During chronic infecDon, fibrosis leads to cirrhosis, liver failure Hepa,,s C virus • • + strand RNA virus, Flaviviridae • 2.2% of human populaDon (185 million) infected Transmiged by exposure to contaminated blood (sex, drug use, during birth) HCV • Acute infecDon: usually asymptomaDc or typical signs of hepaDDs • Chronic infecDon: high level viremia Fields Virology, Wolters Kluwer HCV • • HCV clearance associated with IFN-‐λ3 alleles (GWAS) MulDple immune modulaDon mechanisms Fields Virology, Wolters Kluwer Go to: m.socraDve.com room number: virus Which are shared features of persistent infec,ons with polyomavirus, HBV, and HCV? 1. 2. 3. 4. 5. Genomes are present but not expressed Liver damage Kidney damage Virus parDcles are produced All of the above 2 Latent infec,ons -‐ general proper,es • Viral gene products that promote producDve replicaDon are not made or found in low concentraDons • Cells harboring the latent viral genome are poorly recognized by the immune system • Viral genome persists intact so that producDve infecDon can be iniDated to spread infec9on to new hosts State of the genome • Non-‐replicaDng DNA in a non-‐dividing cell -‐ • Autonomous self-‐replicaDng DNA in dividing cell -‐ • HSV, VZV in neurons EBV, CMV, HPV, HBV, KSHV Integrated into host chromosome, replicates with host -‐ HHV6 Herpes simplex virus infec,ons • • US >80% seroposiDve with genomes in PNS • • • 40 million experience recurrent herpes disease Millions carry latent viral genomes in nervous system without symptoms HSV-‐1, HSV-‐2 A well-‐adapted pathogen Principles of Virology, ASM Press HSV primary infec,on of ganglia 80% of babies infected at birth Sensory and sympatheDc ganglia can be infected Principles of Virology, ASM Press Post-‐infec,on events in neurons • • • Viral genome silenced, coated with nucleosomes • Herpes is forever -‐ drugs and vaccines cannot cure a latent infecDon MulDple copies of episomal viral DNA remain in nucleus No further replicaDon needed to persist -‐ neurons do not divide Fields Virology, Wolters Kluwer Latency associated transcript • • • • Only LATs, miRNAs made in latently infected neurons No proteins translated from LATs RNA silencing to maintain viral genome in latent state Host contribuDon Fields Virology, Wolters Kluwer Reac,va,on • Small number of neurons in ganglion reacDvate • Virions appear in mucosal Dssue innervated by latently infected ganglia, blisters ensue (not always) • This is how infecDon is transmiged (inDmate contact) • Immune response is too slow (viral antagonism) to prevent shedding • Some reacDvate every 2-‐3 weeks; others never Fields Virology, Wolters Kluwer http://www.eyecalcs.com/DWAN/pages/v8/ch089/004f.html Triggers of reac,va,on • Sunburn (UV), physical or emoDonal stress, nerve damage, hormonal imbalance, steroids • SDmulate producDon of viral proteins needed to acDvate viral transcripDon program • Immediate early proteins: ICP0 can reacDvate Principles of Virology, ASM Press Go to: m.socraDve.com room number: virus Persistence of herpes simplex virus in nerve ganglia requires which of the following? 1. 2. 3. 4. 5. ConDnuous episomal DNA replicaDon Low level producDon of virions Silencing of all gene expression except LAT and miRNA UV light, stress, or steroids All of the above 3 Epstein-‐Barr virus • • • • 95% of US adults are seroposiDve and carry genome Genome resides in B lymphocytes Most are infected at an early age, are asymptomaDc Causal agent of: -‐ -‐ InfecDous mononucleosis Human cancers (Hodgkins lymphoma, nasopharyngeal carcinoma, Burkig’s lymphoma) Principles of Virology, ASM Press EBV primary and latent infec,on Lymphoid tissue and peripheral blood InfecDous mononucleosis B cells are essenDal for EBV latency Principles of Virology, ASM Press EBV latency • Viral DNA is self-‐replicaDng episome, associates with nucleosomes in B cells • • • Produces limited repertoire of viral genes B cells home to bone marrow and lymphoid organs Not killed by CTLs or anDbody unless reacDvaDon occurs (modulaDon of MHC) When B cells divide • Episomal viral genome must replicate to be distributed to daughter cells • • • EBV DNA has two origins of replicaDon Ori Lyt is used for lyDc replicaDon: high copy # Ori P is used for episomal replicaDon in latently infected cells: low copy # Varicella-‐zoster virus (VZV) Fields Virology, Wolters Kluwer Principles of Virology, ASM Press VZV • 99% adults infected pre-‐vaccine, 30% develop zoster, 2/3 >50 years of age • Latency: Episomal viral DNA, 2-‐9 genomes in 1-‐7% of neurons (non-‐replicaDng) • • Viral gene expression is restricted, IE, E, L genes Factors that trigger reacDvaDon from neurons are unknown Cytomegalovirus (HCMV) • • High seroprevalence (50-‐99%) globally • Replicates in peripheral blood leukocytes, endothelial cells Transmiged by respiratory routes (virus in saliva), urine, sex Fields Virology, Wolters Kluwer HCMV • Persistent shedding of virus in saliva and urine for months to years • Resolved by cellular immune response, but latently infected myeloid cells remain in bone marrow (precursors of monocytes, macrophages, dendriDc cells) • • Risk of transmission during organ transplantaDon Virus crosses placenta, can cause congenital defects, death Go to: m.socraDve.com room number: virus What do persistent infec,ons with EBV, VZV, and CMV have in common? 1. 2. 3. 4. 5. B cells are essenDal for latent infecDon May cause congenital birth defects Viral DNA persists as an episome The factors governing reacDvaDon are well known All of the above 4 HHV-‐6, HHV-‐7 • • • Agents of exanthem subitum, mild childhood rash (sixth disease) • • Infect lymphoid, endothelial, liver, CNS, salivary cells >85% of adults have anDbody to both viruses Horizontal infecDon through respiratory secreDons, parent to child Latency: HHV-‐6 monocytes, macrophages, CD34+ progenitors; HHV-‐7 CD4+ lymphocytes Principles of Virology, ASM Press HHV-‐6 integra,on • • • In some cell types viral DNA integrates into telomeres About 1% of transmission acquires HHV-‐6 via germline Plausible strategy for latency and transmission Fields Virology, Wolters Kluwer