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Viral Persistence Viral Titer (Log10 scale) Viral persistence in vivo: Some Examples Virus family Example Host(s) Site of persistence Cytocidal in permissive cells Immune response HIGH TITER REPLICAT ION Arenaviridae LCM V Mouse Macroph age NO Restricted Hepadnaviridae HB V Human Hepatocyte NO Restricted LATENT INFECTI ON Herpesviridae HS V Human Sensory neuron YES Brisk Polyomaviridae Papilloma Human Ep idermal cells YES Brisk SMOLDERING INFECTION Picornaviridae TME V Mouse CNS Glial cells YES Normal Paramyxoviridae Measles Human Neurons YES Super normal Lentiviridae HIV Human CD4 lymph ocyte YES Variable Sites of persistence are usually terminally differentiated cells Viral persistence in vivo: Some Examples and Rules RNA and DNA viruses can persist Strategies for persistence can range from “high-titer” replication to “latency” to “smoldering” infections Corresponding strategies for evasion of host immune responses High titer replication: Noncytocidal vs rapid replenishment of target cells Ineffective immune clearance due to tolerance, immune complex formation, viral variation etc. Latency: Viral genome is maintained in non-replicative mode “Hidden” from immune surveillance Smoldering infections: Continuous replication at low levels Effective immune clerance is prevented by antigenic variation, infectious immune complex, transmission via intracellular bridges etc. Cell culture models of viral persistence Characteristics of the carrier culture Nonlytic virus Lytic virus What frac tion of the cells are infected? ~100% <100% Are single cell clones alway s infected? YES NO Must antiviral factors be present in the culture medium to protect the cells? NO YES (1) Can the culture be “cured” by addin g antiviral antibody or interferon? NO YES (1) Does the carr ier culture resist superinfection with the same virus ? YES (1) NO (2) Determinants of viral persistence can be mapped Reovirus: Respiratory Enteric Orphan Virus (dsRNA genome) Reovirus is a lytic virus but can be induced to cause persistent infections in cell culture by co-infecting cultures with a lytic wild type virus (Type 2 wt) and a temperature sensitive variant (Type 3 ts). The virus isolated late after persistent infection is a reassortant carrying the genes of the T2 wt virus except for the S4 and S1 genes of the T3 ts variant virus, and it appears that these two gene segments are responsible for the persistent phenotype S4(s3: major outer capsid protein) and S1(s1 viral attachment protein) from Type 3ts reduce the efficiency of viral entry, thus reducing likelihood of overwhelming lytic infection Predominant gene segments (Type 2wt or Type 3 ts) Gene segments Day 16 Day 230 L1 L2 L3 2 2/3 2 2 2 2 M1 M2 M3 2 2 2 2 2 2 S1 S2 S3 S4 3/2 2 2 3/2 3 2 2 3 Evidence for immune clearance of viral infection: example If immune system can clear virus, what accounts for virus persistence Log10 titer per gm West Nile Virus: IC injection of 10 6.3 suckling mouse LD50 into adult rats No difference in titer in first week, implies difference is due to subsequent immune response (which is abrogated by Cytoxan treatment) Mechanisms of persistence and escape from immune surveillance High titer persistence Not acutely cytocidal or Target cells are replenished at high rate, and Tolerance (absence of virus-specific immunity) Deletion of naive T-cell clones Exhaustion of peripheral virus-specific T-cell clones Absence of specific Ab response E.g. HBV (fig. 6.4), LCMV (fig. 7.4) and HIV Mechanisms of High Titer Persistence: LCMV & Immune tolerance (Fig. 7.4) Mouse infected at high dose---> viral persistence Viremia Exhaustion of LCMV-specific CTL Log10 titer per gm Log10 titer per gm CTL Mechanisms of persistence and escape from immune surveillance High titer persistence Nonlytic viruses Not acutely cytocidal or Target cells are replenished at high rate, and Tolerance (absence of virus-specific immunity) Deletion of naive T-cell clones Exhaustion of peripheral virus-specific T-cell clones Absence of specific Ab response E.g. HBV (fig. 6.4), LCMV (fig. 7.4) and HIV a-LCMV Abs circulate as immune complexes LCMV persistence can be terminated by adoptive transfer of virus specific CTL Similar for HBV ( see fig. 5.11) “Lytic” viruses SIV/HIV Constant replenishment of target cell pool Mechanisms of persistence and escape from immune surveillance Latency (e.g HSV, VZV, EBV, CMV) Virus enters and replicates in permissive cells at portal of entry, after immune induction, virus appears cleared but actually becomes latent in another cell type Genome may be maintained chromosomally (integrated) or episomally If genome is in terminally differentiated cells (e.g. neurons for HSV), no need to replicate genome, but signals required for reactivation (e.g. fever, sunburn, trigeminal nerve insult) Axoplasmic spread towards periphery, conducts virus to skin-->”cold sores” Herpes Simplex Virus Retrograde transport of virions from exposure site to dorsal root ganglion Remains latent Activation results in anterograde transport to epithelial surfaces via peripheral sensory nerves, replication in epithelium results in vesicles Mechanisms of persistence and escape from immune surveillance Latency (e.g HSV, VZV, EBV, CMV) Virus enters and replicates in permissive cells at portal of entry, after immune induction, virus appears cleared but actually becomeslatent in another cell type Genome may be maintained chromosomally (integrated) or episomally If genome is in terminally differentiated cells (e.g. neurons for HSV), no need to replicate genome, but signals required for reactivation (e.g. fever, sunburn, trigeminal nerve insult) Latently infected cells express little if any viral proteins, permitting escape from immune surveillance Mechanisms of persistence and escape from immune surveillance Smoldering Infections Infectious virus is produced, but at minimal levels Virus continues to spread, may produce progressive chronic disease Detectable immune response, sometimes immune response may even be hypernormal (due to chronic viral antigenic challenge) Paradox: why does virus continue to spread in the presence of a potentially effective immune response Mechanisms of persistence and escape from immune surveillance: Smoldering Infections Immunological privileged sites Brain Blood brain barrier limits trafficking of lymphocytes thru the brain Neurons express little or no MHC Class I (resulting in little presentation of viral antigens and ineffective CTL response) Experimental evidence: allogeneic/xenogeneic grafts survive better in the brain than in the skin or other sites Kidney LCMV is cleared more slowly from kidney than any other tissues ??inability of lymphocytes to cross subendothelial basement membrane Mechanisms of persistence and escape from immune surveillance: Smoldering Infections Immunological privileged sites Intracelluar Bridges Cell to cell spread of virus without exposure to immune effector mechanisms (e.g. Abs) Measles in SSPE: neuron to neuron spread in the presence of high titers of neutralizing antibodies About 1:100,000 primary measles infection results in SSPE Virus implicated in SSPE is maturation defective--either mutations in matrix protein or envelope glycoprotein, thus, selects for efficient cell to cell spread Mechanisms of persistence and escape from immune surveillance: Smoldering Infections Immunological privileged sites Intracelluar Bridges Suppression of MHC Class I Expression Virus infected cells rendered less sensitive to CTL attack Adenovirus E1A SIV/HIV nef Viremia Mechanisms of persistence and escape from immune surveillance: Smoldering Infections Immunological privileged sites Intracelluar Bridges Suppression of MHC Class I Expression Infectious Immune Complexes Ab-coated virus remains infectious Ab-virus complex may be internalized by Fc receptors on macrophages-- Ab dissociates from virus in vacuoles, permitting infection of macrophages LCMV, Aleutian Disease Virus can form infectious immune complexes and macrophages are major host cell Treatment of sera From mice persistently infected w ith LCM V LCMV titer (log10 LD50 per 0.02 ml) Anti-mouse immun oglobulin <1.0 Controls Normal rabbit serum Anti-mouse albumin 3.7 3.5 Addition of anti-mouse IgG remove infectivity Virus a-LCMV Y Y Y Ya-mouse IgG Mechanisms of persistence and escape from immune surveillance: Smoldering Infections Immunological privileged sites Intracelluar Bridges Suppression of MHC Class I Expression Infectious Immune Complexes Impaired CTL function E (Effector Cell) CTL MHC Class I T (Target Cell) Ag specific CTL may be deficient in effector molecules HIV specific CTL identified by tetramer staining are deficient in perforin content HIV antigen Y Y Y YY Staining using a-perforin Abs What would be your controls? SAV HIV-specific CTL Mechanisms of persistence and escape from immune surveillance: Smoldering Infections Immunological privileged sites Intracelluar Bridges Suppression of MHC Class I Expression Infectious Immune Complexes Impaired CTL function Antigenic variation Selection for neutralization resistance; allows for viral persistence in the presence of Ab response 11 X 105 pfu/ml Mechanisms of persistence and escape from immune surveillance: Smoldering Infections Immunological privileged sites Virus Intracelluar Bridges isolate (day of Suppression of MHC Class I infection) Expression 0 days Infectious Immune Complexes 20 days 44 days Impaired CTL function 62 days 83 days Antigenic variation 155 days Selection for neutralization resistance; allows for viral persistence in the presence of Ab response In vivo selection for neutralization escape variants Ab escape EIAV Neutralization index (log10) of serum collected on the indicated day after infection Fever spike (day of infection) 21 44 62 83 155 0 days 20 days 44 days 62 days 83 days 155 days 0 0 0 0 0 0 0 0 0 0 0 0 0.7 1.0 0 0 0 0 2.5 1.5 3.5 0 0 0 3.2 1.5 5.4 2.0 0 0 3.2 2.5 >5.4 2.0 3.5 0 --Immune sera neutralizes virus from earlier time points but not concurrent virus or virus thereafter --evidence of antigenic drift, and explains viral persistence even in the face of Ab response Mechanisms of persistence and escape from immune surveillance: Smoldering Infections Immunological privileged sites Intracelluar Bridges Suppression of MHC Class I Expression Infectious Immune Complexes Impaired CTL function Antigenic variation Selection for neutralization resistance; allows for viral persistence in the presence of Ab response In vivo selection for neutralization escape variants Ab escape EIAV LCMV Neutralizing Ab titer Viremia Log10 titer/ml Indicates humoral immunity plays a role in viral clearance Mechanisms of persistence and escape from immune surveillance: Smoldering Infections Immunological privileged sites Intracelluar Bridges Viral Env from Day 16 Suppression of MHC Class I Expression 138 212 Infectious Immune Complexes Impaired CTL function 381 772 Antigenic variation Selection for neutralization resistance; allows for viral persistence in the presence of Ab response In vivo selection for neutralization escape variants Ab escape EIAV LCMV HIV X.Wei. et. al. (2003) Antibody neutralization and escape by HIV. Nature 422:307 Mechanisms of persistence and escape from immune surveillance: Smoldering Infections Immunological privileged sites Intracelluar Bridges Suppression of MHC Class I Expression Infectious Immune Complexes Impaired CTL function Antigenic variation Selection for neutralization resistance; allows for viral persistence in the presence of Ab response In vivo selection for neutralization escape variants Ab escape EIAV LCMV HIV CTL escape HIV, LCMV DNA vaccinated rhesus macaques challenged with pathogenic SHIV 89.6P ? 20 weeks CTL escape via single amino acid change in immunodominant CTL epitope Viral Load CD4 T-cell count p11C Tetramer (Immunodominant) p41A tetramer p68A tetramer weeks Virus family Virus Host Disease ONCOGENIC VIRUSES Retro Mu LV Mice Hematopoietic, lymphoreticular neoplasms Hepadn a HBV Hu mans Hepatocellular Carcinoma Papilloma HPV Hu mans Cervival Carcinoma Herpes EBV Hu mans Burkitt’s lymphoma HIGH TITER PERSISTENCE Diseases associated with persistant viral infections: selected examples Arena LCMV Mice Glomer uloneph ritis, vasculitis Parvo Aleutian disease Mink Glomer uloneph ritis, vasculitis LATENT I NFECTIO NS Herpes HS V CMV EBV VZV Hu mans Hu mans Hu mans Hu mans Cold sores, enceph alitis Pneumonitis, retinitis, encephalitis Mononucleosis Herpes zoster SMOLDERING IN FECTIONS Morbi lli Measles CDV Hu mans Dogs Subacute sclerosing pa nencephalitis Encephalitis, demyelination Retro HTLV I Hu mans Tropical spastic pa rapa resis (HA M) JC Hu mans Progressive multifocal leucoenceph alopa thy VMV EIAV HIV Sheep Horses Hu mans Interstitial pn eumonitis, demyelination Epi sodic hemolytic anemia AIDS Polyoma Lenti