Mechanisms of Viral Persistence Flashcards
Persistent Viral Infection
- Chronic
- Latent
3 conditions for viral persistence:
✷ The virus must be able to infect host cells without being cytopathic
✷ There must be mechanisms for long-term maintenance of the viral genome in the host cells
✷ The virus has to avoid detection and elimination by the host’s immune response (antigenic variation)
Restriction of Viral Cytolytic Effect
✷ Most arenaviruses replicate in animal host without any cytopathic effect
✷ HBV infects hepatocytes with little or no injury
✷ HIV is more lytic for T-cells and less cytopathic for monocytes/macrophages
✷ Infection of non-permissive Cells
- Sensory neurons - HSV
- B lymphocytes - EBV
✷ Evolution of Viral Variants
Mechanisms of Viral Genome Maintenance
✷ Genome integration (HIV)
✷ Genomes of EBV and some papillomaviruses are maintained as episomal circular molecules
✷ HSV as extrachromosomal (episomes) DNA
✷ Mechanisms for RNA viruses not understood
- Low level of replication
- Folding of RNA to provide stability
Avoid Elimination by Host Response
✷ Evasion of Host Immunity
✷ Viral Evasion Strategies
✷ Antigenic Variation
✷ Interference with the host immune system
Host Immunity
✷ Antiviral immunity
✷ Antibodies and T cells
✷ T cells see viral antigens with MHC I and II
✷ All viral proteins can be potential targets for T-cell recognition
✷ The primary mechanism employed by CD8+ T cells is killing of virus infected cells
✷ CD4+ T-cells contribute to antiviral immunity by producing antiviral cytokines
How does a virus evade host immunity?
✷ Restricted Expression of viral genes
✷ reduces lytic potential, escape host immunity
✷ Infection of Immunological Privileged Sites
✷ not readily accessible to the immune system ✷ CNS favored by viruses
✷ Two factors favor viral persistence in CNS
- Blood brain barrier - limits lymphocyte trafficking
- Neurons do not express MHC I or MHC II, no direct recognition by T cells
✷ Viruses can persist in kidney e.g. BK, JC, CMV
• T cells can infiltrate the kidney, but limited access to infected epithelial cells
Antigenic Variation
✷ Emergence of viral variants
- RNA viruses undergo mutation at high frequencies
- This can result in evasion of both T and B cell immunity
- Viral escape from antibody recognition
- Viral escape from T-cell recognition
- CTL escape mutants occur in HIV, EBV, and HBV
Interfernece with the Immune System
✷ Suppression of cell surface molecules required for T-cell recognition
• down regulation of several host molecules that are necessary for T-cell recognition of virus infected cells
✷ MHC I and II
- Adenovirus downregulates MHC I
- CMV, HIV, and measles have been shown to interfere with MHC II expression
✷ Interference with cytokine function
Persistent Viral Infection of CNS
✷ Persistent viral infections of CNS are slow viral diseases due to protracted period between infection and the prolonged course of the illness.
✷ Involve well differentiated cells, such as lymphocytes and neuronal cells.
Persistent Viral Infection of CNS Conventional Viral Agents
- Viruses possess nucleic acid genome and protein capsid
- Induce immune responses
- Replicate in cell culture system
Persistent Viral Infection of CNS Conventional Viral Agents - SSPE
Subacute Sclerosing Panencephalitis (SSPE)
- Rare chronic measles virus infection in children produces progressive neurologic disease
- Usually appears 2 to 10 years after measles virus infection
- Characterized by an insidious onset of personality change
- Caused by measles virus
- Progressive intellectual deterioration
- Dysfunctions of motor and autonomic neuron system
Persistent Viral Infection of CNS Conventional Viral Agents - Progressive Postrubella Panencephalitis
- Rare degenerative neurologic disorder similar to measles
- May be related to persistent rubella virus infection of CNS
- Seen most often in adolescents with congenital rubella syndrome
- Rubella virus isolated from brain tissue of the patients.
Persistent Viral Infection of CNS Conventional Viral Agents - PML
- Caused by JC virus
- Subacute degenerative disease of the brain
- Primarily in adults with other chronic diseases
- Cerebrospinal fluid (CSF) findings are normal
- Slight increase in lymphocytes
- Protein levels elevated
- Characterized by the development of impaired memory, confusion and disorientation.
- Followed by a multiplicity of neurologic symptoms
- Death could occur 3 to 6 months after onset of symptoms
- Incidence is on rise because of AIDS epidemic
Diagnosis:
- JCV particles can be seen by electron microscope
- JCV DNA sequences have been detected by PCR.
Treatment:
- No specific treatment for PML
- Reducing the immunosuppression may have some clinical benefit
Persistent Viral Infection of CNS Conventional Viral Agents - Persistent Enterovirus Infection
- •Persons with congenital or severe acquired immunodeficiency especially with agammaglobulinemia
- Chronic CNS infection due to echovirus or enterovirus
- Headache, confusion, lethargy, seizures and CSF pleocytosis are common manifestations.
- Virus can be isolated from CSF, Clinical improvement by administration of human hyperimmune globulin to the infecting virus type.
- Relapse occurs if therapy is discontinued.
- Mainly Picornaviruses
Persistent Viral Infection of CNS Conventional Viral Agents - AIDS Dementia Complex
- HIV causes a persistent infection of the CNS in many patients with symptomatic AIDS known as AIDS dementia complex (ADC) or HIV-associated dementia (HAD).
- The virus does not directly infect the nerve cells, but the virus produced by perivascular macrophages and/or microglia may produce a bystander effect causing inflammation that may damage brain and spinal cord.
- The clinical course may vary from a mild subacute illness (early stage of HIV infection) to severe progressive dementia (late stages of HIV infection).
- HAD primarily occurs with more advanced HIV infection and symptoms include encephalitis, behavioral changes and a gradual decline in cognitive function.
- HAD is more common is HIV infected infants than infected adults. •AIDS, reticuloendothelial malignancies, and those on immunosuppressive drugs
Persistent Viral Infection of CNS Unconventional
Agents - Prions
- Prions are small proteinaceous infectious particles
- Small with diameters of 5-100nm
- Produce characteristics infections and remain viable in formalinized brain tissues for many years •Resistant to ionizing radiation, boiling, autoclaving, and many common disinfectants
- Protein molecules without genes
- Responsible for some neurologic disorders •PrP gene found on chromosome 20
- PrP gene is expressed as PrPc and post-translational conformational change makes it PrPsc (prion)
- Conformational change is also the way in which prions number increase
- Contact with PrPsc with PrPc results in a conformational change of the normal prion (PrPc ) and the formation of additional abnormal or infectious prion protein, PrPsc
- PrPsc is responsible for transmission and infection
Persistent Viral Infection of CNS Unconventional
Agents - Prions: 5 fatal CNS Diseases
✷Creutzfeldt-Jacob disease (CJD)
✷Variant CJD, Mad cow disease
✷Gerstmann-Straussler-Scheinker syndrome
✷Kuru
✷Fatal familial insomnia
Kuru
- Subacute, progressive neurologic disease of the Fore people of the Eastern Highlands of New Guinea
- Affected adult women or children of either sex
- Symptoms: ataxia, hyperreflexia, and spasticity leading to dementia, starvation and death
- Pathology: changes in CNS with diffuse neuronal degeneration and spongioform changes of the cerebral cortex and basal ganglia
- Transmission: Ingestion of organs of the deceased, mainly the soup of the brain in honor of the deceased
- Incubation period: 60-360 months
- Duration of illness: 3-12 months
- Kuru has disappeared due to elimination of cannibalism from the Fore culture
Creutzfeldt-Jacob Disease (CJD)
- CJD is a progressive, fatal illness of the CNS mostly seen in the sixth and seventh decades of life
- Clinical manifestations: change in cerebral function, usually diagnosed as psychiatric problem, forgetfulness and disorientation progress to overt dementia and changes in gait, increased tone in limbs, involuntary movement and seizures
- Incubation period: 18 - 360 months
- Duration of illness: 1- 55 months
- Transmission: sporadic (85%) and familial pattern (15%)
- Pathology: identical to kuru
Gerstmann-Straussler-Scheinker Disease
- Similar to CJD but occurs at a younger age (4th to 5th decade)
- Cerebella ataxia and paralysis are common
- Dementia is less often seen
- Originally believed to be familial but also occurs sporadically
Fatal Familial Insomnia
- New familial prion disease
- Syndrome of sleeping difficulty followed by progressive dementia
- Occurs in patients aged 25-61 years of age
- Duration of illness 13-25 months followed by death
- Confirmed in experimental animals
Bovine Spongiform Encephalopathy (BSE) (“Mad Cow Disease”) and “Variant Creutzfeldt-Jacob Disease”
- BSE was identified in 1986 in the United Kingdom
- Source of emerging epidemic was found to be a food supplement containing meat and bone meal from sheep
- Incubation period in cattle: 2 to 8 years
- Cows exhibited hyperesthesia, hyperflexia, muscle fasciculations, tremors and weight loss
- Autonomic dysfunction was frequently manifested
- BSE survives the heat of cooking and transmitted to humans consuming neural tissues or bone marrow and both are found on meats
- More than 100 humans with variant CJD have died in the UK
- Frequently present in young adults as psychiatric problems progressing to neurologic changes and dementia and death occurs in an average of 14 months
