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Herpesviruses (Beta (Cyomegalovirus (HHV5 (CMV) (Immune evasion…

- - - - Disease
        
        Diagnosis
        
        Diseases
        
        Primary
        
        IgM 4-7 weeks post-infection (gB or tegument)
        
        Previously seronegative
        
        Caused by CMV lysis, or NK/T cytolysis, B cells destroy but activate macro/DC/NK (inflammatory)
        
        Cardivascular/cancer link due to inflammation. Can aggravate pre-existing immunodisorders
        
        EBV-neg mono/glandular
        
        Congenital
        
        Coinfection with HIV morbidity-associated
        
        Less symptoms in mother immune/exposed before conception
        
        1 more item...
        
        Because immunomodulatory
        
        TORCH disease (major development risk in newborns)
        
        Clinical symptoms: microcephaly, retinitis, jaundice, petechiae, splenomegaly, growth retardation, hearing loss
        
        Lab symptoms: hyperbilirubinemia, high hepatocellular enzymes, thrombocytopenia
        
        HIV
        
        If intestines, diarrhoea If eye, retinitis
        
        CMV DNA in blood = disease progression marker
        
        Transplant
        
        Lung = 50% chance of symptomatic illness
        
        Replicates in kidney, so kidney transplant function can be affected
        
        rt PCR 'fingerprinting', DNA PCR PBMC - DNA present in saliva and urine
        
        Histopathology: 'owls eye' inclusion bodies, enlarged/fusogenic cells
        
        In HIV pneumonitis PCR too sensitive - use histopath, immunohisto, in situ his, culture.
        
        Slow in vitro culture
        
        pp65 antigenemia assay (tegument in blood)
        
        Epidemiology
        
        USA 60%, 36% under 11 Gambia 85% under 1
        
        Seroprevalence increases with age
        
        Transmission: transplacental, saliva, milk, urine, faces, tears, sex, blood/organ donation
        
        Pathophysiology
        
        Epithelia tropism, esp. salivary glands
        
        Latency in mononuclear cells (mono, macro, BM)
        
        Only replicates in differentiated cells
        
        MIE repression prevents IE transcription (latent)
        
        UL81-82 of MIE produces pp71 for activation (lytic)
        
        1 more item...
      - Immune evasion
        
        Latency
        
        Anergic clonal inflation
        
        MHC down regulation
        
        MHCI: US6/11 MHCII: US2/3
        
        Downreg MHC1 signal virus, UL40 upregs HLA-E (NK inactivate)
        
        Chemokines
        
        Produce CXC/IL10/IFN - IRS1, UL146, UL111A
        
        CXCR homologues - sequester CXC
        
        NK cells
        
        Activate: UL16, miR-UL112
        
        Inactivate: UL18 - MHCI recognises, doesn't activate TAP
        
        Attachment complex
        
        Pentameric, variation avoids Ab recognition
      - Structure
        
        200-300nm, spherical, enveloped
        
        Glycoproteins in envelope (lipid from host ER/golgi): gB, H, L, M, N, O
        
        Tegument proteins in matrix (e.g. UL83/pp65)
        
        Genome
        
        dsDNA, linear
        
        230kb
        
        Core enzymes: dUTP, polymerase, DNA binding protein, DNA primase
        
        Internal and terminal repeats
      - Replication
        
        Entry via GPs
        
        Attachment: B to heparin sulphate, M/N to heparin
        
        Docking: B/O to PDGFR, B/H to integrins
        
        Fusion: H/L/O
        
        Exit via nuclear egress (primary envelopment)
        
        Endocytosis (secondary envelopment)
        
        Translocation to nucleus
        
        IE1/2 genes expressed
        
        DNA replicated and capsid assembled
        
        Egress and GPs produced on ER/golgi
        
        Tegument produced on ER/golgi
      - Treatment
        
        vaccine trials (gB)
        
        No congenital treatment
        
        Ganciclovir - resistance UL97 mutation
        
        Foscarnet, not as effective as with alphaherpes, usually BM transplants
  - - - Disease
        
        Examtha subitem (macpap rash) 10-20%
        
        Infant fever
        
        Complications: encephalitis (+/- MS and epilepsy), myocarditis, lymphadenopathy, hepatitis, diarrhoea, respiratory problems
        
        Immunocompromised: fatal encephalitis (transplant) + disseminated infections (HIV)
        
        Lympho + neurotrophic, latent in mono/macro/BM
        
        6A: glial cell precursors (cancer + MS). Also thyroid/myocarditis
        
        6B can bind CD134 co-receptor. Epilepsy and myocarditis
        
        7 can bind CD4 (like HIV)
        
        6A/B both have gQ/H/L complex for CD46 binding
      - Treatment
        
        No licensed, Ganciclovir works well but immunosuppressive
        
        UL97 CMV homologue: UL69
        
        Cidofovir toxic/IV
        
        Unlicensed anti-gH Ab
      - Epidemiology
        
        Transmission: saliva
        
        Diagnosis: indirect immunofluorescence (Sera) for HHV6-specific IgM/H. RT PCT on sera/CSF can detect active infection. Genotyping can identify A or B
      - Immune evasion
        
        MHCI downreg: U21
        
        MHCII downreg: U24
        
        CXCR: U12/51
        
        CXC: U83 (attract new host cells) - not in HHV7
      - Replication and structure
        
        Same as CMV except:
        
        Entry via gQ
        
        U94 integrase for latency U83 during latency
        
        6 Integrates into host in 1% in telomere, next to replication cycle genes (congenital inheritance)