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129 Cards in this Set
- Front
- Back
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to infect a cell, virus must |
attach, enter, multiply, target appropriate organ |
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to be maintained in nature virus must |
shed, taken up by vector (insect, needle), passed congenitally |
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local replication |
confined to organ of entry |
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systemic replication |
involved many organs |
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Respiratory tract entry |
most important sit of entry, via aerosol of infected nasal secretions. large droplets - nose, small droplets = LRT alveoli |
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Respiratory tract barriers |
mucus, cilia, alveolar macrophages, temperature gradient, IgA |
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Respiratory tract local infections
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Rhinovirus - requires URT 35 degrees Influenza - SA and tryptase Clara |
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Mumps virus |
Systemic Respiratory tract virus. Salivary glands swell up |
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Measles virus |
Replicates in URT epith cells, infects macro, lympho, DC and LN. Enter circulation and amplify in lymphoid tissue |
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Alimentary Tract entry |
swallowed of infect oropharynx. Vviruses do not have an evelope. if no receptor, enter via breach in epith |
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Alimentary Tract barriers |
constant movvement of contents (allow receptor contact), mucous, pH, proteolytic enzymes, lipolytic bile, IgA, macro |
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Local AT
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M cells - deliver ag to lymphoid tissue by transcytosis. Viruses may trancytose of infect M cells e.g. Calici - ID w EM. cannot culture or animal model |
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Systemic AT |
polio, rhino, hepato - viruses |
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Trascutaneous route |
trauma - HPV warts injection - HIV, Hep B/C bite - Dengue, rabies |
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Genital tract |
HPV, HSV2, HIV, HepB |
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Conjunctivia |
adeno, HSV |
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mechanisms of spread |
local spread on epith viremia neural spread |
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Viremia types |
free - primary and secondary phases, virus prod by liver, spleen. neutralised by ab and macro cell ass - eg HIV CD4, measles monocytes. may persist |
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Poliovirus |
Ingest, replicates in peters patches monoytes, travel to LN, go to blood as free virus Can target MN = paralysis OR target gut = excreted. |
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Tissue invasion |
Entry from blood to tissue - barriers are basement membrane and endothelial cell Replicate and release progeny in endothelium |
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Neural spread |
via peripheral nerves. uncoated NC carried passively along axons and dendrites Replicate in nerve body can cross synapse. Protexted from CTL - nerves = no MHC1 |
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Rabies |
neural spread. can infect muscle which is controlled by the iR. infects neurons and kills brain sites = aggression, thirst. infect salivary glands for transmission |
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Placenta transmission |
to infect fetus. baby at birth may be infected via the birth canal, fecal contamination or be immunoogically tolerant (carriage state) |
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Congenital Rubella |
Slows rate of cell division = small babies, microencephaly, congenital heart defects, deaf, cataracts |
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ZIka virus |
mosquitos, sexual transmission NO VACC |
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Congenital HCMV |
Herpes, most common congenital inf. no vaccine, no screening |
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Shedding |
Respiratory tract = aerosols, nasopharyngeal secretions Skin - warts, or vesicles/vesicular rash Blood - Dengue and yellow fever viral levels are Urine, milk, oral/genital secretions |
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Determinants of tropism |
-receptor availability -local factors - temp, ph, survival of enzymes -accessibility - ability to replicate in cells or travel in blood, polarised release -availability of cleavage activating proteases e.g. tryptase clara, furin -transcription requirements e.g. HPV rep in differentiated skin cells |
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Pathogenicity vs virulence |
P - inherent genetic capacity to cause disease V - measure of degree of disease = qualitative. |
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Virus induced changes in cells |
-transformation -lysis -chronic infection - release of virus w/o cell death -latent infection - no damage to cell, can reemerge later for lysis |
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Cytocidal virally induced damage |
-shutdown protein synth - e.g. polio 2A cleaves elF4G reuired for translation -shutdown NA synth - due to shutdown of protein or DNAse -viral proteins - accumulation = cytotoxic |
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Noncytocidal virally induced damage |
-Loss of function e.g. rhinovirus kills cilia -Infected cells = target of immune system -Transformaation - viral oncogenes = tumour |
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Immunopathology |
-cytokine inflammation -ag-ab complexes deposited on kidney/blood vessel - FcR mediated uptake o commplexes into macro/mono enhances infection - CD4 - induct cytokines, responsible to measles rash due to inflamm - CD8 - kill hepatocytes |
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Autoimmunity |
molecular mimicry - produce proteins that resemble host cells polyclonal B cell activation |
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Immunosuppression |
-HIV replicates in CD4 (and kills them) and mono (inhib function) - measles temporary immunosuppresion from replication in Tc and macro |
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Host resistance |
Genetic - inherited defects (no Ig class), polymorphisms (MHC genes), IFN inducible genes, receptor genes (CCR5) Non genetic - age, malnutrition, homones and pregnancy, dual infections |
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Outcomes of viral infection |
fatal full recovery recovery w permanent damage persistent infection |
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Innate immunity |
First line = immediate, passive Second line = require activation |
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Ligand signalling pathway |
Ligand binds, TLR dimerise, adaptor molecules assemble. Adaptors MyD88 and TRIF activate TF and MAP kinases. NFkB - IL-6 and TNFa |
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RIG-1 and MDA5 |
RNA helicases. Bind dsRNA and and induce dimerisation and interaction with adaptor MAVS on mitochondria via the CARD domains. Induces activation of IRF3 and NFkB |
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cGAS-STING |
cGAS recognises cytoplasmic DNA, generates cGAMP to bind STING and activate RF3 and NFkB |
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Cyotkines |
Low molecular weigh proteinns with regulatory functions to alter gene expression in target cells. Work locally for antiviral defense and in larger quantities product global effects eg. fever
autocrine (self), paracrine (nearby), endocrine (distant)
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JAK STAT signalling |
IFNa binds Jak1, Stat heterodimer dimerises and gets phos, enters nucleus to bind ISRE IFNgamme binds Jack heterodimer, Stat homodimer dimerises and gets phos, enters nucleus to bind GAS |
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ISG |
proteins only produced upon IFN stimulation |
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MxA |
-MxA found in cyto, recognises capsids. used as a marker for infection |
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OAS |
.-OAS forms a tetramer to dimerise and activate RNAseL to degrade viral RNA RNAse L is always present in small amounts |
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PKR |
PKR binds dsRNA, gets phos and dimerises = active. PKR phos host translation factor ELF2a stop host translation, therefore stopping any viral translation. |
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Viral countermeasures |
RNA recognition - interfere w recognition, helicase activation, MAVS signalling or TF activation Inhibit IFN signalling by preventing phos or nuclear umport Inhibit PKR - cleavage, preventing activation. most viruses do this |
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Latency characteristics |
- infect non replicating cells or viral genome is replicated with the host genome -genome is intact -low or no gene expression -low or no detection of virus |
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Viral persistence |
-Latency -Chronic infection -Noncytopathic inf of inaccessible site to avoid IR induction -Acute with late complications e.g. measles to SSPE |
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Antigenic variation |
antigenic drift = change in antigenic structure of the virus to escape neautralisation by ab drift in Tc epitopes - change anchor residues, flanking AA or TcR contact residues |
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Inhibit T cell priming |
-block cytokine induced maturation -block signal transduction -block Tc stim |
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Evade CD8 Tc |
-antigenic variation in CTL epitopes -endocytosis of class 1 -binding TAP = no peptide translocation to ER -bind MHC peptide complex to keep it in the ER -bind tapasin = loads peptide onto MHC in ER -decrease class 1 gene transcription - evade proteosome degradation |
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Evade NK cells |
Inhib receptor binds MHC1, activation receptor binds to target cell -murine CMV keeps the activation receptor ligand in the ER -human CMV encodes MHC1 like molecule to bind the inhib receptor, upregulates HLA-E |
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Interfere with cytokine function |
-soluble cytokine receptor homologues -redirect Tc response -intracellular blocking of cytokine synthesis -intracellular interference with cytokine function |
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Apoptosis |
Cell death mediated by caspases when cell cycle is disrupted or when there is cell stress. DNA is fragmented Dying cells release apoptotic bodies that APC take up and present on MHC2 for activation of CTL. |
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Apoptosis pathways |
Extrinsic pathway TNF/Fas bind recept, caspases, apoptosis Intrinsic pathway mitochondria permeabilised by BCL2, cytochrome C released, caspases, apoptosis |
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Autophagy |
The cytoplasm gets engulfed by double membrane autophagosome, lysosome degrades. Antiviral - targets viral components for degradation (xenophagy) and has a role in initiating innate/adaptive IS. Viruses may use autophhagy components for replication |
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Complement evasion |
Virus encodes homologues of control proteins that bind to complement components to stop the cascade e.g. Vaccinnia protein binds C3b |
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Passive evasion of host defence |
-cell tropism -spreading via cell fusion -free passage through barriers (needle, transplants) |
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Active evasion of host defence |
-limit expression of viral genes -non cytopathc infection -block specific immune defences (cyto, antibody, MC, coreceptors_ -block apoptosis -genetic evolution -immunosuppressive or anergic epitopes |
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Herpesvirses and persistance sites |
all herpesviruses form lifelong persistent inf w periodic reactivation (cytopathic) alpha - HSV1/2, VZV = neuronal persistance beta - CMV = monocyyte/secretory gland gamme - EBV = lymphocytes (Bc) |
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Herpesvirus latent genomes and ori |
dsDNA, regulated gene expression in latency EBV = replicating latency HSV= non replication latency |
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HSV-1 diseases |
primary inf = lips and tongue gingivistomatitis Recurrent = cold sores |
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HSV1 and 2 latency |
virus enters skin/mucous membrane, local multiplication and enters nerves, goes to trgem (HSV1) or sacral (HSV2) ganglion via retrograde axonal flow, latent, reactivate an travels down SAME neuron. virus is maintained in the cell bodies, multiple copies. express LATs |
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LATs |
Latency Associated Transcripts non translated transcripts, no protein produce associated with reactivation |
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Selection of replication and latency |
IE genes are blocked by interferons. LAT is expressed to inhibit apoptosis and therefore promote latency, resulting in immune suppression |
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Varicella Zoster Virus infection |
Primary inf = chicken pox viremia (via DC and Tc) produces vesicular rash. Neural spread virus goes to DRG, latent, reactivate and moves back down ALL the neurons of the DRG to produce shingles dermatome rash reactivation in elderly - immune deficit/decline |
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VZV vaccine |
chickenpox vaccine = live attenuated, recommended for seronegative children and at risk e.g. teacher |
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EBV infection |
glandular fever, acq by contact of infected saliva w oroparynx. Primary inf = lytic, orophayngeeal cavity epith cells. Then it spreads to Bc to generate wide IR, LN swelling. Bc = latency reservoir, no replication |
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EBV Latency |
associated with expression of genes -EBNA1-6 - EBN1 involved in replication in dividing Bc -LMP1 and 2 = latent membrane proteins Has 2 ori - OriP and OriLyt |
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EBV tumorogenesis |
reactivation of EBV from Bc leads to Hodgkins disease Burkitts Bc lymphoma Nasopharyngeal carcinoma |
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CMV |
infection in older = mild, leads to persistence reactivated by immunosuppression congenital inf = deaf, microencephaly. mother primary inf - 32% chance fetus gets inf, 15% smptomatic, 70% long term sequelae |
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HIV Tat |
Tat - produced by alternative splicing,activate transcription through binding TAR RNA element to recruit RNAP |
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HIV Rev |
regulator of structural gene expression through binding RRE to transport unspliced or partially spliced RNA to the cytoplasm. accumulation of Rev leads to late transcription |
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HIV non essential proteins |
Vif inncreases infectivity and blocks the IR for ssDNA Vpr for nuclear import of cDNA, activate transcription, stop cell growth Vpu regulates release and env processing Nef multifunction protein |
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HIV entry and receptors |
binds C type lectin receptors = selects for R5 strains because DC bind virus w C type lectin receptors and R5 receptor. bind CD4, CCR5 promotes fusion. Later CXCR4 used to inf Tc in the draining LN, then viremia. CCR5Δ32 homo deletion mt = HIV resistant |
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HIV phases |
1 - high viral load, CD4 loss, hard to spot. ELISA and WB
2 - asymptomatic, load decreases and plateaus. Has CTL and non neutralizing ab for decoy ag. HIV evades IR 3 - symptomatic and AIDS |
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HIV IR evasion |
sequence variation high replication level viral proteins to downreg MHC1 infect IS cells - Tc clonal exhaustion latency in resting cells = priveleged site |
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HIV rate of progression |
dependent on age, strain of virus, presence of CCR5Δ32 mt, HLA type, IR |
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HIV reservoirs |
-LN -Blood -Resting memory Tc -macro in tissue and LN -accumuates in LN germinal centres as immune complexes on FD -in microglia and astrocytes -testes and secretions |
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Drug development issus |
must have proof of principle must quickly and completely block replication and spread, avoid persistance resistance must be managable safe cheap easy to make/deliver |
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Interferons |
IFNab bind cell receptor to activate TF for IFN regulated genes that inhib penetration, uncoating, mRNA synth, translation, assembly, release purified recombinant proteins for therpeutic use - side effects fever, nausea |
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Haemagluttanin inhibitors |
HA binds to SA for infection Amantadine M2 ion channel blocker, binds M2 and prevents acidification of HA during fusion. |
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Neuraminidae inhibitors |
NA cleaves SA resdues for release from infected cells Relenza (inhale) and Tamiflu (oral) bind to the active site of NA with higher affinity than SA does |
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HIV drugs |
Acyclovir nucleoside analogue, no 3'OH to inhibit DNAP. requires activation by viral TK phos to triphosphate form, therefore it is specific to infected cells Addition of side chain changes bioavailability - can pass digestive tract |
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Nucleoside vs nucleotide |
nucleoside has no phos groups nucleotide has more than one phos group. used for polymerisation od DNA |
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Ribavarin |
guanasine analogue, inhibits DNAPand RNAP monophosphate form reduces NA synth triphosphate form alters viral mRNA formation Hep C, Influenza |
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AZT |
HIV RT inhibitor Thymine analogie, phosphorylated by cellular kinase to triphosphate form. Used in preferennce of thymine. does not eliminate provirus drug resistant mutant viruses occur |
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NRTI |
nucleoside reverse transcriptase inhibitor for HIV1 T/G/C analogues, kinase phos to triphos form used in preference to cellular nucleosides to prevent chain elongation used individually = mutant.s therefore HAART |
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NNRTI |
Non nucleoside reverse transcriptase inhibitors for HIV1 do not bind the nucleotide binding sit of RT, are not DNA analgoues. inhibit RT enzyme directly by other mech |
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HIV protease inhibitors |
peptidomimetics that have close structural similarity of the AA recognition sequence bind to the active sit of protease |
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Raltegravir |
blocks integrase strand transfer of HIV-1 DNA causes the LTRs to anneal and form 1 and 2 LTR circles that degrade or recomb |
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Drug Resistace |
-high replication and mutation rate -selective preessure favoring combo therapy -resistant mutants preexisting -resistant virus often has reduced replicative capaciy and pathogenicity |
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HAART |
potent durabble antiviral response minimise resistance Rapid viral rebound when HAART stopped due to integrated provirus = undetectable viral load |
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Viral hepatitis |
non cytolytic, replicates in hepatocytes of the liver. acute disease (A&E) = jaundice chronic (BCD) = cirrhosis, liver cancer disease = immune mediated, age relatedearly exposure = less severe acute disease but higher rates of chronic inf |
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Diagnosis of hepatitis |
sero tests (ELISA) - IgM = acute, IgG rising titre confirms acute infection NA test - PCR blood/faeces |
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Hep A |
picornaviridae, non env +ssRNA resistant to stomach acid single serotype replicates in cell culture - inactivated vacc |
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Hep A and E pathogenesis |
ingest orally replicate in intestine epith viremia replicates in liver hepatocyte secretes in bile/faeces |
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Hep E |
non env BUT FRAGILE associated with contaminated water, low person to person spread |
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Hep B |
have double walledvirus particles and incomplete particles with only env protein gapped circle genome, many starts one stop |
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Hep BCD pathogenesis |
sex or injection penetrate mucosal epith viremia replicate in liver shed in blood, semen, secretions. perinatal transmission also high |
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Hep B sequelae |
Chronic carrier (HBsAg+) liver damage cirrhosis, liver failure liver cancer in 2-10% of patients, usually partial integration of the HBV genome |
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Diagnose Hep B infection |
-HBsAg = marker of inf -anti-HBs Ig = recovery or immunity -IgM=acute, IgG = chronic -HBeAg = active replication -HBV DNA = active replication |
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Hep D |
deltravirus with delta ag capsid coinfects with HBV = acute superinfects with HBV = chronic |
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Hep C |
most infections via drug use no vaccine, animal model, high mutation poor immunity NS5B RNAP mediates replication, error prone - 6 genotyes |
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Hep C treatment |
no vaccine, only drugs use IFNa and Ribavirin. quasispecies may not respond |
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Hep B treatment |
vaccine, no drugs. cannot eradicate - latency vaccine = yeast purified sub viral particles antiviral therapy - IFN, RT inhibitors, nucleoside analogue (Tenofivir) - used to decrease viral load in mothers |
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Eradicate vs Cure |
eradicate = elimination of virus from Earth
cure: complete =eliminate cccDNA, prod ab functional = lose surface ag, prod ab. may still lead to latency |
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Hep B drug targets |
target cccDNA -eradication involves cleavage of the genome - can reform with homologous recomb prot x = hijacks SMC56 that chromatinises DNA in the nucleus - required for chronic. coat protein stabilises cccDNA |
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Transfection |
transfer of NA into eukaryotic cells use molecular conjugates - CaPO4 precipitate of DNA or catioic liposomes for DNA/RNA |
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Transduction |
viral vector delivery systems |
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Viral vector design |
- seperate struct genes into transpackaging cell line - flank transgene w cis acting seq for translation and packaginng signals |
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Retrovirus vector |
place gag/pol/env in packaging cell line inf dividing cells keep LTR and packaging signals integration into an oncogene = cancinogenic limites env tropism |
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Retrovirus vector replication reversion |
modify to preserve RT and integration but stop LTR transcription by replacing LTR with CMV LTR inactive as promotor |
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Lentivirus vector |
Similar to retrovirus infects NON dividing cells - terminally dierentiated |
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Retrovirus vector applications |
Gene correction therapy due to no vector IR Cancer therapy - transient high level expression. Cytotoxicity specific to tumour cells vaccines |
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Adenovirus vector |
E1 genes into cell line, keep the ITR efficient for mammalian cells, high immunogenic, high titres, short term expression, wide tropism
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Adeno associated vectors |
small, do not require replicating cells for gene transfer, no insertional mutagenesis can integrate into host DNA = persistant expression |
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RNA replicons |
self replicating RNAs derived from viral genome high expression of heterologous genes delivered as VLP and naked RNA/DNA delete genes for strucctural proteins |
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West Nile Virus replicons |
high expression, non cytopathic, no integration, no recomb use for vacc and cancer preexisting immmunity and small size |
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- RNA virus vectors |
-RNA genome = segments, expression depends on location of the gene. product via genetic reassortment parents = virulent virus with target ag and a weakly pathogenic strain select for attenuated strains exp target ag |
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Smallpox vaccine |
Cowpox antigenically similar, vaccinia not able to eradicate because: no secondary host, one stable sero, virus is infectious after symptoms occur, no persistance |
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Polio vaccine |
not 100% successful due to provirus SALK = inactivated vacc SABIN = live atten vacc, lots of passages, provides mucosal IR, MAY REVERT TO WT |
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Measles vaccine |
measles - no more SSPE, reduced encephalitis mumps - no more orchitis, reduced encephalitis rubella - no more congenital rubella syndrome, reduced encephalitis |
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Live attenuated vaccine pros and cons |
pro - fewer doses, long lasting IR that is similar to the pathogen response con - consider immunocomp, needs boosters, can revert to virulence and be shed |
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Vaccinia vector |
construct plasmid with viral TK disrupted (TK-) by early gene promotor with gene inserted downstream. infect cells with plasmid + WT vaccinia. select for TK- cells with BUdr = toxic in TK+ cells
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DNA vaccines |
plasmid contains ori, euk promotor, vaccine antigen, poly A and marker (antibiotic resistance) can target specific cells by expressing specific molecules |
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VLP |
capsid or env proteins can self assemble, are taken up efficiently by APC HepB vaccine from yeast HPV Gardasil vaccine from yeast L1 capsid prot |
