Live vs Killed Vaccines

• Live Vaccines: natural/injection, low dose, long duration, more natural immunity, poor stability and higher risk
• Killed Vaccines: injection, high dose, shorter duration, not natural (Th2 response) immunity, good stability and no risk (except for allergies
• live oral polio vaccine can cause a mutant polio infection (much more superior in protection compared to killed though)

Vaccination Schedule

• Early Vaccines (1-12 mo): polio, Hep B, DPT, HiB, pneumococcal conjugate, ROTAvirus: infantile diseases and Ab is sufficient (not live vaccines)
• After 15-24 mo: MMR, VZV: after maternal Ab is gone, enveloped viruses require mature T cell function (live vaccines)
• Later in Life: Influenza, HPV, Zoster, Tdap boosters, pneumococcus, meningococcus
• Vacation/Travel: Hep A, (adeno for military) Yellow fever, rabies, adenovirus, JApanese B encephalitis, VEE, WEE, EEE

Antibodies that block T cell Function

Anti-Allergy Therapies

• Desensitization: shift Ab response away from IgE: switch Th2 to Th1 type of response to reduce production of IgE by injectio of increasing doses of allergen
• produce IgG to bind allergen and prevent binding to IgE
• inhibit mediator action and symptoms
• Block Symptoms: Epinephrine for anaphylactic reactions
• Anti histamines, Anti inflam drugs and Anti IgE (in trial)

Classification of Retroviruses

(classical scheme)

• Oncoviruses (now spilt into 5 genus groups): includes retroviruses associated w/ tumor induction (RNA tumor viruses); they may carry oncogenes
• Lentinviruses: Includes retroviruses associated w/ immune dysfunction and other slowly progressive diseases
• Spumaviruses: includes retroviruses associated with persistent chronic infection; no known clinical disease
• HIV is member of lentivirus group (slow group)

Virus oncogenes

(retroviruses)

• simian sarcoma virus (v-sis): platelet-derived growth factor
• Murine sarcoma virus (v-ras): signal transduction (G-protein)
• Avian myelocytoma virus (v-myc): transcription factor

Adult T Cell Leukemia

• caused by HTLV-1 (retrovirus)
• acute form is an aggressive lymphoproliferative disease accompanied with skin lesions, bone lesions and immunodeficiency; often fatal
• depends on host response to virus
• fatigue, nausea, vomiting, fever, abdominal pain, lymphadenopathy, thirst due to hypercalcemia

 Tropical Spastic Paraparesis (TSP)

• caused by HTLV-1 (retrovirus)
• chronic demyelinating disease usually begins in adults; can develop in patients within a few years of HTLV-1 infection after blood transfusion
• characterized by weakness and spasticity of the extermities; rarely fatal

HIV as a Lentivirus

HIV Progression to AIDS 

• Typical: Homogenous HIV transmitted during primary infection
• slow replication, non-syncytium HIV during latency
• more rapidly replicating T cell tropic HIV variants close to AIDS (virus that use CXCR4 more virulent)
• Rapid: high viral load and levels and levels in primary infection that does not fall to typical levels; may be infected with rapidly replicating virulent HIV strain
• Nonprogressors: Viral load lower; may be less pathogenic HIV variants
• host mutation in the CCR5; A homozygous delta 32 allele may result in a strong resistance to infection and progression to AIDS 
• More focused Anti-HIV CD8 response due to MHC I binding of antigen

CDC HIV Testing Guidelines

2014

• First; immunoassay that detects HIV-1, HIV-2 Ab as well as HIV-1 p24 antigen
• Second: reactive specimens undergo testing with immunoassays that differentiate btw HIV-1, HIV-2 Abs
• Third: if necessary proceed to HIV-1 nucleic acid testing for resolution of indeterminate results

Six Classes of Anti-HIV Drugs

• Nucleoside reverse transcriptase inhibitors (NRTIs): Zidovudine (AZT), lamivudine (3TC), tenofovir
• Non-nucleoside reverse transcriptase inh (non-NRTIs): nevirapine and efavirenz
• Protease inh: ritonavir (all names end in navir for no virus)
• Fustion inhibitors, attachment (CCR5) inhibitors and integrase inhibitors

Persons Dying of HIV disease increasingly 

Consist of:

• women (28%)
• blacks/african americans (56%)
• Residents of the south (53%)
• persons of 45 years of age or older (55%)

Risk factor for increased Transmission of 

occupational exposure to HIV

• Deep injury
• visible blood on needle
• type of needle of needle: hollow worse than suture
• proceduce involving needle in artery/vein
• adnvanced illnesss in source patient

PrEP: Pre-exposure Prophylaxis

• truvada (emtricitabine and tenofovir) daily
• high risk: high risk MSM, sex workers, IVDU, discordant couples
• can reduce risk by up to 92% in high risk people
• still need condoms and other prevention strategies

Influenza and Pregnancy

• Pregnant woman at high risk for severe complications and death: cellular immune response diminished
• Maternal influenza associated w/ inc maternal hospitalization, fetal malformation and other illnesses
• prevention is best approach
• newborns are at high risk for severe complications: several reports of 2nd MRSA infection, no approved vaccine for infants less than six months and all care givers need to be free from possible transmission to this vulnerable population

Hepatitis Mnemonic

• Hot Key words:
• A-Acute
• B - Blood
• C - Chronicity
• D - Defective
• E - Eat it!

Prion Diseases

• Infections, genetic and sporadic origins
• Humans: Kuru (laughing death), Creutzfeldt-jakob disease(CJD), NEw variant CJD, Gerstmann-Straussler-Scheinker syndrom (GSS), Fatal familial insomnia (FFI), and sporadic fatal (sFE)
• Animals: Scrapie (sheeps and goats), transmissible milk encephalopathy, feline spongiform enceph, bovine spongiform enceph (BSE; Mad cow), chronic wasting disease (CWD; Deer, elk and moose)

Kuru

"Laughing Death"

• first described in Papua, New Guinea
• disease primarily of children and women
• associated w/ ritualistic cannibalism. no one born since cessation of this has developed kuru (1958)
• signs: tremor, involun movnt, and ataxia progressing to complete immobility
• often accompanied by dementia charact by sudden bursts of maniacal laughter and exhaustive mycoclonic activity
• critical insight: post mortem brain samples were infections to chimpanzees
• incubation period from months to 40+ years
• no treatment and lab tests not helpful

Gerstmann-Straussler-Scheinker Syndrome

(GSS)

• autosomal dominant form of prion disease
• Point mutations in PRNP gene at codons 102, 105, 117, 145, 198 or 217. P102L most common
• 1 to 10 per 100 million population
• 50 extended families  identifed
• onset: 43-48. Duration 5 years
• char. by cerebellar features such as clumsiness, incoordination, ataxia, but also includes difficulty speaking (dysarthria), and eventually global dementia w/ impaired intelligence, memory, attention and cognitive skills. in contrast to CJD, myoclonus is rarely a feature
• No PSWCs
• plaques present throughout the brain, especially in the cerebellum
• spongiosis is variable

Fatal Familial Insomnia (FFI) and

Sporadic Fatal Insomnia (sFI)

• FFI caused by D178 mutation w/i a M/M 129 PRNP backgroup. 9 extened families identified
• autosomal dominant
• onset: 35-61. duration 7-25 months
• Presentation: progressive insomnia, loss of circardian rest activity, w/ nonREM cleep entirely absent, motor disturbances (ataxia, myoclonus, spasticity,hyperreflexia), and dysautonomia (excessive sweating, hyperthermia, tachycardia, hypertenstion)
• mental status changes apparent, however frank dementia is rarely seen
• sFI is clinically/path indistinguishable from FFI, but no germline mutation. Victems M/M129
• Both FFI and sFI are transmissible to mice with identical neuropathology and PrP electrophoretic mobility signatures
• neuro char by loss, gliosis and very low lvls of PrPsc acc
• spongiosis and EEG PSWCs almost always absent
• PET shows reduced activity of the thalamus

Hepatitis B Sequelae

• Primary Hepatocellular Carcinoma: Chronic HBV can lead to this and prevalent in indoasian countries where HBV is prevalent(therefore chronic)
• Hep C can also cause cancers
• Polyarteritis nodosum, glomerulonephritis: type 3 hypersensitivity disease due to immune complexes
• cirrhosis 

Occupational Transmission of HCV

• sex and drugs usually primary transmission method now
• Inefficient by occupational exposures
• average incidence 1.8% following needle stick from HCV-positive source (associated w/ hollow-bore needles)
• case reports of transmission from blood splash to eye; one from exposure to non-intact skin
• prevalence 1-2% among health care workers: lower than adults in general population, 10 times lower than for HBV infection
• scary because many people dont know they have HCV

Stages of Rabies

• Incubation: 30-90 days (50%) with no findings
• Prodrome: 2-10 days: pain at wound site; fever; malaise, anorexia, nausea and vomiting
• Acute Furious: 2-7 days: hallucinations, bizarre behavior, anxiety, agitation, hydrophobia and biting
• Acute paralytic (other form): 2-7 days: ascending flacid paralysis
• Coma (0-14 days) and death

Ebola Symptoms in Most Patients

• few days after infection: high fever, headache, muscle aches, stomach pain, fatigue, diarhea
• w/i one week of infection: chest pain, rash, shock and death

Ebola Symptoms in Some Patients

• few days after infection: sore throat, vomiting blood, bloody diarrhea
• With in one week of infection: can have blindness and bleeding (on top of normal chest pain, rash, shock and death)

Creutzfeldt-jacob disease (CJD)

• mean age at onset: 57-62
• dementia followed by lack of coord and myoclonus(sometimes reversed)
• can be sporadic (90%) or genetic but rarely latrogenic (doctor caused)
• clinical disease usually less than a year (1 month to 10 years)
• PrP^sc accumulates in the CNS but not in peripheral tissue
• no definitive diagnostic test available (CSF and blood tests normal)
• EEG sometimes shows periodic sharp wave complexes
• MRI-T2 signal hyperintensity can be seen in putamen and head of caudate
• genetic test for PRNP mutations
• post mortem: wester blot or histo/IHC(PRPsc acum, neuronal loss, vaculation andnd gliosis)

New Variant CJD

• initially reported in 1995
• assoc with BSE in Britain: result of changes in rendering process for generating protein supplements used in cattle feed
• average age of onset: 28 years (14 month duration)
• PrPsc glycosylation and electrophoretic mobility uniquely char of BSE rather than sporadic CJD or other prion diseases
• all affected individuals have M/M at residue 129 of PrP 

Passive Immunization

• preformed Ab (human, horse, monoclonal)
• drug like activity neutralize virus, toxin or cytokine
• temporary protection
• treatment for recent exposure: Rabies, HAV, HBV, VZV and tetanus
• problems: temporary, serum sickness (type III hypersensitivity)

Inactivated Vaccines

Immne Response

• injection of bolus of immunogen
• phagocytosis by DC and macrophage w/o innate activation (resembles waste removal rather than infection)
• presentation to CD4 T cells
• Th2 response: Ab (no CD8 T cells or angry phagocytes)
• limited memory!!! need boosters

Adjuvants

• increases immunogenicity
• Alum (aluminum and Ca Salts)
• bacterial and plant products
• toxins (cholera and ecoli)
• surrfacants/detergents
• TLR ligands: MPL
• Alum is most common and percipitates immunogen into glob that phagocyte gobles up (safe and requires booster)

Dendritic Cell Vaccines

• properly activated Dendritic cells
• loaded w/ appropriate antigen
• potent antigen presentation
• Tumor vaccines

Rheumatoid Arthritis

• joint damage and release of collagen
• DC presentation of Collagen to T cell
• stimulation of Th17 cells: cytokine/chemokine production and recruitment of neutrophils and macrophages
• Inflamation and tissue damage which leads to more joint damage and release of collagen

Rheumatoid Arthritis Treatment

• induce syn of inh kappa beta which blocks NF kappa Beta (NFkB) activation
• down regulation macrophage production of NO
• decrease production of prostaglandins
• Down regulate epression or block action of acute phase related cytokines
• increase Treg (dont know how yet)
• decrease adhesion molecules

T Cell Activation Pathway

• co-rec pathway (Anti-CD28) CD28 to nucleus
• Ag rec/stimulus (Anti-CD3): TCRcd3 activates calcineurin and TOR and both go to nucleus
• Cytokine (Anti-IL2R): IL2R activates TOR or the nuclease directly 
• Rapamycin inhibits TOR
• Cyclosporin (tacrolimus) inhibits calcineurin

Calcineurin inhibitors

• block activation of T cells (made transplants possible)
• cyclosporin interacts w/ cyclophillin to inactivate calcineurin
• Tacrolinus interacts w. FKBP to inactivate calcineurin
• powerful drugs that allow titration of immune respons
• inhibitor of IL-1,2,3,4 and 5
• problems: nephrotoxic, neurotoxic (tremors and seizures), hpertension, hirsutism, variable Abs, numerous drug interactions

TOR (target of Rapamycin)

Inhibitor

• inh of coordinator of metabolism
• selective blockage of cellular signal transduction
• inhibitor of cell division and differentiation
• problems: hyperlipidemia, hypertriglyceridemia, poor wound healing
• Rapamycin (sicolimus)

Cytotoxic Drugs

• disrupts DNA func, stops growth of T cells
• interupts purine syn and salv pathways in lymphocytes, hematopoetic cells and endothelial cells
• supresses bone marrow prod/kills act and dividing inflammatory cells
• mycophenolate decreases adhesion molc expression and cellular interaction
• methotrexate inhibits folic acid pathway
• problems: kills fast growing cells (hair folicles, GI linning cells), not easy to titrate response
• severe diarrhea with mycophenolate (cell adhesion)

Immunotherapy for Graft vs Host 

• cyclosporine, tacrolimus inhibition of IL-2
• Anti-CD3 Ab (OKT3)
• cytotoxic treatments: steroids?
• corticosteroids block acute phase proteins

Retrovirus Sympbols

• Long Terminal Repat (LTR): all retrovirus are terminally redundant, important for reverse transcription, integration, promotor and transcript startsites/enhancers
• GAG: codes for matrix, capsid and nucleic acid binding proteins
• POL: encodes for proteins having reverse transcriptase activity, integrase protein and protease (PRO)
• ENV: encodes 2 env glycoproteins

HTLV-1

• adult T cell leukemia
• Tropical spastic paraparesis (TSP)
• mode of transmission: most to infant (breast milk and transplacental), STD, parenteral(blood tfs/IV drugs)
• many infected but few get assoc diseases
• low replication and mutation rate (less threatening than HIV)
• oncogenesis is complex: no oncogene or insertion mechanisms, may be driving genomic instability

HIV-1 Proteins

• Viral Tatm Nef, and Gag form essential interactions w. host cell proteins to maintain infections
• Tat stim transcription
• Nef helps in escape of CD8 T cells
• Gag directs virion formatino and buding
• viral genes to combat cell defenses(inate immunity: Vif, VPX and VPU
• Vif protein counters cytidine deaminase that normally knocks out viral cDNA infectivity
• VPU allows detachment
• VPx llow macrophage infection

HIV Clinical Features

• neurologic: dementia; demyelinating neuropathy (AIDS dementia; may be caused by high lvls of virus in blood)
• Endocrine/metabolic: wasting syndrome
• GI: enteropathy
• Pediatric: growth and developmental retardation
• Diagnose first with HIV ELISA (p24 Ag) and than with Western blots (react proteins from gag, pol and env genes) to confirm

Viral Hepatitis: Common Symptoms

• virus induced inflammation of the liver
• prodrome: due to cytokines and liver dysfunction: fever, rash, arthritis, malaise, anorexia, vommiting, abdominal pain and headache
• disease: due to dysfunction: jaundice, dark urine, prodrome symp, light colored stools and hepatomegaly
• resolution: cell mediated immunity
• sequale: (HBV, HCV, HDV): cirrhosis, hepatic failure, and primary hepatocellular carcinoma (HBV and HCV)

Hep A Virus (HAV)

• RNA virus of the Picorna family(enterovirus)
• primarily fecal oral transmission (highest lvls in stool)
• no chronic sym or long term sequale
• rare complication of fulminant hepatitis, can also have cholestatic hep and relapsing hep
• Transmission: only in you short period of time, usually close personal contact or contminated food (handler or raw shellfish)
• inactivated virion HepA vaccine
• can also give immune globulin

Hep B Virus

• hepadnovirus family, ds circ DNA, enveloped 
• reverse transcriptase
• 5-10% risk of chronic, having mild acute puts you at higher risk
• 1% chance of acute phase fatalit
• most likely transmission when HBe Ag is positive
• perinatal transmission: 70-90% if mother is HBsAg and HBeAg positive and only 10% if only HBsAg is positive
• 90% of inected infants become chronic
• antiviral drug lamivudine
• Sequalae: primary hepatocellular carcinoma (PHC), polyarteritis nodusum, glomeronephritis, and cirrhosis
• recombinant Vaccine for Hep B 

Hep C virus (HCV)

• ssRNA (+) enveloped, Flavivirus
• primarily parenteral; sexual and vertical transmission less common
• often asymptomatic (rarely acute): 60-120 day incubation
• 80-90% chance of chronic infection
• Serology: Anti-HCV if chronic or not, use Ag (HCV RNA) testing to determine
• occupationl transmission inneficient
• infected infants do well (severe hep rare)
• antivirals not recomended for prophylaxis
• ELISA for blood and RT-PCR

Hep D Virus

• RNA virus of Deltavirus family (viroid in HBV env)
• need HBV envelope to replicate
• transmits sex, vertial and parenteral(60-180d incub)
• usually smptomatic; more severe acute or chronic disease than HBV alone
• coinfection has severe acute disease but low risk of chronic infection
• Superinfection (getting D after already having B infection) usually develops chronic (high risk of severe chronic liver disease)
• for coinfection pre or postexposure prophylaxis to prevent HBV infection
• for superinfection educate to reduce risk behaviors

Hep E virus (HEV)

• ssRNA (+) naked capsule, calicivirus primarily fecal-oral transmission
• incubation 21-42 days
• often asymp, similar to Hep A
• worse than Hep A in pregannt women
• no chronicity or long term sequalae
• normally 1-3% fatal but 15-25% fatal in pragnant women (older you get, more severe it is)
• can test for IgM and IgG anti-HEV
• most causes assoc w/ fecally contaminated drinking water (eating shit)
• minimal person to person transmission (how it differs from HAV
• avoid water, fruits/veggies, uncooked shell fish (mexico)
• Ig From western donors doesnt work well

Hepatitis G Virus (HGV)

• RNA flavivirus
• transmission parenteral; sex and vertical too
• often asymp: can be acute and chronic
• long term sign unknown

Rhabdovirus

(etiology and pathogenesis)

• ssRNA (-); large bullet shaped env
• replicates in cytoplasm; must bring in viral polymerase
• Replic: attachs to cells via viral glycoprotein G: nicotinc ACh rec/ ganglioside rec
• viral capsid dumped into cytoplasm: full length (+) template intermediat sym, progenylviral (-) RNA genome syn
• infects thru break in skin, replicates in muscles, spreads to nerves innervating (can also inf sensory nerves)
• once done w/ latent: spreads quickly thru CNS and out to many tissues
• neuronal dysfunction rather than neuronal death is considered responsible for fatal outcome (absence of necrosis)
• high amounts of virus in saliva (allows transmission)
• can also go to eyes 

Rabies Diagnosis

• easy if patient presents w/ hydrophobia after bite (cant swallow liquids)
• IF staining skin biopsy from neck 
• serology testing for anti-Ab against rabies common in US
• cytoplasmic inclusions: Negri bodies (not always there and only confirmatory; only post mortem)

Filovirus

• ssRNA (-) genome with envolope: distinc filamentous
• ebola and marburg virus (looks like yellow, dengue and lassa when first infection)
• viral glycoproteins: GP (masked by carbs) for rec binding, membrane fusion and cytotoxicity; secretory GP as a possible decory for Ab
• incubation 2-21 followed by sudden onset (fever, headache, joint and muscle pain, sore throat)
• symp followd by diarrhea, vomiting, stremoach pain, rash, internal and external bleeding may occur, death due to shock is common
• transm: direct contact or droplet spread onto mucous membranes or abrasions in skin (resp not a route)
• primary targets are DCs and macrophages
• secondary spread: liver, spleen lung and reticuloendothelial cells (cytotoxic in targets)
• apoptosis endothelial cells
• causes inflam cytokine storm that damages body and is resistance to interferon
• Viral Hemmorhagic fever (disables response by attacking cells that initiate antiviral responses (IFN)

Prion Disease

• transmissible spongiform enceph (TSE)
• rare neruodegenerative disease of CNS
• caused by prions-unconventional infect agents
• TSE can also be sporadic or genetic
• char by: lack of inflam, long latent period (40yrs), variable motor, cognitive and behav abnormalities, vacuolar pathology (empty), amyloid plaques, giosis, and acum of prion protein PrPsc
• no effective treatment and variable fatality

Two Major Forms of PrP

• coded by PNPP?
• PrP^c: glycophasphotidyl inositol (GPI)-linked membrane protein (needs this to cause disease/attachment); high alpha helical structure
• PrP^sc: AA sequence identical to PrP^c, high beta sheet structure (no alpha helices), PrP allele (129 M/M allele) determines susceptibility

Prion Detection and Quantification

• histology/immunochemistry-static gold standard
• Wester Blot/ELISA: rapid test kit-comercial purchse/use illegal; conformational dependent immunoassy (ELISA)
• Bioassy-active gold standard: wild type mice/hamsters, transgenic indicator mice, scrapie cell assay
• PMCA: protein misfolding cyclic amplification