Viruses (Week 1) Flashcards
3 things viruses cannot do on their own
1) Synthesize protein
2) Generate energy (no mitochondria)
3) Maintain ionic potential across membrane
Structure of a virus
1) Nucleic acid either RNA or DNA (ss or ds)
2) Protein capsid around nucleic acid
3) Some have envelope around capsid
Non-enveloped virus
MORE stable
Viral attachment proteins part of capsid
Transmitted fecal-oral
Ex: Hep A, poliovirus
Enveloped virus
LESS stable
Viral attachment glycoproteins on envelope (so if envelope destroyed by alcohol, attachment proteins gone too!)
Transmitted host-to-host (think skin to skin)
Ex: herpes, HIV
Why are enveloped viruses LESS stable than non-enveloped viruses?
Because envelope can easily be destroyed by alcohol, salt, etc, and the virus’ attachment proteins are on that envelope, once the envelope is gone, the virus has no way of entering/infecting a cell!
Viral life cycle (in general)
1) Enveloped virus uses its glycoproteins to attach to cellular receptor
2) Fusion of envelope with cellular membrane allows penetration of virus into cell
3) Production of empty capsids and nucleic acis
4) Empty capsids filled and pick up envelope and glycoproteins as they begin to egress
5) Viral production/completion and egress
What viral attachment proteins does influenza virus use?
Influenza virus has hemagglutinin (HA) on surface that binds to cell’s sialic acid protein to enter
Note: can surround HA with antibodies to prevent attachment/infection of cells with influenza
Types of human herpesviruses
1) Herpes simplex 1 (HSV-1)
2) Herpes simplex 2 (HSV-2)
3) Varicella zoster virus (VZV)
4) Cytomegalovirus (CMV)
5) Epstein-Barr Virus (EBV)
6) Human herpesvirus 6 (HHV-6)
7) Human herpesvirus 7 (HHV-7)
8) Human herpesvirus 8 (HHV-8)
Properties of all herpesviruses
1) Large double stranded DNA virus (125-240kb)
2) Enveloped virions
3) Establish life-long latent infections in host
4) Periodic reactivations from latent state
5) Diverse biology
HSV-1
Disease: fever blisters, ocular lesions, encephalitis
Site of latency: nerve ganglia
50-70% of adults seropositive
HSV-2
Disease: genital lesions, neonatal infections, meningitis
Site of latency: nerve ganglia
20-50% adults seropositive
VZV
Disease: chickenpox (primary), shingles (recurrence)
Site of latency: nerve ganglia
Sequence of events of CHICKENPOX: airborne transmission –> viremia, replication in organs, incubation of 2 weeks –> virus emerges from capillaries to skin
CMV
Disease: mononucleosis, congenital infections, immunocompromised gastritis, retinitis (AIDS pts), pneumonia (bone marrow transplant pts)
Site of latency: monocytes, neutrophils, vascular endothelia
Transmission: in utero (TORCHES), perinatally, postnatally (saliva, sexual)
Negative monospot (heterophil antibody) test
Cytopathic effect = owl’s eye (nuclear inclusions, factories making lots of viral DNA)
Treat with gancyclovir
HHV-6 and HHV-7
Disease: roseola in infants
Site of latency: T cells, monocytes, macrophages
EBV
Disease: infectious mononucleosis, Burkitt’s Lymphoma, nasopharyngeal carcinoma
Site of latency: B lymphocytes
HHV-8
Disease: Kaposi Sarcoma, tumors
Site of latency: virus infected tumors
Life cycle of HSV-1
Overall: get into cell, create proteins needed for DNA replication, do DNA replication, create proteins for virus to be packaged, package virus with new DNA inside and egress
1) Viral glycoproteins attach to receptors on cell membrane, allowing fusion and entry of virus into cytosol
2) Transcription (then translation) of 5 viral genes using the cell’s DNA-dependent RNA polymerase, and 2 of these genes activate early gene transcription
3) 2 important early genes are DNA polymerase and thymidine kinase, which activate viral DNA synthesis
4) Rolling circle of viral DNA replication (note: acyclovir blocks this step!)
5) After DNA synthesis, THEN late proteins (capsid, viral glycoproteins) made and form empty capsids to be filled with viral DNA
6) Viral glycoproteins from first cell fuse the surrounding cells so virus plows through cells (need CD8 cell-mediated immunity to kill virus!)
HSV-1 and HSV-2 in latency
HSV-1 enters through lips or eye and establishes latency in trigeminal ganglion
HSV-2 is latent in DRG
Latent DNA exists as episomal circles and no viral proteins transcribed, only RNA for LAT (intron)
Stimuli such as UV light may cause reactivation
Why don’t we kill HSV latently infected neurons?
No viral protein made in latency so no target on cell membrane to go after to kill latently infected neurons!
How are HSV transmitted?
Skin to skin contact when there is some abrasion or chapping (cannot penetrate intact skin)
Remember though, virus can be shed asymptomatically–no sores, but still little breaks in skin!
NOT hematogenous spread!
Tissue tropism of HSV
HSV-1 causes 95% of orofacial herpes and 10-30% of primary genital herpes (NOT recurrent); anything above the belt
HSV-2 causes primary and recurrent genital infections and rarely causes oral herpes
Note: when in its tropic area, will reactivate more but if not in tropic area will not reactivate
Disease syndromes caused by HSV-1
1) Gingiviostomatitis
2) Herpes Whitlow (finger)
3) Encephalitis
4) Keratitis (ulcers on cornea)
5) Eczema makes lesions worse
Do you usually have viremia (virus in the blood) with HSV?
Not sure?!
However, have viremia in 30% of primary vaginal infections
Genital herpes
HSV-2 (definitely if recurrent, and most likely primary too)
Lesions more prone to secondary bacterial infection by S. aureus, Streptococcus, Trichomonas and Candida albicans
60% of patients experience recurrences
Recurrences usually longer than oral HSV-1 lesions
Herpes simplex encephalitis
One of most serious complications of herpes simplex
1) Neonatal: entire brain almost liquefied; mortality almost 100%
2) Focal disease: temporal lobe most commonly affected; appears in kids and adults; could be from reactivation of virus; 70% mortality without treatment
Give IV acyclovir if HSE is suspected, before lab tests come back
Neonatal herpes simplex
Baby infected during passage through birth canal
Greatest risk when mother has primary infection (has sex and contracts HSV days before birth)
Have lower viral titer and have specific antibody if recurrent infection so smaller risk
Spectrum from mild skin infection to fatal disseminated infection
Disseminated herpes simplex
Widespread vesicular rash (like chickenpox)
Other organs involved (liver, spleen, lungs, CNS)
More likely in immunocompromised individuals
Zosteriform herpes simplex
Rare presentation of herpes simplex where HSV lesions appear in dermatomal distribution similar to herpes zoster
Antiviral drug mechanism of action
Examples of antiviral drugs: acyclovir, ganciclovir, famciclovir, valaciclovir
Viral thymidine kinase adds monophosphate onto 5’ OH –> cellular enzymes add 2 more to make triphosphate –> acyclovir incorporated into DNA –> however, acyclovir has no 3’ OH so DNA chain is terminated! –> also, viral DNA polymerase binds and is inhibited by acyclovir so can no longer be active
Note: acyclovir has to be phosphorylated by viral thymidine kinase to even be added to the DNA chain, so will only halt DNA synthesis in virally infected cells that HAVE viral thymidine kinase. In other cells that acyclovir enters, it won’t get phosphorylated (because cellular thymidine kinase will NOT phosphorylate it), so won’t be added to the DNA chain!
Use of acyclovir for HSV
Acyclovir taken daily suppresses oral and genital recurrence
IV acyclovir effective against encephalitis (HSE) and neonatal herpes
Lab Diagnosis of HSV
Immunofluorescence of skin scraping (distinguish HSV from VZV)
PCR (used to diagnose HSE)
Virus isolation (cultivate for 1-5 days; easy to do)
Serology not helpful because takes 1-2 weeks for antibodies to appear after infection
When do we use antiviral chemo-therapy?
Only if severe primary infection, dissemination, sight threatened, herpes simplex encephalitis (HSE)
Very expensive!
Asymptomatic shedding of HSV
Can transmit virus to another person (via skin to skin contact) even when no presence of lesions
Both HSV-1 and HSV-2
Only form of shedding in ~2/3 of patients
Accounts for most transmissions
Low viral titers
Not completely suppressed by acyclovir
Positive (+) stranded RNA viruses
Just like mRNA
When (+) RNA enters host cell, can immediately be translated by host’s ribosomes into protein
Negative (-) stranded RNA viruses
When (-) stranded RNA enters cell, must be transcribed into (+) strand RNA using RNA-dependent RNA polymerase
(only virus has RNA-dependent RNA polymerase–has to carry it in their capsid)
2 types of capsid
1) Icosahedral (20 triangles put together)
2) Helical (protein capsomers bound to RNA)
Why do people get blisters as a result of HSV infection?
HSV migrates out to skin via nerves –> HSV causes cell destruction (multinucleated giant cells and intranuclear inclusion bodies as a result of cell fusion) –> separation of epithelium causes blisters (vesicles)
Note: CMV and EBV have less of this cytopathic effect
How does varicella (chickenpox) cause infection?
Virus infects respiratory tract –> replicates for 2 week incubation period –> viremia (viral dissemination in bloodstream)
Note: VZV is unitue in being transmitted so readily through air
Is shingles contagious?
Yes someone with shingles can give the VZV to someone else
However, that person would get chickenpox, NOT shingles
“you get shingles from yourself” (by definition it is a reactivation)
Enterovirus
Subtype of picornavirus
Infect intestinal epithelial and lymphoid (tonsils, Peyer’s patches) cells
Spread fecal-oral route
1) Poliovirus
2) Coxsackie A viruses
3) Coxsackie B viruses
4) Echovirus
Complications of chickenpox (varicella)
1) Bacterial superinfection of lesions (mainly children)
2) Varicella pneumonia (more in adults)
3) Neonatal varicella (mother is seroNEGATIVE but baby gets it from a nurse)
4) Encephalitis
5) Reyes syndrome, a neuroencephalopathy (liver failure –> toxic buildup of bilirubin –> brain cells damaged); because of Aspirin
Varicella vaccine
Actively replicating, attenuated virus (33 mutations)
Prevents 70-90% of chickenpox and reduces severity in the rest
2 doses
Can still reactivate to cause shingles (because TK gene intact, and virus still replicating)
Vaccine is just a low enough dose of virus so you don’t get a rash
Probably fewer vaccinated children will get shingles becaus the vaccination seeds fewer neurons so lower chance of getting reactivated
Note: zoster vaccine given to people over 65 is SAME virus, just higher dose
Complications of Zoster (shingles)
1) Postherpetic neuralgia: affects 25-50% of zoster patients over 50
2) Ramsay Hung syndrome: pain and vesicles in external auditory canal; lose sense of taste in anterior 2/3 of tongue; ipsilateral facial palsy; involves geniculate ganglion of sensory branch of facial nerve
Why only a few vesicles in HSV and many in VZV?
HSV can only go from cell body to axon to dendrites to next neuron (linearly)
VZV can go horizontally through myelin sheath to many other nerves in the bundle
Prevention of varicella
1) Zoster immunoglobulin (ZIG) for passive immunization in children who need urgent protection
2) HNIG (human normal serum?) for passive immunization too because has many antibodies
3) Varicella vaccine
How does our body recognize virus?
1) TLR3 recognizes viral dsRNA; TLR7 recognizes viral ssRNA (Macrophages and neutrophils have highest levels of TLRs; Dendritic cells, NK cells, T cells and B cells have a few TLRs)
2) Our own RNA helicases recognize dsRNA, try to unwind it and in so doing, signal the presence of dsRNA (end up producing IFN-a, IFN-b, etc)
How do interferons fight viral infections?
1) IFN-a and IFN-b (Type I INFs) cleave host and viral mRNA to block translation into proteins (kill cell, but kill virus too)
2) IFN-a and IFN-b (Type I INFs) activate NK cells to kill viral infected cells
3) IFN-g (Type II IFN), secreted when IL-12 activates NK cells, activates macrophages which secrete cytokines to help T cells
4) All IFNs upregulate expression of MHC-I on cells so they’re more susceptible to T cell destruction
5) IFN-a and IFN-b induce strong Th1 response
Which T cells are needed for which types of infection?
1) CD4 Th2 needed for extracellular (bacteria)
2) CD4 Th1 needed for intracellular within phagosomes (bacteria)
4) CD8 needed for intracellular viruses and uses MHC-I which is on all cells (?)
What is the best APC for viral antigens?
Dendritic cell
4 steps to make a cytotoxic T cell
1) Virus infected dendritic cell activates TLR3, RIG-1 or MDA-5 (RNA helicases) for dsRNA or TLR7 for ssRNA
2) Activated DC presents viral peptides on MHC-I to naive CD8 T cells
3) IL-2 secreted by T cellls, increased affinity of IL-2 receptors on T cells, CD8 T cells differentiate into cytotoxic (killer) T cells
4) Cytotoxic (killer) T cells recognize viral infected cells by seeing viral peptides on MHC-I, secrete granzyme B (protease) and perforin to destroy cell membrane and cause lysis
Congenital CMV infection
Most common congenital viral infection, second most common cause of mental handicap (after Down’s)
May result in Cytomegalic Inclusion Disease (CNS, eye, ear, liver, lung, heart, blood sequelae)
CMV gastroenteritis/colitis
In immunocompromised individuals, get effects on esophagus, stomach, small intestine, colon (pain, dysphagia, nausea, vomiting, ulcers, diarrhea)
Infectious Mononucleosis
Caused by EBV
EBV infects B cells –> causes B cells to be transformed and proliferate and pass on copies of EBV DNA to progeny –> cytotoxic T cells react to abnormal B cells to kill them (this immune response is what causes disease symptoms) –> eventually T cells win (however, EBV can reactivate later just like all good herpesviruses can!)
Disease symptoms: fever, chills, sweats, headache, painful pharyngitis (sore throat), enlarged lymph nodes, enlarged spleen (prone to rupture!)
High WBC count with atypical lymphocytes (large activated T lymphocytes)
Positive Monospot test (heterophile antibody against EBV that cross reacts with and agglutinates sheep red blood cells)
EBV latency
10 EBNAs (Epstein-Barr nuclear antigens) and LMP (latent membrane protein) are made in latently infected B cell
EBNA-1 binds origin of replication of EBV genome and partitions circular DNA among B cell chromosomes as it divides
Other EBNA proteins immortalize B cell in return for B cell keeping many DNA circles around
What causes proliferation of mononuclear cells in Infectious Mononucleosis?
1) B cells transformed by EBV so are proliferating more than normal
2) EBNAs and LMP are foreign antigens inside B cell during latency, but are presented on MHC-I on surface of B cell BECAUSE they are foreign and this triggers a CD8 cytotoxic T cell response to those latently infected B cells
How do you tell the difference between EBV mononucleosis and CMV mononucleosis?
1) EBV will have positive monospot test (heterophile antibody positive) and CMV will not
2) EBV will have VCA (viral capsid antigen) antibodies and CMV will not
EBV and lymphoproliferative disorders
EBV found in cancer cells of Burkitt’s lymphoma which affects children in Africa –> since people in other places with EBV don’t get Burkitt’s lymphoma, thought that EBV is just a co-factor –> since EBV causes rapid uncontrolled B cell growth, may cause chromosomal arm translocation (c-myc with immunoglobulin enhancer on chrom 14, 22, 2) that has been associated with Burkitt’s lymphoma
Other lymphoproliferative diseases may also be secondary to EBV reactivation (Non-Hodgkin’s lymphoma, Hodgkin’s disease)
Picornaviruses
Non-enveloped, (+) stranded, IRES where translation begins, codes for long polyprotein that has viral proteases within it, fecal-oral transmission (ingestion of contaminated food and water)
1) Enterovirus: infect intestinal epithelial and lymphoid cells ( poliovirus, coxsackie A and B, echovirus, enterovirus
2) Rhinovirus: 185 serotypes
3) Heparnavirus: hepatitis A virus
Replication of retroviruses
1) 2 ssRNA molecules and reverse transcriptase contained in virions
2) ssRNA –> RNA-DNA hybrid –> remove RNA to make DNA-DNA –> dsDNA (cDNA) integrated into human chromosome using viral integrase enzyme
3) Viral genes transcribed using host cell RNA polymerase and LTRs as promoters
Poliovirus
Picornavirus
Viremia –> infection of anterior horn cells of spinal cord and motor cortex of brain
2 poliovirus vaccines
1) Live oral polio vaccine (OPV): Albert Sabin; attenuated; can revert/pick up virulence and cause paralysis; used only in areas where polio is endemic (NOT used in US)
2) Inactivated polio vaccine (IPV): Jonas Salk; injected, causes IgG antibody response to prevent viremia; only 94% effective; used in US
Coxsackievirus A
Picornavirus
Causes herpangina, hand-foot-and-mouth disease
Coxsackievirus B
Picornavirus
Causes pericarditis, myocarditis, pleurodyina
Enterovirus 70
Picornavirus
Causes paralytic disease and acute hemorrhagic conjunctivitis
Enterovirus 71
Picornavirus
Causes paralytic disease and hand-foot-and-mouth disease
Echovirus
Picornavirus
Causes paralytic disease, encephalitis, meningitis, myocarditis, GI disease
Rhinovirus
Picornavirus
Replicates in the nose; optimal replication temp is 33 degC; sensitive to low pH so doesn’t replicate in GI tract
Causes common cold
More than 100 different serotypes
Rhinovirus A and B found in nose; Rhinovirus C causes lower respiratory tract disease
Coronavirus
Not part of a bigger class, but enveloped and (+) strand RNA virus
Causes common cold (less frequently than rhinovirus)
Includes SARS virus
Arbovirus
Means that is transmitted by insects
Includes bunyavirus, togavirus, flavivirus
Togavirus
1) Alpha viruses cause encephalitis (Western equine encephalitis; Eastern equine encephalitis; Venezuelan equine encephalitis)
2) Rubivirus causes rubella
Rubivirus (rubella)
Togavirus
Only infects humans
Congenital rubella (TORCHES)
This virus causes rubella = German measles
Transmitted via respiratory tract
Flavivirus
Not part of bigger class, enveloped, (+) strand RNA virus
Cause encephalitis (Japanese encephalitis, Russian encephalitis, St. Louis encephalitis), Yellow fever, Dengue fever, West Nile fever
Retrovirus
(+) strand RNA viruses (2 RNAs per virion); enveloped, packages reverse transcriptase
Includes oncoviruses (HTLV-1, HTLV-2), leukemia (rous sarcoma virus in chickens), lentiviruses (HIV-1, HIV-2)
Reovirus
dsRNA, non-enveloped, double-layered capsid (outer capsid digested in GI tract), 10-12 RNA segments (can get reassortment)
Rotavirus is a type of reovirus (?): causes infantile diarrhea; fecal-oral route
3 strains of influenza virus
Influenza A: toggles between human and animals
Influenza B: only humans
Influenza C: not pathogenic
Influenza A
Shuttled between humans and animals
Has 8 RNA segments of (-) sense ssRNA
Life cycle of influenza virus
1) HA protein binds sialic acid receptor on cell surface
2) M2 ion channel imports H+ ions, denaturing HA protein and releasing capsid into cytoplasm
3) Enclosed RNA polymerases transcribe 8 RNA segments (in the nucleus)
4) HA protein cleaved before packaging
5) NA helps virus egress (cleaves sugars that still attach virus to membrane)
How do we make subtypes of influenza A virus?
Use 3 HA subtypes (H1, H2, H3) and 2 NA subtypes (N1, N2)
Ex: H3N2
Proteins contained on envelop of influenza virus
Hemagglutinin (HA)
Neuraminidase (NA)
Why is it that human flu strains (influenza A or B) can only infect the lungs (not the stomach)?
Because the HA of human flu strains are only cleaved by a protease in the lung, so human influenza viruses can only infect cells in the lung (can’t affect cells anywhere else in the body!)
H5N1 is a non-human influenza virus that can be cleaved by furin, which is present in all tissues (pantropic!)
Pandemic
Nobody on earth has seen this virus before
Antigenic shift
Reassortment/trading of RNA segments between animal and human strains
Two influenza types co-infect same cell, undergo replication and capsid packaging, and RNA segments are mispackaged into a new virus!
Complete change in HA, NA or both
Humans have never been exposed to this HA or NA ever before!
Orthomyxoviridae
Spherical virions
8 segments of (-) strand RNA put together with nucleocapsid protein into helical symmetry capsid
Around nucleocapsid is outer membrane with long glycoprotein spikes (either HA or NA)
Hemagglutinin (HA)
Glycoprotein on envelope of influenza virus
Attaches to host sialic acid receptors (which are on RBCs and upper respiratory tract cell membranes
HA needed for adsorption
Neuraminidase (NA)
Cleaves neuraminic acid which is in mucin and is part of host’s upper respiratory defense barrier –> exposes sialic acid binding sites beneath
Critical for release of newly formed virion from infected host cell (as virus buds out of host membrane, virion’s HA still attached to host’s sialic acid receptor, so NA cleaves this)
Antigenic drifty our immune system
During viral replication, mutations occus in HA or NA
Small changes add up and resulting new strains aren’t attacked well by our immune system
Can you get a pandemic a second time?
Yes, if the initially infected people have all died already
Ex: H1N1 in 1918 then again in 1977?
Drugs for treatment and prophylaxis of influenza virus infections
1) Adamantanes (amantadine and rimantadine): M2 ion channel inhibitors inhibit acidification of inside of virion which is required for viral uncoating; effective only against influenza A
2) Neuraminidase inhibitors (zanamivir (Relenza, inhaled) and oseltamivir (Tamiflu, oral)): interfere with release/egress of progeny virus from infected host cell; effective against influenza A and B
3) Antibodies neutralize HA so can’t bind to sialic acid to enter the cell
H5N1
“Avian flu” that started in Asia, is epidemic in birds and spread to a few people
H5 protein binds better to a2,3 sialic acid (in chickens) than to a2,6 sialic acid (in humans), but we worry that mutation in H5N1 will cause it to be able to bind a2,6 well and then will be able to grow to high titer and transmit from human to human
Very pathogenic for 3 reasons:
1) More invasive than human viruses because HA can be cleaved by furin which is in all tissues (can infect all tissues) = pantropic
2) Two genes of the virus are able to mask immune response and increase replication efficiency
3) Humans have no exposure to H5N1 so have no immunity to the H5 protein
When someone is reinfected with similar or same strain of influenza, which antibodies are used to neutralize the response?
IgM against HA
IgG against HA
Nasal IgA against HA
Which sialic acids do humans have?
Mostly alpha2,6
Only very few cells in the nose and lung have alpha2,3
SARS virus
Coronavirus
Was transmitted from bats, due to antigenic drift (couldn’t have reassortment/antigenic shift because only has 1 RNA)
Clinical features: 2-10 day incubation, then fever, myalgia and chills, then dry cough and chest pain and SOB (no sore throat or rhinorrhoea), can progress to ARDS
Classic flu-like symptoms
Fever, malaise, myalgia, sore throat, nonproductive cough
In children: high fever (watch for seizures, keep temp under 101), GI symptoms (due to cytokines, not stomach bug), otitis media, croup, myositis (inflammation of muscle)
Complications of influenza
1) Viral pneumonia (primary)
2) Secondary bacterial pneumonia (usually Streptococcus pneumonia)
3) Reye’s syndrome if give kids Aspirin for fever (so give acetaminophen instead!)
How do we make influenza vaccine?
Take one strain in human population (H1N1) and reassort it with Puerto Rico strain, then take another strain in human population (H3N2) and reassort it with Puerto Rico strain, and one more –> get 3 different flu strains into a vaccine strain by reassortment
What can we use for the influenza vaccine?
1) Formalin-inactivated whole virus
2) Chemically disrupted virus (subvirion)
3) Purified antigens
FluMist
Live attenuated influenza vaccine administered by intranasal spray
Cold mutant (grows better in colder temperatures)
Gives T cell immunity, mucosal immunity (IgA) and IgG immunity
Much more effective than inactivated flu vaccine that most people get
Parainfluenza (PIV)
1 segment of RNA (so no reassortment)
ssRNA (-) sense
3 serotypes so no antigenic drift
No vaccine, highly infectious, respiratory transmission, cause pediatric infections
Complications: croup (inflammation of subglottal region –> difficulty breathing, high pitched inspiration and barking, spasmodic cough and stridor)
Respiratory Syncytial Virus (RSV)
1 RNA segment
ssRNA (-) sense
Lower respiratory virus
Major cause of bronchiolitis, important cause of infant pneumonia
Mumps
1 RNA segment
ssRNA (-) sense
Infects epithelial cells of nasal mucosa and upper resp tract
Parotid gland swelling
Complications: CNS involvement, infection of ovaries and testicles
MMR vaccine
No link between MMR vaccine and autism!
Measles, Mumps, Rubella
Live attenuated virus
Measles
1 RNA segment
ssRNA (-) strand
Infets epithelial cells of oropharynx and upper resp tract
Virus spreads to regional lymph nodes
Viremia
Prodromal phase of coryza, conjunctivitis, cough
Clinical syndrome: Koplik’s spots on buccal mucosa, head to toe rash
Nipah virus
In Asia, in fruit bats (then to pigs then to humans)
Encephalitis (often fatal) in humans
Human metapneumovirus (hMPV)
Causes rhinorrhea, congestion, cough, tachypnea, wheezing, rales
Patients more at risk are cancer pts, elderly, and adults with underlying medical conditions
Rabies
Rhabdovirus
Can be asymptomatic or can show symptoms 60-365 days after bite
Symptoms: fever, nausea, vomiting, lethargy
Negri body is the inclusion body of rabies virus
Bunyavirus
200 different versions of them
Most are arboviruses (from arthropods/insects)
Hantaan virus is not arthropod borne, and can infect lung or kidney
Haantavirus
Bunyavirus
Aerosol inhalation of rodent excreta; infection initiated and remains in lung; no human to human transmission
Hantavirus pulmonary syndrome (HPS): fever, myalgia, abdominal pain, pulmonary edema, sometimes shock
Capillary leak syndromes: infection of endothelial cells, no cytotoxicity, T cells and cytokines create gaps between endothelial cells
Lung: HPS with pulm edema, shock and resp failure
Kidney: Hemorrhagic fever with renal syndrome (HFRS) with hypotension and shock, renal failure
Filovirus
Marburg virus
Ebola virus: comes up in Africa
Modes of transmission: direct contact, droplets onto mucous membranes, fomites, body fluids, airborne
Symptoms: flu-like, bleeding (petechiae is bleeding from capillaries and eccymoses are large purple spots), rash, death by shock
2 groups of viruses that require really high CD8 immunity
1) Paramyxoviruses
2) Herpesviruses
What virus is most likely to cause pneumonia in children vs. adults vs. immunocompromised?
Children: RSV, PIV
Adult: influenza
Immunocompromised: CMV
IgG vs. IgM
IgM: produced in primary (immediate) response to antigen)
IgG: main antibody in secondary (delayed) response to antigen; most abundant in blood
Viruses that cause gastroenteritis
1) Calicivirus: norovirus (most common in US)
2) Reovirus: rotavirus (most common worldwide)
3) Other: adenovirus 40 and 41, sapoviruses, astroviruses, aichi virus-picornavirus
Rotavirus
Reovirus
dsRNA, 11 RNA segments, non-enveloped
Most common cause of infantile diarrhea worldwide
Causes wintertime vomiting disease
Group A capsid most common in US
Treatment is IV hydration for diarrhea
Vaccines: Rotateq (bovine rotavirus x 5 human strains of rotavirus), Rotarix
Norovirus (Norwalk agent, Norwalk virus)
Calicivirus
ssRNA, (+) sense, non-enveloped, fecal-oral
Outbreaks on ships, in schools, in older children and adults
Viruses that cause hepatitis
Hep A, B, C, D, E
EBV, CMV, yellow fever virus
Which hepatitis viruses produce only acute phase?
Hep A and E (AcutE)
They are both non-enveloped
What happens during the chronic phase of hepatitis?
Chronic hepatic inflammation
Hepatic fibrosis, cirrhosis, liver failure
Increased risk of hepatocellular carcinoma
(note: only with Hep B, C, D, G)
Hepatitis A virus
ssRNA, (+) sense
Non-enveloped (very stable capsid), icosohedral capsid
4 genotypes but only 1 serotype
Transmitted fecal-oral
Pathogenesis of HepA virus
Enters portal bloodstream through intestinal epithelium
Replicates in hepatocytes and Kupffer cells
Released by exocytosis (not cell lysis!)
Goes into bile, intestine, excreted in feces (in blood transiently)
Shed virus for 10 days prior to symptoms
Note: immune response causes damage to hepatocytes (hepatitis), not cell lysis!
Acute HepA infection
May be mild or asymptomatic, especially in children
Abrupt onset of disease in adults
“Self-limited” so cleared by immune system
Low mortality
Diagnosis and treatment of Hep A
Antibody detection: IgM in acute infection (4-6 months) and IgG present for decades
Virus in feces by electrom microscopy
PCR
There is no antiviral treatment, just supportive care
Hep A vaccine
Passive immunization: Hep A immune globulin (polyclonal anti-Hep A antibodies persist for 6 months) but not used much for pre-exposure prophylaxis, only sometimes if <2 weeks post-exposure
Active immunization: inactivated whole virus vaccine
Hepatitis E virus
Calicivirus
ssRNA, non-enveloped, fecal-oral transmission
Similar to Hep A but higher rates in pregnancy (10-20%)
Vertical transmission (during birth)
No vaccine available
Incubation periods for different hepatitis viruses
Hep A and E: 15-50 days
Hep B: 45-160 days
Hep C and G: 15-180 days
Hep D: 15-64 days
Symptoms during acute infection of hepatitis
Prodrome: malaise, anorexia, fatigue, fever, nausea, vomiting, RUQ pain, if doesn’t progress to icteric phase, could never know that this was hepatitis!
Icteric phase: elevated serum bilirubin causes jaundice (>2.5mg/dL), acholic stools (light), dark urine, hepatomegaly, elevated ALT>AST, elevated alkaline phosphatase, decreased synthesis of albumin and clotting factors
Symptoms during chronic infection of hepatitis
Chronic hepatic inflammation
May progress to hepatic fibrosis, cirrhosis, liver failure, increased risk of HCC
Most of global morbidity and mortality of viral hepatitis due to chronic infection (not acute)
Hepatitis B
(partially) dsDNA, small circular, enveloped, unusually stable to solvents/heat/low pH
Huge amount of surface antigen (appears free in serum of infected patients)
Antibody response to HBsAg associated with viral clearance; core antigen (HBcAg) not detected in serum (but antibody can be measured!); e antigen (HBeAg) made from precore protein, detectable in serum and associated with chronic active hep B with increased production of virus and increased activity of infection
Transmission: blood and bodily fluids
Pathogenesis of Hep B virus
Virions released by exocytosis, not cytolytic
Cell-mediated immune response (CD8) leads to injury and destruction of infected hepatocytes: infants have mild symptoms/asymptomatic because weak CD8 immune response, but adults have good immune response and some can even get such a huge immune response that get fulminant hepatitis and die from acute hep B infection
Acute Hep B infection
Longer incubation period prior to symptoms
Insidious onset of symptoms rather than abrupt like Hep A
Can get immune complex disease related to HBsAg: rash, arthritis, fever, necrotizing vasculitis (polyarteritis nodosum), glomerulonephritis)
Diagnosis of Hep B
NOT based on clinical symptoms
Serologic tests
DNA assay (PCR)
Chronic Hep B infection
Occurs in 5-10% of acute infection
Happens when cell mediated immune response doesn’t clear all virally infected cells
10% go on to develop cirrhosis of liver failure
Always see HBsAg, but only in early phase see HBeAg
If see anti HBe, means have cleared HBeAg, and that is associated with better prognosis
Will see anti-HBc antibodies early on–good way to detect infection
Phases of chronic Hep B
1) Replicative, immune tolerance: high levels of replication, HBeAg, HBV DNA, little/no evidence of active liver disease
2) Replicative, immune clearance: spontaneous clearance of HBeAg with HBeAb, may be minimally symptomatic or severe with acute liver failure
3) Low or non-replication (“chronic persistent”): no HBeAg but have HBeAb, may have HBsAg but less HBV DNA (via PCR), no HBsAb; less likely to develop cirrhosis of HCC
Hep B vaccine
Recombinant HBsAg
Series of 3 injections
All newborns are required to get Hep B vaccine
Hepatitis D virus
Defective virus
ssRNA, small circular
Single Hep D antigen
Need lipid envelope from HBV in order to package so can only get Hep D if you have or are getting Hep B too!
Replicates very efficiently in hepatocytes
Increases risk of fulminant hepatitis, cirrhosis
No vaccine
Unlike other hepatitis viruses, Hep D KILLS liver cells!
Hepatitis C virus
(+) RNA virus
Prolonged cell-associated state where virus in hepatocytes but not replicating much, low level chronic cell-mediated host immune response (person can be infected but never know that they have it)
Some patients get hepatic fibrosis and cirrhosis
Transmission via blood (not sexually)
Diagnosis: RNA in serum, HCV antibody positive (but this is not associated with viral clearance like Hep B is!)
No vaccine
Hepatitis G virus
Flavivirus (distantly related to yellow fever and dengue fever viruses)
30% homology to hep C, but probably does not even cause hepatitis!
May have protective effect in HIV
Transmission is parenteral (blood, body fluids)
Serology for acute hepatitis infection
sAg +
sAb -
eAg +
eAb -
cAb +
How do you know if someone has had a natural hepatitis infection?
Will always have antibody to core protein (cAb +)
Human papillomavirus
Papovavirus
dsDNA, non-enveloped
Causes benign cutaneous warts (feet, hands, face, also oral, laryngeal, genital)
Malignant potential: HPV-16, 18 (for genital carcinoma)
Functions of early genes of HPV
E1: DNA replication
E2: downregulates transcription of E6 and E7
E5: on cell membrane; can stimulate transforming action of EGF
E6: in oncogenic HPV (16, 18), binds p53 tumor suppressor protein and degrades it
E7: binds Rb tumor suppressor protein so can no longer bind/inactivate E2F and now E2F is free to activate transcription
Koliocytes
HPV-producing cells
Have dark stained nuclei with halo (no cytoplasmic staining) with pyknotic nuclei
Appear in granular layer?
Do colposcopy, and if see red or white cells, that is abnormal
If you have negative HPV test (no HPV DNA, so no/undetectable HPV infected cells), does that mean you don’t have HPV?
Not necessarily
All HPV infected cells present antigenic proteins on MHC-I to attract CD8 cells, so can get spontaneous loss of HPV-positive cells between pap smears
How does HPV cause invasive cervical cancer?
1) Integration with E2 causes increased synthesis of E6 and E7
2) E6 inactivates p53 and E7 inactivates Rb
3) Cell division, DNA damage, aneuploidy
4) Invasive cervical cancer
(CIN1 then 4-7 years later CIN3 then 15 years later invasive cervical cancer)
Treatment for HPV
Imiquimod (induces IFN-a, cytokines)
Also cryotherapy, loop or cone section, podophylin
Gardasil
Quadrivalent vaccine against HPV: strains 16, 18 (likely to cause cervical cancer), 6, 11 (likely to cause genital warts)
Contains virus-like particles of empty DNA surrounded by L1 protein
Almost 100% effective in women, and also some protection against other strains
Effective in males to prevent genial warts
Polyomavirus
Papovavirus
SV40 (monkeys)
Polyoma virus (mouse)
BK (ubiquitous)
JC (causes PML in immunocompromised)
Transmissible spongiform encephalopathies (TSE)
These are all prions
1) Scrapie (sheep)
2) Mad cow disease
3) Creutzfeld-Jakob disease (CJD)
How do prions form?
1) Mutations cause misfolded proteins = prions
2) Prions can interact with normal proteins to turn them into prions
Categories of CJD
1) Sporadic (85%)
2) Hereditary (5-10%)
3) Acquired: transmitted by exposure to brain or nervous system tissue usually through medical procedures
Parvovirus (B19)
ssDNA, non-enveloped
Replicates in erythroid precursor cells
Causes Fifth disease/erythema infectiosum (slapped face rash on cheeks and fever), aplastic crisis (suppression of erythropoiesis), hydrops fetalis, arthralgia and arthritis
Respiratory transmission
Two phases of infection: (1) fever, malaise, myalgia, viremia for 1-2 weeks; (2) drop in hemoglobin, rash caused by immune complexes and infection of epidermal cells
No therapy, no vaccine
Five childhood exanthems or rashes
1) Measles (paramyxovirus)
2) Rubella (togavirus)
3) Roseola (herpesvirus 6 and 7)
4) Varicella (varicella zoster, a herpesvirus)
5) Fifth disease (B19 parovirus)
Poxvirus
dsDNA, enveloped, largest virus
Variola (smallpox), vaccinia (vaccine strain; combo btwn variola and cowpox), molluscum contagiosum
Replicates in cytoplasm!!
Carries many enzymes in virion
Respiratory transmission (very contagious)
Adenovirus
Different serotypes cause many different symptoms
dsDNA, non-enveloped
Cause 10% of respiratory infections in children
For what diseases would you give passive immunization after exposure?
Varicella
CMV
Hep A
Hep B
Rabies
For which diseases do you give active immunization?
MMR
Influenza
Rotavirus
Hep A and B
Varicella
HPV
For which diseases do we give antiviral therapy?
Influenza, RSV
HSV-1, HSV-2, VZV, CMV, EBV
Hep B, Hep C
Papillomavirus
Retrovirus (HIV-1, HIV-2, HTLV-1)
Neuraminidase inhibitors
Both Zanamivir and Oseltamivir are structural analogues of sialic acid
Oseltamivir has good oral bioavailability due to ester moiety
Drugs for ophthalmic infections caused by herpes viruses
Cidofovir: nucleotide analogue; treat CMV (delay progression of CMV retinitis in AIDS), herpesviruses; nephrotoxicity, neutropenia and metabolic acidosis
Fomivirsen: 21 nucleotide antisense oligonucleotide for intravitreal injection; suppress reactivation of CMV retinitis; iritis, vitritis, other complications
Trifluridine (trifluorothymidine): topical treatment for herpetic keratitis
Foscarnet
Treat acyclovir-resistant HSV, ganciclovir-resistant CMV
Block cleavage of pyrophosphates –> interfere with viral DNA synthesis
Side effects: renal tubular dysfunction, electrolyte abnormalities, anemia, diarrhea, genital ulcers (lots of toxicity, so this is second line drug!)
Drugs for Hep B
INF-a-2b
Peginterferon a-2a
Lamivudine
Entecavir
Telbivudine
Adefovir
Tenofovir
Lamivudine
3’ thiacytidine
Interferes with viral DNA polymerase and reverse transcriptases
Side effects: uncommon at doses used to treat Hep B (if treating HIV with larger dose: pancreatitis, lactic acidosis, hepatomegaly, steatosis, headache, fatigue, nausea)
Resistance develops in 25% of patients within a year
Entecavir
Deoxyguanosine nucleoside analogue –> inhibits HBV DNA polymerase
Well absorbed, little metabolized
Side effects: well-tolerated; headache, fatigue, dizziness, abdominal pain, fever, diarrhea, cough, myalgia
Telbivudine
Thymidine analogue –> inhibits HBV DNA polymerase
Well absorbed, little metabolized
Better than lamivudine!! (less resistance)
Side effects: well-tolerated but similar to lamivudine; lactic acidosis, myopathy, creatine kinase elevations
Adefovir
Acyclic adenosine monophosphate nucleotide analogue –> interferes with DNA polymerase and reverse transcriptase
Side effects: at doses used to treat Hep B get severe exacerbations of hepatitis in 25% after cessation
Resistance: several percent per year
Drugs for Hep C
Ribavarin with INF-a-2b
Pegylated IFN (plus ribavarin)
Telaprevir and Boceprevir
Hep C protease inhibitors
Combined with pegylated IFN
Side effects: anemia, neutropenia, nausea, diarrhea, taste disturbance
Imiquimod
Treat papillomavirus (anogenital and common warts)
Immunomodulator, likely stimulates TRL-7
Topical 3x per week
Only 50% success
Side effects: irritation, itching, flaking
Treatments for papillomavirus
Imiquimod
Polofilox 0.5% (mechanism unclear)
Surgical, cryotherapy
Non-FDA approved uses for antivirals
Ribavirin for RNA viruses (measles, SARS-CoV, hantavirus)
Cidofovir for DNA viruses (papovaviruses, variola)
Do we give everyone antivirals?
No, mostly immunocompromised patients
Agglutination
Clumping of particles
Occurs when antibody can crosslink two things
Hemagglutination: virus antigen attaches to RBC
