Virology - 2

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M2?: ion chanel in flu envelope
Flu A infects:: humans and animals
Flu B infects: humans, esp kids
what is reye's syndrome a complication of?: mainly Influenza B
genetic stability of flu B HA and NA glycoproteins?: relatively stable
which flu is most severe? Least?: A most
C least
what does HA do?: mediates binding to host cell
binds to sialic acid, the cellular receptor
HA is cleaved by extracellular proteases, which is required for ucoating to occur later. The more easy cleavage occurs, the more virulent

Antibody to HA blocks infection.
Role of NA in flu infection: NA cleaves sialic acid residues, which facilitates cell to cell spread by releasing virus from infected cells
Antibody to NA lessens severity of disease.
where does RNA rep and transription occur?: nucleus
how is i tinsured that each of the 8 required segments are present in each virion: as manty as 12-15 nucleocapsids can be incorporated into each particle
transmission of flu: spread via inhaled aerosol drops during coughs or sneezes. deposited thruout tracheobroncial tree
clinical signs of flu: sudden riseo f Temperature 1-4 days post eqposure
describe primary viral pneumonia: less common than secondary bacterial
usuall in elderly or people with CP disease
may rapidly progress to hypoxemia and death
what is reyes syndrome: Cerebral edema, fatty degeneration of liver
esp in flu B, but also VARICELLA
unclear mechanism
may have to do with aspirin use
which is the important antigen for disease protection (flu): HA
treatment of flu: 1) supportive (not asprin!)
2) antivirals
3) NA inhibitors
4) prophlactic antivirals
what factors lead to antigenic shifts in flu A?: 1) Flu A is zoonotic. And there are more HA and NA types in birds. So this may be a source of new human subtypes
2) individual cells may be multiple infected by viruses of different strains
3) segmented genome allows for random combination of segmetns from different strains.

Resulting virus may be invisible to exxisting antibody.
What antiviral treatment is there for flu?: Amantadine/rimantadine

1) inhibits uncoating
2) lessens severity
3) does not work on B
4) must be given within 48 hours
what causes the cough with flu: destruction of respiratory epithelium. may take long time to recover
What do neuraminidase inhibitors do?: Pind to sialic acid binding sit in NA glycoprotein

Blocks cleavage of sialica cid by NA

This blocks replication and spread of virus

soon to be available
what is NAI effective on: A and B, unlike amantadine, which does not work on B
What is flu vaccine made of?: inactivated/killed virions, purified from eggs. Gives anti-HA antibody.
what is relenza?: a neuraminidase inhibitor
who gets flu vaccine?: 6-23 months
65 older
moms in 2-3rd trimester
kids on long term asprin therapy
health care workers
how many type sin flu vacine?: 3 (trivalent)
new virus strategy?: develop live attenuated virus vacines
immunity from flu vac?: 6-12 months
which of the flu have animal reservoirs: only a
which flu causes mandemics?: A
name the arhropod borne encephalitises: Togi:
Eastern equien encephalitis
western equine encephalitis
venezuelan equine encephalitis

Flavi:
SLE
JE
Tick borne encephalitis
West nile
Dengue
what factors influence development of clinical disease in the arthropod borne encephalitis causers?: manner of innocullaiton
diferences in non specific host susceptibility
difference in inndividual host immunity
strain differences
alphavirus (togi) desease process, generally: usually subclinical
can cause febrile illness, which may progress to encephalitis with HA, maialise, dizziness, seizures, coma.
Recovery due to development of Ab to env glyocproteins
alphaviruse (togi) env proteins?: M and F

antibodies against them are protective
what development may make EEE a more serious problem?: arrival in US of the asian tiger mosquito, since it feeds both on birds (amplifying host) and humans)
vaccine for EEE?: no
vaccine for WEE?: yes, through military
vaccine for VEE?: yess, from military
what is the most prevalent arthropod borne encephalitis in the us?: SLE
Disease course of SLE?: begins: fever, malaise, HA, drowsiness
Then can cause encephalitis, emengitis, febrile HA
what is amplyifying host of SLE?: birds, like EEE and WEE
what is the disease peak for SLE?: July - september
name a lab method for detecting SLE: paired sera: did the serum ab for the disease rise from acute to convalescent stage, indicating that that is indeed what the body was fighting
vaccine for SLE?: no
treatment for SLE?: supportive
WNV family: flavi
flavivirus during pregnancy: may cause abortion, but no real association w/birth defects (one case with WNV in preg mom)
clinical features of polio: 1) most are subclinical
2) most clincal are "abortive poliomyelitis", self resolving malaise, fever, HA, nausea go away in a few days
3) a few of those will progress into aseptic meningitis. Also self resolving
4) a small minority develop paralytic polio, and even most of these will recover
5) BUT: 25-40% of polio victims have ADDITIONAL MUSCLE DETERIORATION DECADES after the initial illness. But this is not due to persistence of the virus.
describe polio genome: has a 5' vpg on its RNA (instead of 7mg) (and note HepA has this also), but unlike HepA (which also has this), polio shuts off host cap binding complex, which shuts off all 7mg-mediated translation.

Translation occurs via IRES.
Which viruses have IRESs?: ALL PICORNAVIRUSES
what good is the ires: it bypasses the need for a CBC or 7mg cap on RNAs
describe enterovirus (polio, hep a) replication?: 1) atach to cellular receptors
2) penetration via RME
3) uncoating is energy dependent
4) cap-independent translation via IRES
5) polio, hepA makes large poly protein and cleaves it with virus proteases
where in the body does polio come in, go: 1) enters tonsils and peyers patches
2) multiplies locally
3) spreads in blood to other nodes, CNS
4) in nCNS it spreas along nerve fibers
why can paralyisi in polio occur?: either direct destruction of neurons by virus or by edema induced damage (the latter may be reversible)
where is polio still endemic?: subsaharan sfrica
South asia
who still gets polio in the us?: 1) immunocompromised vaccinees
2) imported WT polio
3) adults exposed to live vaccine virus shed by a caccinated contact (grandpa changing baby diaper)
what is something else caused by an enteric poliovirus?: NPEV: nonpoliomyelitis enterovirus
What does NPEV cause?: mild or asymptomatic, generally in kids in the summertime
Symptoms: varied. Uusually not enteric. can cause rash, fever, CNS symptoms
what enterovirus vaccines are there?: Only polio
how many polio serotypes: 3
Killed vaccine advantaes: IPV

Can be conmbined with other injectibles (DPT)
No mutation or reversion potential
can be used in immunosupressed
Killed vaccine disadvangtages: low percentage deveop antibodies after 3 doses
repeated boosters necessary
does not induce local intestinal immunity
expensive
scarcity of monkeys for developing it
can cause tragedy if virus incompletely inactivated
Live polio vaccine advantades: 1) gives humoral AND intestinal immunity
2) can be lifelong
3) induces antibody QUICKLY for most
4) oral administration is easier
5) cheap
6) no neaed for monkeys
Live vaccine disadvantages: 1) mutants can revert toward virulence
2) vaccinees shed the virus
3) cant give to immunodeficcient
4) need monkeys for safety testing
describe history of polio vaccine use: 1) IPV is first to be developoed
2) replaced in 60s with OPV use
3) due to cases of paralytic polio from OPV, in 98 protocol changed from 3 OPVs to 2 IPVs followed by 2 OPV
4) this still caused polio. So they switched back to IPV, but this time 4 doses
name some polyomaviruses: JC and BK
what does JC cause: PML: progressive multifocal leukoencephalopathy: progressive, fatal neurodegenerative disease.
why give 2 doses IPV before 2 doses OPV?: That idea was to give some immunity to virus before giving OPV, to prevent the rare occurance of vacine associate poliomyelitis. Problem is it didn't really help.
What does salk virus contain?: 3 formalin inactivated/killed polio strains/serotypes
where does polyoma virus replicate?: in the cell nucleus, using host DNA dependent DNA polymeras.

Assembly aslo occurs IN the NUCLEUS
what is an additional feature of HSV structure?: envelope surrounded by "tegumen" - a proteinaceous layer of varying thickness
where do herpes lefe cycle events occur?: Transcription and replication and assembly all occur in the nucleus

uses host DNA dependent RNA pol II to transcribe
Uses vurus coded DNA dependent DNA pol for dna replication.

envelope acquisition, maturation occurs in the cytoplasm
Does it cause giant cell formation?: yes, in epithelial cells
how does acyclovir work?: 1) dG analog
2) unphosphorylated, it can pass thru viral membrane
3) viral infected cells have TK, which phosp/activates acyclovir. Normal host kinases don't activate it well.
4) once it is phosphorylated once, it is phosphorlated again twice by host kinases
5) host DNA del DNA pol is good at excluding the dGTP analog; viral is less so. So viral dna Pol will incorporate it and cause chain termination.

DOES NOT WORK in latetly affected cells
describe a new potential HSV treatment: Ab against glycoprotein D on envelope. but it seems toonly work on people that are seronegative for both HSV-1 and HSV2 antibodies
two kinds of acyclovir resistant mutants: Mainkly TK mutants
Fewer are viral DNA pol mutants
name the disseminated, systemic viral infections?: VZV
CMV
Pox
name some chickenpox complications: 1) secondary infection of irritated lesions, with septicemia risk
2) post-infectius ENCEPHALYMYELITIS: but self limiting
3) pneumonia in immnocomporomised
4) varicella pneumonia in primary infection in adulte
5) Reye's syndrome (see also flu B)
symptoms of chickenpox: mild febrile illness in kids
disseminated vesicular rash, consisting of clear fluid filled blisters
HA and malaise, rash, fever and irratability
resolves in a few weeks
Describe shingles disease: reactivation of latent VZV
chickenpox like vesicles coalesce into big lesions defined by margins of infected dermatome
odds of infection increase wiht age
MAIN COMPLICATION: post herpetic neuralgia
what makes fragility of VZV hard to explois?: rapid replication and ease of transmmission
pathogenesis of primay VZV: 1) binds in nasopharynx
2) replicates in epithelium
3) spreads to nodes,where it furhter spreads via viremia to liver and spleen
4) infection of mononuclear cells peripheraly also transports vrus to epiuthelium where it causes rash and to respiratory mucosal sites, where it can spread to others
5) estabilshes latent state in sensory nerve ganglia
why is avoiding VZV hard?: shedding by respoiratory droplet occurs before symptoms
treatment of VZV: 1) acyclovir may helop symptoms if used promptly
2) Hyperimmune serum can be given to at risk nonimmunes
3) "booster vaccine" may prevent shingles in seniors
wht is the scheme of HCMV clinical features?: Presents differently among

1) normal kids and young adults
2) fetuses
3) immunosuppressed individuals including recipients and HIV
Normal, immunocompetent HCMV infection features: 1) primaryin kids: unremarkable. most kids get it , and are subclinical

2) pirmary infection can occur in results, causing pharngitis or something LIKE MONO.

continue to shed.
CMV infection of fetuses: 1) occurs only when mom gets hcv for first time when pregnant (less severe outcome if post-infection mom sheds during pregnancy)
2) 1st trimester: severe birth defects
3) later: congenital abnormalities
4) may get progressive damage, esp hearing, in the kids.

MOST COMMON CONGENITAL VIRAL INFECTION!
what is the other congenital late appearing disease:: congenital rubella syndrome: hearing loss and cataracts
infection of CMV in the immunosuppressed?: Severe disease, bothe primary and reactivated

1) interstitial pneumonia
2) retinitis
3) enteritis
4) other DISSEMINATED disease
5) may synergistically increase AIDS severity
6) the primary POST TRANSPLANT INFECTION. Esp bone marrow.
where is HCMV found?: all body fluids
how is HCMV transitted?: in all bodhy fluids, so any close personal contact can cause it. But it is pretty fragile, so it needs ot be close.
common HCMV transmission routes: babies to day care providers
shedding from the immunocomprommised
positive moms give it to babies via breast milk
HCVM treatment?: none
HCMV vaccine?: none
check that: what CAN you use to trat CMV?: ganciclovir.
why ganciclovir for CMV?: CMV has no viral TK, so acyclovir doesnt work

Gancyclovir can be used becuase CMV DOES encode a kinase that phosphorlyates gancyclovir.
how does gancyclovir work: similar to acyclovir and penciclovir: it is a dG analog
where does pox virus replication, transcription, and synthesis occur: CYTOPLASM!
what enzymes does pox contain?: DNA dependent RNA polymeras in the nucleocapsid (this explains staying in the cytolasmm)
what is the first infected cell in variola?: macrophages.
Describe the rest of the smallpox pathogenesis: 1) infection of macrophages in URT and LRT
2) migration to lymph nodes where replication and viremia ensue
3) replication in spleen and bone marrow
4) migration of hage to the epidermis causes characteristic symptoms of smallpox. Migration to URT epithelium facilitates spread. (Like VZV).
epidemiology of smallpox: urban areas: most get exposed to it, and it is a disease of childhood. (Adults that survive are generally protected)

Rural areas: affects adults and kids
Monkeypox: resembles smalllpox in severity

but relatively rare

transmitted from monkeys

Less ontagious
what makes smallpox a good vaccine-based eradication target: 1) humans only reservoir
2) one serotype
3) all infections symptomatic
4) limited time of contagiousness (only during acute disease)
5) seasonal epidemics
6) vaccinnees marked with variolation scar
Acyclovir and Poxviruses: they DO make TK (unlike CMV). BUT: TK (for some reason) does not phosphylate ACV in infected cells.
were does primary hcmv infection occur?: salivary gland epithelium
rotavirus desease:: vomiting, then diarrhea and fever for 7-10 days. very contagious.
Rotavirus family?: reo
Norwalk agent family?: calici

(along with HepE)
what is rotavirus mainly seen in?: 6-24 month old
what disease does norwalk agent cause? What age?: epidemic diarrhea for 12 hours
in older kids and adults
where does rabies multiply?: striated muscle ("rhabdo")
Pathogenesis of rabies: muscle-->nerves-->spinal cord-->brain-->salivary glands
clinical features: 3-8 week incubation
Prodromal stage of 2-4 days
Fever, HA, Malaise
Then increased irritability anxiety, depression, sensitivity to sound and light
Difficulty swallowing
Generalized encephalitis that is always fatal
what are most rabies cases attributable to?: Bats, though few have history of bites
diagnosis of rabies: most mortem exam
May be able to do nexk biopsy n humans
prevention of rabies: vaccinatino of animals (inactivated)
some post0exposure prophylactic vacines
Can inject human rabies hyperimmune globulin to inject wound area
pathogenesis of hemorrhagic fevers: 1) virus enters via injection, ingestion, inhalation

2) transient viremia -> infection of RES (monocytes, macrophages)

3) secondary viremia--> fever,chills, HA, mucle ache, malaise

4) other orfgans may get involved later
Outcomes of hemorrhagic fever virus: 1) inapparent infection (most common)
2) fever, cills, HA, back pain, muscle pain, rash on day 3-4 (primary Dengue, colorado tick.)

3) 2, followed by a hmemorrhagic fever with blotches oon skin and membranes and bleeing from any orifice. Die of hypotensive shock. (Dengue hemorrhaggic, ebola)

4) Hantan virus syndrome: progreses to fatal pulmonary edema
antivirals for hemorrhagic fevers: Ribavirin against arenavirus and bunyaviruses
Hemorrhagic fever vaccines?: Yellow ever
Rift valley fever.

NOT DENGUE
Symptoms of transmissible spngiformencephalopathies: loss of motor control
dementia
wasting
progresive loss of brain function
Infectious agent of TSEs: prion
define prion: A small, proteinaceous infectious particle that resists inactivation by procedures that modiffy nucleic acid
how do prions work?: they somehow force normal protein particles in alpha helix to assume beta sheet configuration, which eventualy leads to formations of fibrils and amyloid plaque
CJD: Rapidly fatal
presenile dementia
memory loss with confusion, vertiggo, blurred vision
-->dementia and motor dysfunction

most cases sporadic, some may be due to mutations in APP

No treatment
BSE: bovine spongiform encephalopathy

"scrapie" in sheep..."Mad Cow disease"
nvCJD: similar to CJD, though ataxia is more common

younger agegroup

may be variant of BSE
evidence nvCJD be caused by exposure to BSE: 1) temporal/geographic link to UK outbreak
2) similar glycoylation patterns in proteins in teh prions of both
3) abundant plaques, like BSE, but unlike CJD
4) mice innoculated with either BSE or nvCJD desplay similar diseases
arenavirus vector: rat crap
arenavirus diseases: Lasaa fever
Argentine + Bolivian hemorrhagc fever
what tranmits bunyaviris: rat crap
What does bunyavirus cause?: 1) hemorrhagic fever + renal syndrome
2) hantaan pulmonary syndrome
whne faced with a mysterious febrile illness, the physician should...: always consider zoonotic infections
pox genome replicates in: cytoplasm
Herpes genome replicates in: nucleus
adeno genome replicates in: nucleus
Papova genome replicates in: nucleu
Parvo genome replicates in: nucleus
Hepadna genome replicates in: nucleus and cytoplasm
complete list of viruses that have Ires: Picorna
Flavi
Calici
HIV/retrovirus replication and assembly strategy: 1) makes DSDNA from RNA template. RT makes hyprid, RNAseH degrades RNA, RT then is also able to make DSDNA.

2) DSDNA transported to nucleus

3) integradse responsible for inserting virus into host genome

4) virus uses hose replication machinery to replicate.

5) genome is translated to large precursor proteins

6) proteins cleaved by viral protease
how does hiv get in?: HIV protein binds to host CD4 molecule on T lymphosctes.

this event also allows HIV to bind to a host cell chemokine receptor
what predicts clinical course of HIV?: levels of virus present within 6 months of infection
How can a more agresive HIV form in chronic patients?: Sometimes it will mutate and it can bind to a different cellular corecptor that makes it more virulent
opportunistic HIV infections: FUNGAL
1) candida
2) pheumpscytis pneumonia
3) cryotococcus neoformans (meningitis)
4) histoplasma capsulatum (pneumonia)

PROTOZOAN
1) cryptosporidium (gastroenteritis)
2) toxoplasma (encephalitis)

BACTERIAL
1) myco tuberculosis
2) MAC (disseminated infection)

VIRAL
1) CMV
2) HSV
3) EBV
4) VZV (shingles)
when is HIV usually diagnosed?: 1) appearance of AIDS illness in otherwise healthy person
2) person who tests positive for anti-HIV antibodies
3) personson has flu-like symptoms as result of acute HIV-1 infection (may have no AB, but probably has High viral RNA levels
4) following known exposure
5) following birth of baby to HIV infected mom
classes of HIV drugs: 1) nucleoside analogs
2) nun-nnucleoside RT inhibitors
3) protease inhibitors
nucleoside analogs used in HIV: AZT
3TC
ddI
ddC
what happens when drug suprresoin of HIV is incomplete?: virus replication gets high enough that resistance selection occurs
prophylactic treatment of opportunistic infections?: Pneumocystis pneumonia: start at 200
Toxoplasma encephalitis: start at 100
MAC: start at 50
HIV vertical transmission rate: 15-30%
rare problem for screening for HIV in blood: NOT ALL BLOOD has HIV antibodies! acute infection, prior to seroconversion
HIV vaccine strategy: must actuall block initial infection...not like polio where you can allow infection but prevent bad consequences/symptoms. Because once you get it, body can't get rid of it.
which HIV strain is more pathogenic?: HIV-1
where is HIV-2: western africa, India
when is viral load high in HIV?: early and late
how do concurrent STDs increase risk of infection?: probably due to localization of lymphoid cells involved in the STD infection
what is HTLV-1: human t-cell leukemia virus
what does htlv cause: 1) mainly ATL: adult T-cell lymphoma
2) also TSP: tropical spastic paraperesis (spinal cord inflammation)
3) and HAM: htlv associated myelopathy
What family: HTLV: retrovirus
clinical presentation of ATL: 1) quick HTLV seroconversion
2) high WBC count
3) malignant ATL cells have distinctive multilobed nucleus, produced in episodes
4) infiltrates CNS with rapidly fatal course
how does HTLV cause disease: 1) causes rapid expansion in infected cells
2) this may cause an increase in chance of additional changes that makes this population cancerous--e.g., it may increase expression of IL and IL-2 receptor, chronically stimulating cell growth...and upping chance that it acquires mutation
is HTLV found in the tumor: hard to find in the tumor
What viral protein may lead to upregulation of growth: viral protein Tax bay be a transcription activating protein for IL2 and IL2 receptor
complication of ATL: immunodeficiency-->opportunistic infections
Thransmission of HTLV: semen, blood, milk
HPV family: papova
HPVs cause...: epithelial diseases (warts)
some strains are more efficient at causing cervical cancer.
how do some HPVs cause cancer: It seems that the viral genome gets integrated, breaking its circular DNA in a way such that an important viral regulator is not produced.

This leads to overexpression of E6 and E7, which inactivates host Rb and p53.

The better they are at integrating and inactivating, the better they cause cancer
How do you contract HPV?: direct contact wiht lesionsof infected people

contact with virus-containing material in teh environment
contagiousnes of HPV: not very---although HPV6 is the #2 STD in US, behind chlamydia
Fate of most skin warts: 50% go away on their own
EBV family: herpes
Infectious process of EBV: Targets B cells and induces their continuous growth. But most cells in infected lines do NOT produce infectious virus and are therefore "latently" infected. Rather, linear EBV genome goes to nucleus and is replicated as an episome, thanks to OriP and the expression of EBNA1 (nuclear antigen).

After ssalivary exchange of virus, it replicates in epithelial cells, establishes a viremia, and infects a portion of B cells making them EBNA positive.
Diagnosing IM: "monospot test": but sample in sheeps blood. EBV+ IM+ patients carry "heterophile antibody" that causes agglutination of sheep blood.
Cancers associated with EBV: 1) burkitt's lymphoma
2) Nasopharyngeal carcinoma
3) Hodgkins lymphona
4) immunosuppression-associated lymphoma
Burkitts lymphoma description: endemic in africa
tumors in jaw area
ALL tumors have EBV in them

EBV seems to cause a choomosomal transolcation that upregulates c-myc, causeing division
NPC: nasopharyngeal carcinoa
endemic in China, SE asia
probably associated wiht other cofactors
Hodgkins disease: common malignant lymphoma
Malignant cells ("reed-sternberg cells") have EB viral DNA

history of IM-->2-4x increase in HD risk
Immunosupresion lympoma: seen in post transplant or immunocoompromised
can be treated by reducing immunsupression and giving EBV-specific cytotoxit T cells
Antiviral therapy and EBV: doesnt respond, because most of the infeceted cells are "latent".
EBV vaccine: none
HHV-8 causes...: Kaposi's sarcoma
how does HHV8 induce cellular growth: probably by inducing infiltrating cells to secret cytokines and by expressing autocrine growth stimmulatory molecules
Kaposi's sarcoma: clinical features: usually not agressive
forms multiple skin lesions
used to show up in HIV patients

caused by an STD

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