Exam 2 week 2 Flashcards
Which viruses depend on host DNA dependent DNA pol
Parvo papilloma polyoma
define eclipse period
time from infection to detection of new virus
define latent period
time from infection to detection of EXTRACELLULAR virus
burst size
amount of new virus from a single infected cell
what are the receptors for HIV virus
Primary- CD4, secondary= CCR5, CXCR4
EBV receptors are
primary CD21, secondary MHCII
Influenza receptors are
terminal salic acid on glycolipids or glycoproteins
rhinovirus receptors
ICAM1
rabies virus receptors
nACHr, NCAM
measles receptors
CD46, CD150
what is tropism
the kind of cells a virus can infect depending on the host cell receptor expression
How do enveloped viruses enter cells
1) viral lipid membrane merges with PM of host cell and releases nucleocapsid into the cytoplasm.
2) endocytosis of virus, low pH of endosome allows fusion to the endosomal membrane and release of nucleocapsid to the cytoplasm
how do naked viruses enter cells
by endocytosis. the low pH of endosome changes the capsid and release of material to cytoplasm
what is uncoating
the release of genetic material from the nucleocapsid. Reo is loose capsid
how does herpes reproduce
enters cells and uses RNA poll to make TF and DNA pol
how does polyoma and papilloma replicate
they do not have or encode viral DNA pol. they need to activate the cell in order to get viral DNA replicated
Which viruses uses their own pol to copy genetic material. why is it important
Adeno, herpes, pox, hepadna have own DNA pol. The DNA pol is a great target of antiviral therapy
What viruses do not have own virally encoded pol? How do they replicate
Papillomo, polyoma and parvo. Papilloma and polymer kicks the cells into S phase to replicate. Parvo must enter actively dividing cells.
What is the replication for Pox viruses like
Exception: DNA virus that carries their own RNA Pol in the virion can replicate in the cytoplasm. Have a complex envelope
What is notable about HBV/hepadna
HBV is replicated in both the nucleus and the cytoplasm. It replicates DNA genome through RNA intermediate via own reverse transcriptase. NTRIs can be used in therapy
What is notable about herpes virsus
it can enter latent period for years like shingles and cold sores
How do +ssRNA replicate
They can be made directly into mRNA. They make polyproteins that need to be cleaved by viral proteases (all +ssRNA viruses have viral proteases) and viral RNA dependent RNA pol is made. The viral RNA pol can make both mRNA and -ssRNA.
GOOD TARGET FOR THERAPY IS PROTEASE OR POLYMERASE
What type of pol do +ssRNA viruses use
they encode (don’t bring in) their own RNA dependent RNA pol.
How do retroviruses replicate
Retroviruses- HIV and HTLV convert +ssRNA into 2 copies to make DNA (called diploid). Proviral DNA integrates into the host cell DNA via integrate and remains for the life of the cell.
How do -ssRNA replicate
viral RNA pol must first make mRNA from -ssRNA. VIRAL RNA pol MUST BE INCLUDED IN THE VIRON.
what is special about orthomyxoviruses
they are -ssRNA viruses with replication in both the nucleus and the cytoplasm.
what is special about HDV
it is a -ssRNA virus that has no viral pol. must use cell machinery. Also no enveloped glycoprotein so can’t make infectious visions without co-infection with HBV to use HBsAg as viral envelope glycoproteins. HDV cannot replicate on its own.
what is special about Reovirus
is naked, segmented genome, and contains viral RNA pol in its iron. It MAKES dsRNA!!!
Assembly- what DNA virus not in nucleus. which self assembles
Pox not in nucleus
papilloma capsid self assembles
How do naked viruses bud
they escape when the cell dies or through vesicular transport
How do enveloped viruses bud
They assemble their virion as they acquire the cell lipid membrane that has viral envelope glycoprotein. the cell lipid bilayer is usually from the plasma membrane.
How do DNA viruses obtain mutations to change and escape antiviral= genetic shift
through strand breakage or homologous/non homo recombination. results usually defective
How do RNA viruses obtain mutations= genetic shift
through strand jumping of RNA pol and recombinations homo and non homo. results usually defective
what viruses use gene resortment as a genetic shift
must have segmented genome and two strains infect same cell. Influenza makes viruses with different neruaindase and hemaglutin. difficult to make vaccines and can lead to pandemic. also Reovirus
what has the highest mutation rate
RNA viruses d/t the RNA pol lacking proofreading ability. Then the more complex the more stable
What is a quasi viral species and why is it important to therapy
The host viruses are not identical to but slightly different. When antiviral therapy is started there may be a mutant resistant to the therapy present making combination therapy important
What are some defective viruses
HDV and aden associated viruses. on their own they are not infectious. need co-infections to spread.
what is a defecitve interfering particle
they interfere with the growth of the virus and can’t replicate on their own without complement virus. they take up resources needed by WT virus
polypoidy
more than one copy of genome is packaged from the same virus
heteroploidy
two viruses infect the same cell and the virus packages more than one genome, one from each virus
phenotypic mixing
two viruses infect the same cell and the resulting A virus has the viral proteins from virus B or a mixture of viral proteins from virus A and B but the genome from virus A.
pseudotyping
two viruses infect the same cell, virus 1 acquiers glycoprotein from virus 2. this new virus can infect cells with the receptor tropism for virus 2. however if new viruses are produced they will have virus 1’s glycoprotein and 1’s tropism
Define lytic
virus lyses from cell killing it in the process
define cytopathic/cytocidal
kills cell but not necessararily from lysis. could be a by product released
Latent virus is an important part of what virus
are not productive- do not produce virus and non cytocidal. herpes virus is latent. stimuli can activate into reproductive cycle
Syntcia formatioin
when infected cell membrane of neighborning cells fuse to form a MULTINUCLEATE cell
Describe virally transformed cells
Virally transformed cells have no contact inhibition. the cells grow on top of each other. they can grew indefinetley and cause tumors when injected into animals. The cells have altered cell morphology
What uses are there for growing viruses in cell culture
It is useful for diagnostic tests and needed for some vaccine production
what important cells are used in cell culture for viruses
Primary cells, Human diploid cells- kidney and fibroblast cells from embryonic tissue, are safer than the immortal cell lines of humans and can grow for 20-50 divisions, used for vaccines.
Immortal cell lines- can grow indefinetly, useful for growing virus and diagnostic virology
What vaccines used human diploid cells
adenovirus, HAV, polio, rabies, rubella, varicella (chicken pox and shingles)
What vaccines use chicken embryo fibroblast
measles and mumps
what vaccines use embryonate chick eggs
influenza and yellow fever
Why is diagnostic virology useful
used to confirm and dx, rx for antiviral drugs, monitor chronic infections and epidemlogical monitoring
What is EM used for
EM can be used for fecal samples but nucleic acid detection techniques are often used now
Cytology- what is it and what diseases is it used in?
Look for presence of viruses in patient sample but usually not very specific. Inclusion bodies in HSV encepholitis and CMV owl eyes. Tzanck smears in herpes simplex virus and VZV from lesions
What is DFA and what is it used for
Direct fluorescence antibody test- DFA binds antiviral antibody to tissue of cell without culture. If positive test more for type of virus. if negative deterimine if true negative by cell culture or nucleic acid amplification test.
It depends on the antibody detecting the virus. if there is divergence in the virus like in influenza then antibody might not recognize the virus. not corona or rhino but influenza and rabies and other
What are drawbacks to cell culture test
the cells must be permissive to infection, still need to confirm with other tests, takes weeks and expensive
What is a hem absorption test
Viral hemaglutinin expressed on the surface of the infected cells can bind RBC. If a cell infected with one of the viruses that expresses hemaglutinin these cells will bind RBC. Most useful for influenza, parainfluenza, mumps
What is a rapid culture shell via spin amplificiation
a viral sample is added to a tube that has a cover slip. the culture is 16hr to 5 days. presence of virus by fluorescent abs
What are neutralizing abs and what tests use them
neutralizing abs bind to outside of virus and prevent infection of cell. enveloped=glycoproteins, naked=capsid proteins
Can type virus by blocking plaque formation-CPE, synctia, or immunoflorense. or block hem adsorption which is useful in deterring viral type in hemaglutination assay and quick way for influenza type
hemagglutination assay
RBC will clump together normally. Add viruses that bind RBC and will prevent clumping and diffuse the cells. eeasy 30 min test for influenza
Hemagglutination inhibition assay
If the virus is incubated with the correct neutralizing ab it will not bind to the RBC and the cell will look negative for virus- useful in influenza or titer neutralizing ab
What does ELISA or EIA detect
detects IgM for acute infections and IgG for chronic infections. the tests are specific for one virus.
what is EIA used for specifically
it can detect infections or vaccine efficacy
How do you test for viral antigens? what is the difference?
In ELIZA or EIA testing for viral antigens the tests actually tests for presence of virus in body. for viral ab tests the ab can be there long after infection is cleared.
lateral flow assay
viral antigen picks up virus specific gold labeled ab that is captured on strip
what is the accuracy of influenza testing
50-70% sensativity (pick up true positives) and 90-95% specificity (true negatives identified)
what are benefits to nucleic acid amplification tests?
High sensativites in the 90%. Use PCR.
How do NAAT work
Use PCR for DNA viruses and PCR with reverse transcriptase for RNA viruses to make DNA.
What are some advancements in NAAT
Isothermal tests- NSABA and LAMP
Describe NASBA
uses one temperature, only detects RNA, need sample RNA RT and RNA pol primers. used in HIV
What is the use for Real Time PCR
to determine viral load- amount of virus in sample, uses big or short probe with quencher. The greater the starting martial the faster fluoresence is detected.
Define incidence
The number of new cases of infection
Define prevalence
the total current cases of infection new and old per time
Define endemic
The base line level of disease in a community. the usual number of cases in a region
Define epidemic
An increase in the normal number of disease for a population. often sudden
Reasons for epidemics
1) an increase in the virulence or transmitibility of virus
2) intoduction to new population
3) increasing the exposure to population Ex: in water supply
4) increased susceptibly of host, aka low vaccine or immunity
define pandemic
an epidemic spread to other countries
What is R0
the total number of infected over the course of the disease on average. the avg amount of people infected from an infected person in SUSCEPTIBLE population
What is the formula for Attack rate?
calculated for an epidemic and gives %
AR= number of new cases in pop/population at risk
What is the formula for secondary attack rate?
2ndary AR= Number of contacts infected/total # of contacts
What is a communicable disease?
An infectious disease that is transmitted from one source to another. Includes contagious and non contagious diseases
Contagious is defined as what?
Contagious comes from the word contact, a very communinicable disease spread by contact or close proximity to an infected person, isolation could stop an epidemic of contagious disease
how are contagious diseases spread
Respiratory droplets, fecal oral, contact with skin abrasion is less common
What are non contagious diseases
Communicalbe diseases that are spread by more than casual contact. Needs needles sharing, sex, congenital transmission or by vector or perinatal shortly after birth (breastfeeding)
What factors increase transmissibility
1) longer survival outside the host
2) having an alternate host
3) Having a non human host that humans often contact
4) Port of entry ease, respiratory droplets>sex or blood
5) Ability to evade the immune system- replicating on mucosal surface first, mutating different strains
6) Having a long incubation may help. Person gets virus and doesn’t show symptoms but is infectious, ex: HIV. Incubation period is the time from infection to the start of sx
7) What route the virus is spread? Fecal oral is pretty efficient
What is the benefit to human to human transmission
No animal resoviour, easier to eradicate with vaccine
Zoonotic infections and arboviral transmission
Zoonnotic is animal to human, arboviral is insect to human- most of the time can’t be spread human to insect to human
Vertical transmission
parent to child, happens in germline for viruses. retroviruses in utero let transmission right after or during birth or in breast milk possible
Horizontal transmission
person to person
What diseases peak in winter and spring
Viruses that are enveloped and transmitted through the respiratory route- Influenza RSV and measles
Gastroenteric viruses- norovirus and rotavirus
What diseases peak in the summer and fall
enteroviruses in the picorna family and arboviruses peak in summer
Is there a peak for STDs or blood viruses
nah
Define incubation period
Time from infection until sx
Define latent period
time from infection to virus is shed in body
what is the primordial period
time from infection with generalized sx that are common to all infections before specific sx start
Ex; measles feel sick before rash
What is the infectious phase
the that the infected person can spread the disease to others. can be infectious before sx arise. most of time stop being infectious prior to sx resolving. some people asx throughout infection
what is the iceberg concept
when the number of asympomatic people with virus outnumber the ones who develop sx. asx can still spread disease
what is infectivity
viruses ability to spread or infect individuals.
what is pathogenecity
pathogenicity aka toxicity- the extent to which a overt disease is present in infected individuals. # of ppl with clinical disease/#infected. ABILITY TO CAUSE DISEASE
Virulence
the extent of serious clinical disease present in infected individuals. # ppl with serious clinical disease/#infected
How does age affect disease or infection
Young and old are at risk for serious complications. Poor immune response or acquired immunity in young and old. Some are worse in old people- Hep A VZV
How do genetics influence disease susceptibility
mutuation in CCR5 makes people less susceptible to HIV, IL28B a INFgamma genes helps clear Hep C
What are important things about local infections
It spreads on the surface of mucus membreanes in the organ but does not spread via the blood or lymph to different parts of the body. IgA is important. Can have short or long immunity. Incubation time is short. Targets skin, eyes, lungs, GI, respiratory tract. restricted by temp
What is important about generalized infections
They enter the body and do not replicate at site of entry. Goes to lymph and to blood- viremia- then to large reticulendothelial organs and replicates- secondary viremia. now the virus to target organs. can be spread through nerves- rabies, HSV, VZV. longer incubation periods, 10 days to years, lead to lifelong immunity. IgG important. Rashes occur often
Acute infections key characteristics
Most infections are acute and cleared by the immune system. Can lead to lifelong immunity to reinfection of same strain.
Latent infections key characteristics
Are preceded by an acute infection. The virus lies dormant and does not replicate but periodic reactivation of virus occurs with reactivation of sx (HSV VZV).
Chronic infections key characteristics
Are preceded by an acute phase where there is an early spike of virus the is reduced by the immune system. The initial spike is accompanied by primordial sx or subclinical. Can be long time no sx (HIV EBV HBV HCV HTLV) or can be asx for life.
Slow infections
NOT proceded by acute infections or phase but a steady level of virus is present leading to disease many years after initial infection (usually decades). Slow infections are also chronic infections but with longer incubation period time to disease and lack of sx until disease
What is the first line of defense to viruses? ex?
Physical barriers. Intact skin, mucous barrier, cilia, tears, low pH stomach and vagina
Where are antimicrobial products secreted?
from the epithelial or MUCOSAL surface. SP-A and D MBL against glycoslayed proteins, B defensins against lipid env on HSV, SAP against influenza
What is the main innate system defense against viruses and how is it triggered
Type I INF. Interferons are triggered by infected cells by patern recognition receptors on infected and neighboring cells. They can be produced by almost any type of cell upon infection.
How do viruses avoid innate immune response? What is the counter by immune system
By shutting down type I INF by degrading proteins in the interferon pathway and avoiding pattern recognition receptors.
Plasmacytoid DC produce IFN without being productively infected so virus cannot shut down, pDC can produce large amount of IFN
What is another playa in innate defense to viruses? When are they activated? How do they work?
NK cells are innate defense against viruses. They are activated by day two and kill infected cells in nonspecific innate manner or help clear adaptive response cells
How are NK cells activated?
A balance between postive and negative activating signals
Postive- from receptors that recognize a variety of ligands that signal like MHC I that say cell is stressed or infected
Negative- binds lingands like MHC I that say cell is healthy and normal. Potent negative signal is receptor engagement of MHC I. Some viruses downreg MHC I on infected cells to keep from CTL killing but makes NK cells activated
What is ADCC
Later in infection when ab response is active NK cells can kill infected cells that are coated by abs recognizing viral antigens expressed on the surface of the cell and FcgammaII receptor on NK cell. NEEDS viral antigen expressed on surface of cell
What is macrophages role in viral protection
Innate and adpative immunity. They can phagocytize virus and dying infected cells. they produce NO TNF alpha and IFN. produce cheekiness and cytokines that help guide immune cells to site of infection and help NK cells survive. Very important in clearing body of infected cells
What are DCs role in virus defense
Sample virus and activate PRP to produce IFN for non specific response. DC also produce cytokines and cheekiness that help guide the immune response to specific pathogens through activation of PRP.
How can viruses start a systemic infection
by infecting DC or macrophages that travel to LN and tagging along and spreading to body
Describe class switching in B cells to viruses
Ab response with B cells requires T cell Help CD4. The T cell signals determine the Ig isotope of ab. Antigens encountered in mucosal surface produce IgA primarily in MALT. Antigens in blood make IgG.
What type of tissue produces IgA
In mucosa IgA dominates, made by IgA plasma blasts that also express a chemokine receptor that allows them to traffic to the respiratory tract and breast tissue that secrete chemokine specific to that receptor.
Where is IgG made
In the blood, but some in mucosa (IgA primarily). In gut but much less in the upper respiratory tract where IgA dominates. More IgG in lower RT and Genitourinary tract
What viral antigens are used in immune response
only the viral antigens on the surface of the virus are exposed to antibodies and are exposed. Infected cells only express antigens on the surface of the cell that would normally be on the surface of the virus
what are the most important abs to virus protection
Neutralizing abs block the virus from infecting a cell. many viruses change their surface proteins to escape. still get CTL killing
what are the role of CD8 CTL in virus defense
part of adaptive immune response. they recognize virally infected cells by presentation of viral proteins in MHC class I. they keep virus in check by killing infected cells. can kill any virus antigen presented on MHC I not just on the surface like neutralizing abs. Attack conserved “immunodominant” proteins in viruses
why are you protected from reinfection by same virus strain
Long lived plasma b cells and secreted abs. the abs stay in mucosa and blood. Nuetralizing abs (IgA muc and IgG systemic) can bind to the virus and prevent infection and induce sterilizing immunity. better and higher abs from affinity maturuation and CTL memory response
Why can you get sick from same virus again
IgA immunity doesn’t last past several years and wains- partial immunity, get sick but not as bad
What is the life span of CTL memory response
memory CTL response helps clear an infection faster if cells are infected. In respiratory infections the memory is not long lived, only several years for influenza. CTL response is important in chronic infections though
How can you get lifelong immunity/sterilization
from systemic infections like measles or chickenpox. IgG mediated in blood
What 5 ways do viruses subvert the immune system
1) antigenic drift through mutations protect from neutralizing abs
2) latency- not producing virus. If reactivated CTLs can keep in check
3) Infecting immune priveldge sites yes brain testes. Ebola and zika
4) generalized immune suppression- measles, suppression for months or HIV destroys CD4 cells
5) specific immune suppression- reduce IFN I or reduce MHC I to escape CTL, produce mimics of cytokines like TNF receptor or ILIB to block cytokines from acting
Describe a case of pathogenic CTL killing from virus infection
In liver infections with HBV and HBC it is the viral specific CTLs killing of infected cells that causes liver damage
serum sickness
TIII HS, in HBV 1-10% with acute infection develop serum sickness
Describe ab dependent enhancement in terms of Dengue virus
Dengue has four serotypes. Initial infection with one serotype creates neutralizing abs. If infected with another serotype the Nabs are present as bind virus weakly but not enough to neutralize. The ab coated viruses are taken up by macrophages enhancing the virus and leading to dengue hemorrhagic fever.
Cytokine storm
excessive cytokine production d/t vigorous immune response leads to LUNG pathologies in resp infections
goal of vaccines
to generate an immune response that protects against subsequent challenge with pathogen
What makes a good pathogen to vaccinate against??
1) produce life long immunity from natural infections
2) not large number of strains
what makes a hard pathogen to vaccinate against
lots of strains and changes season to season. Also not life long immunity (RSV) or produce chronic infections (HIV)
what is most important in effective vacination
The ability of the vaccine to elect neutralizing abs
What is the best vaccine method
Attenuated virues, few boosters needed, mimic natural infections and virus replicates in host, good ab and CTL response. Made version of virus that replicates but poorly in human. Are tested to make sure they don’t revert to pathogenic strain but small chance of getting infection ex: oral polio. Consider risk/benefit in immunocompromised patients
What is the second best vaccine method
whole killed virus is 2nd best. requires large amounts of virus to be produced bc more material is needed in whole killed virus than attenuated. Need more innoculation than attenuated. No possibility for infection
When is a subunit vaccine used
when virus cannot be grown in culture. Need adjuvant if subunit virus is used and might decrease dose in whole killed
what adjuvants are used in vaccines
Alum causes antigens to aggregate boosting ab response. MPL is a detoxified version of LPS that is at least 1000 times less toxic than LPS- in Cervarix in HPV
What vaccines do you need to pick proteins correctly?
only in subunit vaccines. WK and attenuated already have proteins for neutralizing ab response. Must pick antigen to elict neutralizing abs so must be on surface of virion
MMR vaccine- type of vaccine, what is the dosing and response
Live attenuated vaccine, first dose at 12 months and second dose at 4-6 years, maternal IgG abs present in infect can prevent attenuated strain of virus from replicating making vaccine ineffective before age 1. Can be give at 6 months if going overseas
What is herd immunity
Protection of whole community against an infectious agent by limiting the spread of infection. most people protected if large component of population can be immunized. Reduces the R value of virus
what is passive immunity
Passive immunity is Ig transfer into a person. the protection is immediate but not long lived only weeks to months. active immunity takes weeks to develop but last a lifetime.
natural passive immunity- at birth from maternal abs that cross the placenta during the last trimester. majority is IgG that protect for months up to one year. Nursing prolongs passive immunity- colostrum is rich in ab. Breast milk has mostly IgA > IgG that protect for GI infection.
when is passive immunity used that is not naturally occuring
used to prevent infection after potential exposure when no vaccine is present or indicated. or to prevent infection pre exposure in ab deficient disorders or RSV in premature infants
What are Type I IFN produce? And where is receptor expressed
IFN I is IFN alpha and beta and others. Expressed on almost all cell types
Where are type III IFN expressed and what type
IFN III = lambda, only expressed on epithelial cells, important in infections in mucosal cells- GI RT and liver
What is the first thing triggered in viral infectioin
Pattern recognition receptors that recognize viruses turn on TF IRF3 and 7, makes IFN B which acts on infected and uninfected cells. IFN beta turns on IRF7 which activates IFN alpha and INF lambda 2-3 activated. pDC have IRF7 so make lots of IFN alpha quick- up to half of IFN in immune response from pDC without being productively infectected
What does Type I and III IFN do?
They both turn on the same TF and so turn on same set of genes through STAT
Remember type III only on epithelial cells though
What is the effects of interferons response genes? ISG
1) proteins turn off IFN signaling- IFN signaling is tightly regulated, downreg the receptor of turn off downstream signaling
2) Proteins in IFN pathway are upregulated, ampilifies the IFN signal and allows uninfected cells to be able to switch on IFN fast if infected
3) Antiviral genes- proteins that interfere with different stages of viral replicati
How do you turn off IFN signaling
Remember genes ISGs code for proteins that regulate and turn off IFN signaling. USP18 binds to the receptor and prevents signaling from IFNalpha but still allows some IFNbeta signaling and IFN lambda signaling
CHC patients have upreg USP18
What is IFN antiviral mechanism
IFN turns on the expression of OAS (oligoadenylate synthetase) but not active. If cells is virally infected OAS binds to viral dsRNA and is activated. OAS activates RNaseL which cleaves viral and cellular RNA.
What is another antiviral of IFN
IFN turns on lots of genes that interfere with viral replication
Antiviral PKR- protein kinase RNA activated
Gene is turned on by IFN but is inactive, binding viral RNA turns on so that only infected cells activated PKR, activate NFKB, stops most protein systhesis!!! Stop cap dependent translation of proteins and some cap indep
what are IFN effects on the immune system
1) increase antigen presentation and chemokine production
2) increase ab production
3) increase NK and CTL response to kill virally infected cells
What is the role of half life in IFN therapy
IFN alpha has short half life, 3-8 hours so need 3 injections per week. If PEG then increase t1/2 and weekly injections
What does IFN therapy treat
Tx for HBV HDV and some genotypes of HCV
Aleferon N for anogenital warts and resp papillomatosis
What are some side effects of IFN therapy?
Within 8-24 hours- flu like sx but can resolve
BM suppression, granulocytopenia, thrombocytopenia
20-30% develop neuropysch side effects leads to DC in 10-16%
what are some indicatioins for NSAIDs
Pain- decreases PGE2 which sensatizes nerves to bradykinin
Inflammation- inhibit COX and decrease PG
arthritis- pain and inflammation
Heachache, pain syndromes,
anti-pyretic- PGE2 increases temp in hypothalamus when activated by infection HS malignancy or inflammation, reset thermostat
what levels do NSAIDs and glucocorticoids work
Glucocorticoids work upstream at phospholipase A2 preventing AA formation. NSAIDS block COX from making PG from AA
How does NSAIDS block pain
by blocking COX can’t make AA to PGG-2 which is made to other PG and prostacyclin for pain
Where is COX 1 and 2 found and expressed?
Cox1 is found in GI tract and constitutively expressed
COX2 is induced and found in the periphery
what NSAID does not indiscreminately block COX 1 and 2
Celebrex only inhibits COX2 leading to less GI toxicity
What NSAIDs slowly reversible bind to COX? and quicker
diclofenac flubiprofen indomethacin
Ibuprofen is quick and piroxicam and mef acid
What are main NSAID cautions
Renal disease- deplete PGs and vasoconstrict afferent arteriole
Highly protein bound
monitor guiac stools- blood in stool from ulceration
Asthma- more leuktrienes
premature closure of DA from breast milk but also can close PDA
How do NSAIDs lead to gastric ulcers following H pylori infection
they are acidic, they are anti platelet, decrease mucous production from dec PG production
what are chronic overdose signs of NSAIDs
tinnitus, from increased AA,
also renal, bleeds, bruising are signs of too much too long
NSAIDs can raise BP increase Na retention,
what is the triple whammy of renal blood flow
Glomerular bloodflow depends on BV which is dec by diuretics, PG which is impaired with NSAIDs, and angiotensin II which is impaired by ACE ihibitior
Can cause acute renal failure in elderly
What are the roles of PGs made by COX1 and 2
Cox 1 PG- inhibit gastric acid secretion, stimulate GI mucus, maintain Renal bloodflow, enhance platelet aggregation
Cox2 PG- inflammation, (pain fever edema)
What is REYES syndrome and what causes it
DO not USE ASA in children with varicella or flu sx
RS- acute brain damage and liver function problems that do not have a known cause
What are highlighted side effects of ASA
Can increase serum UA levels and anatagonize gout drug. But can potentiate MTX. MUST BE DC at least 5 days before sx.
Can create HS reaction with bronchospasm and nasal obstruction mediated by cysttenyl leukotrienes
In asthma lipoxygenase is more active = more leukotrients
ASA uses
at low does anti platelet, pyretic and angelic effect
high does - anti inflammatory so not used for that
What is drug Ribarvirin used for?
Tx Hepatitis C but not used alone, inhaled (children) or oral for RSV, hematopoietic cell or heart/lung transplant in adults, hemorrhagic fever
what is ribarvirin MOA
Inhibits IMPDH- results in a lower pools of guanine nucleotides to inhibit RNA and DNA viruses
Ribavirin side effects?
major side effect of ribavirin is hemolytic anemia. increased levels of ribavirin in cells that they can’t rid causes RBC death
Ribavirin in pregnancy
Nah. its is Category X teratogen. M and F birth control. health workers watch out for aersol form
What polymerase inhibitors need to be activated by viral protein base analogues- HSV
Acyclovirs are pro drugs in nucleoside form that need phosphates added. The first is added by a viral kinase and the rest are added by cellular kinases. Only cells that are infected by HSV will be infected bc viral pol is more affected
How does CMV activate drugs?
its uses Kinase UL97 to add first phosphate, most efficient for activation of ganciclovir
Name the acyclovirs prodrugs and their active components and whats special for the three
1) Valcyclovir- active is acyclovir- most efficient chain terminator but short cell half life
2) Famiciclovir (oral)- active penciclovir (topical)- not obligate chain terminator but competitive inhibition of viral DNA pol. less potent but longer half life.
3) valganciclovir- active= ganciclovir, not obligate chain terminator but incorporation of several ganciclovir into DNA cause chain termination. More side side effects
What is a drug that also acts against HSV but doesn’t need to be activated by viral kinases??
Cidofovir, can be used for viruses resistant to acyclovirs. also works against other DNA viruses
What RT inhibitor does not need to be activated by cellular phosphorylation
Tenofovir- a nucleotide NRTI, do not need to be be activated by cellular phosphorylation
What is the mechanism of action of NNRTI
bind a pocket in RT distal to active site and prevent RT. prevent forming active in RT.
What is the MOA of foscarnet? what used to tx
it is an organic phosphatic acid that binds the phosphate binding site of pol and prevents nucleotide binding
used in Herpes and HIV-salvage therapy
What is major dose limiting side effect of foscarnet
Nephrotoxicity
What are the pol inhibitors used for HCV?
HCV inhibitors of NS5B pol ending in -buvir
blocks replication of viral RNA
sofosbuvir- nucleotide analogue and
dasabuvir is non nucleoside analogue
what is the ending for HIV protease inhibitors
-navir
Ending for HCV protease NS3/4A inhibitors
-previr, prevent polyprotein cleavage and thus replication
what is the ending and MOA of NS5A HCV inhibitors
they inhibit binding of NS5A protein of HCV to reduce viral RNA levels and assembly and release of new virus.
end in asvir
What are the name of HIV integrase inhibitors and what is MOA
Integrase inhibitors have tegavir in them
The integrates needs Mg cation, inhibitors chelate Mg active site
Also called INSTI
What is MOA of maraviroc
it is an HIV entry inhibitor. It binds to CCR5 and prevents HIV envelope glycoprotein 120 from binding. If using CXCR4 as secondary receptor then ineffective
Enfuvirtide (T20) fusion inhibitor MOA
blocks HIV envelope gp 41 from fusing viral membrane to plasma membrane. Mimics HR2 and binds to HR1 blocking entry
what drugs prevent the infection of a cell vs. the spread of virus
Entry, RT and integrate prevent infection. Protease inhibitors prevent the production of infectious virus from an already infected cell.
What is the uncoating inhibitor for influenza A? MOA side effects
Amantadine and rimantadine only influenza A
Amantadine has CNS and rimantidine has GI side effects
they bind to M2 protein of influenza A and prevent ion channel formation in endosome, no uncoating=no replication
What are the budding inhbiitors of influenza? MOA and name
Neuraminidase inhibitors- amivir
works for A and B
neuraminidase cleaves off salic acid residues declumping and freeing virus to infect new cells. inhibit= tethered viruses and particles non infectious
Do you treat HIV or HCV with one drug
no d/t drug resistance
do you treat HBV with one drug
yes can be treated with tenofovir or entecavir that have little drug resistance. hard for HBV to mutate bc reg regions overlap DNA viral genes
why do immunosuppressed people have more drug resistance
weak immune system leads to more replication of virus- higher chance of mutations, higher chance of resistance
Why look at viral load
when to tx: HBV CMV
Efficacy of tx: HBV CMV HCV HIV
how look at viral load
usually best is RT PCR for HIV HCV HBV CMV, if RNA virus must make cDNA first with RT
branch DNA- no amp, bind DNA or RNA (HIV HCV), not as sensitive as PT PCR
When is genotypic testing used?
In HCV it is used to find subtype to tx differently
in HIV HCV HBV CMV genotype test for resistant viruses but a drawback is can only test for know resistance polymorphisms. there may be a new change that confers resistance not found in these tests.
Describe HTLV1 vs 2
HTLV1 infects CD4> CD8. HTLV2 infects CD8>CD4
What causes ATLL
HTLV1 in 2-5% of infections after 30-50years if infected before 20
What causes HAM/TSP and what is sx
HTLV1 and 2 cause it by causing inflammation in the SC in 2-4% of cases after 4months to years. HAM sx= spasticity in legs with slow progression, no arm affected, some urinary problems
Where is HTLV1 endenmic
Central africa, caribeean, south american parts, SW japan
in US more HTLV2 slightly, HTLV in US in indiginous people like Seminoles Navajo and Pueblo and with IV users 10-16%
How is HTLV transmitted
Breast feeding (25% MAJOR WAY) but less if BF for 3-6 months, M-child is only 1:20 if no BF,
IV needle or transfusion, sex THROUGH INFECTED CELLS then clonally expands infected T cells. HARD TO FIND IN BLOOD SO NO BLOOD TRANSMISSION except in transfusion (85%) or needle use (10-16% of pop). CTL can keep in check but 5% develop ATLL
What genes in HTLV involved
Tax initiates and HBZ sustains
What histo finding in HTLV
Flower cells in ATLL
What are the complications of HTLV1
2% develop HAM TSP tx with corticosteroids but 93% asx
How do you detect HTLV
Ab ELISA test, Western blot to confirms
What are the two important proteins in HIV
1) Gag is cleaved in matrix p17, capsid p24, and nucleocapsid p7
2) pol- cleaved in protease PR, reversere transcriptase RT, and integrase IN
What are the other proteins in HIV
1) Tat- transcription activators can be excreted and increase expression of cellular genes
2) Nef- required for pathogenies- down reg MHC 1 CD 3 and CD4 and has SH3 down and can potentially activate cell signaling and excreted from infected cell
3) envelope glycoprotein precursor pg160 cleaved in p120 (receptor binding) and p41 (fusion of virus envelope with cell membrane)
what does p120 bind
binds cd4, can be shed from infected cells, potential for binding CD4 on uninfected cells causing abberrant activation
What are key characteristics of HIV2
Majority in west africa, lower levels of viremia, longer asx stage, slower decline of CD4 cells, difference in genes, resistant to NNRTI and enfuvirtide (fusion inhibitor), no protection to HIV1
What are the key points of reverse transcription
Two strands of RNA- both the same
RT can bounce btn strands, how recombination occurs btw two strands/clades
**Proviral DNA has long terminal repeats needed to get into host genome, RNA does not have LTR, LTR contain many regulatory regions of HIV like promoters, polyadenation, transcription start site
What leads to such high diversity in HIV
the high error rate of RT!!! more diverse than influenza world wide,
what is goal of HIV tx
to get virus undetectable, 20-70 coopies/ml
How are HIV designated by how they enter cells
Different designation based on chemokine receptor binding:
1) HIV that binds to CCR5 initially need high CD4 counts t infect- called macrophage tropic non syncia nducing
2) HIV that binds CRCX4 are called T cell tropic and syncia inducing
3) or dual tropic
What co-receptors are expressed on which cells
CCR5 expressed on memory or activated CD4 T cells GALT macrophages DC microglia
CXCR4 is expressed on memory naivee resting CD T cells
How do the co-receptors work for infection of HIV
Initial infection by CCR5 with high CD4, people will CCR5 deletion are protected from infection
over the course of infection the CXCR4 will present in a majority of infections with LOW CD4 counts
How does for receptors effect rate to AIDS
If only have CCR5 still progress to AIDs but dual tropic progress faster
Describe the acute infection of HIV
Initial infection by free virus of R5 strain through break in epithelium or DC/macrophage APC. A CD 4 T cells is infected or a macropahe with local replication for 3-4 days before the infected cells travel to the draining LN.
In days to weeks the virus goes to Lymph tissue and replicates high viral load. Immune system can reduce load but not clear the infection. Est the latent viral resouvir
Where is an important place for HIV replication
GALT in gult in all stage of HIV. loss of th17 memory cells never recovers, less IL17 is less response, never gets better even with cART
disbosis and increased LPS in blood=continued immune activation
How does HIV affect the brain
HIV can cross BBB or infected macrophages
infects microglia, perivas macrophages and sometimes astrocytes
without cART 20% develop demenita
How does HIV progress
70% with flu like sx or mono with lymphadenopathy 2-4weeks after infection, initial level of virus is high, the more virus the worse off, 8-10 years to AIDs and95% die
side effects of cART
increased risk of DM, CV diseases, bone fx, renal failure
where does HIV hide
in resting memory CD4 cells, very low levels of replication in LN
benefits of starting cART early
LN not destroyed, less GALT damage, less thymus loss, CD4 levels can be normal, lower co-morbidities
