ICL 1.12: Parvo, Papova & Poxviruses Flashcards
what type of virus are parvoviruses?
naked DNA virus
what type of viruses are polyomaviruses?
naked DNA virus
what type of viruses are papillomaviruses?
naked DNA viruses
what type of viruses are poxviruses?
enveloped DNA viruses
which viruses are associated with cancers?
- papillomaviridae
- herpesviridae
- hepadnaviridae
- retroviridae
- flaviviridae
the cancers are usually cancers of the cells that the virus infects; it’s because the virus is changing the cell programing to keep them dividing
also the viruses are usually very specific for a certain type of cancer
which cancers are associated with the papillomaviridae family?
virus: human papillomaviruses
benign disease: benign warts
tumor: cervix, skin, anus, penis
which cancers are associated with the herpesviridae family?
#1 virus: EBV
benign disease: infectious mononucleosis
tumor: Burkitt’s lymphoma, Hodgkin’s lymphoma, B lymphoproliferative disease and nasopharyngeal carcinoma
#2: virus: Kaposi's sarcoma-associated herpesviruses
benign disease: Castleman’s disease
tumor: Kaposi’s sarcoma, body cavity lymphoma
which cancers are associated with the hepadnaviridae family?
virus: HepB
benign disease: hapatitis, cirrhosis
tumor: hepatocellular cancer
which cancers are associated with the retroviridae family?
virus: human T-lymphotropic virus 1
benign disease: tropical spastic paraparesis
tumor: adult T cell lymphoma
which cancers are associated with the flaviviridae family?
virus: HepC
benign disease; hepatitis, cirrhosis
tumor: hepatocellular cancer, lymphoma
what are papovaviruses?
polyomaviridae and papillomaviridae were formally called papovaviruses
what is SV40?
polyomavirus
SV40 is an abbreviation for simian vacuolating virus 40 or simian virus 40, a polyomavirus that is found in both monkeys and humans
like other polyomaviruses, SV40 is a DNA virus that has the potential to cause tumors in animals, but most often persists as a latent infection
why is SV40 historically important?
SV40 is a polyomavirus that was the first DNA tumor virus isolated
studying it led to the concept of tumor antigens (T-Ag), oncogenes acting on cell p53 & RB to induce cells to divide, the nature of first eukaryotic promoter, splicing, first vector for introducing genes into cells, etc.
what are the general characteristics of the polyomavirus?
naked, icosahedral virion
very small genome
*circular dsDNA
how does the polyomavirus replicate?
this is a small circular dsDNA virus so there will only be E and L genes, no IE genes
the virus needs to get to mRNA so they will have highly active promoters that are recognized by transcription factors in the host
host RNA polymerase will transcribe a long primary transcript from the E region which is spliced into 2 mRNA – there are 2 possible splicing sites
the first splicing site creates a longer mRNA which leads to translation of a larger protein called large T antigen (T-Ag)
then the alternative splice site doesn’t remove a premature stop sequence so when you splice here, you get a smaller protein called small T antigen (t-Ag)
T-Ag and t-Ag are viral proteins that are very good at transforming cells to inactivate tumor suppressor genes so that the host cell will keep replicating
what does p53 do?
- it is a tumor suppressor that is mutated or abnormally expressed in many human cancers
- it allows cells to repair DNA damage or die by apoptosis
- it binds to DNA and activates or represses many genes
how do T-Ag and t-Ag interact with p53?
they are E genes products expressed in the polyomavirus!
T-Ag and t-ag from SV40 polyomavirus are precipated out and interact with p53 in the host cell
these viral proteins bind to the host p53 protein and inactivates it so that the virus can better replicate in the cell
what does T-ag do?
it’s an E gene product of polyomavirus that:
- induce cells to proliferate if they are in G0
- forms complexes with largest subunit of DNA polymerase a, p53 tumor suppressor protein, and p105RB + RB-related proteins
- turns on viral DNA synthesis
- binds to ori (origin of replication)
- turns on transcription of late genes turns off transcription of early genes
what does t-Ag do?
small t-Ag works with the large T-Ag in transformation of cells. Its targets are different: t-Ag binds a cell protein phosphatase and can activate pol II and pol III transcription
what are the two main human polyomaviruses?
- JC virus
- BK virus
70-80% of adults have antibodies to BK and JC viruses!! so most people have actually been exposed to this virus but only in immuno-compromised patients will it cause a problem
primary infection is in childhood
what is JC virus?
a polyomavirus = small naked virus with circular dsDNA
JC = John Cunningham virus
the hallmark of this virus is that it causes progressive multifocal leukoencephalopathy (PML)
PML is a demyelating disease so it kill oligodendrocytes that produce myelin for the CNS and it’s progressive so patients who get it will die within a few months
PML patients will have non-enhancing multifocal brain lesions in white matter that can be seen in brain imaging
only effects people where CD4+ < 200 like in HIV patients
what is BK virus?
a polyomavirus = small naked virus with circular dsDNA
BK causes nephropathy and other urinary tract problems like hemorrhagic cystitis –> this usually happens in kidney and BM transplant patients
mild respiratory illness common in renal transplant patients too
what are the clinical features of polyomaviruses?
polyomaviruses produce inapparent infections in natural hosts but are oncogenic in species different from their natural host
currently, polyomavirus-associated nephropathy (PVAN) is a serious, emerging complication in renal transplant recipients
how do you diagnose polyomaviruses?
PCR for genome DNA and ELISA for antibodies
when would you do RT-PCR?
for RNA viruses
you would use it to convert RNA to DNA
how do you treat polyomaviruses?
no vaccines or antivirals currently available….
what are the characteristics of the papillomavirus?
small, naked icosahedral virion
circular dsDNA
what is the hallmark presentation of human papillomaviruses?
warts! aka papillomas lol
papillomaviruses cause papillomas in natural hosts and are implicated in epithelial-derived cancers in several animal species, including humans
how does HPV replicate? (human popullomavirus)
HPV has a unique niche where they replicate only in replicating epithelial cells and this makes it hard for them to infect cells
the virus has to find a way to get to the right cells to cause an infection – in a normal epithelium we have columnar cells that are alive and replicating and as the cells replicate and head outwards they differentiate and become less of a cell because they lose their nucleus and become your skin!
HPV needs to replicate in the live cells, not your dead skin cells and the way the get to the deeper skin layers that are replicating is by a scratch in your skin that introduces the virus to the cells
so once the replicating cells are inflected, they will make E genes, which for the papilloma viruses these are E7 and E6 which bind to and inhibit p53 and RB = cell keeps replicating
as the cells differentiate towards the outside layers of skin, you get L gene expression
how does HPV cause warts?
warts are just extra cell growth
this is caused by early gene produces E6 and E7 which bind to and inhibit p53 and RB, respectively
p53 and RB are the cellular safeguards that are checkpoints in the cell cycle
so transcription of early genes and translation of early proteins induce a steady state of viral DNA synthesis and proliferation of basal and suprabasal epithelial cells
what are the clinical features of HPV?
- verrucae vulgaris = cutaneous common warts
- condyloma acuminata = genital and anal warts
- epidermodysplasia verruciformis
think Treeman for worst case scenario of HPV…
what is epidermodysplasia verruciformis?
a skin condition caused by HPV that often becomes cancerous
how do you diagnose HPV?
we CAN’T grow HPV in a tissue culture, it can only grow in those happy replicating skin cells which are hard to reproduce
this means we CAN’T serotype HPV
so to diagnose, you have to look at the genome, sequence it and do PCR
how do you proclaim a new strand of HPV?
clone the HPV genome, radioactively labeling it and crosshydridizing to reference HPV DNA — if less than 50% of laveled genome is protected by binding to the reference HPV DNA then it is a new type of HPV
if the nucleotide sequence of a short highly conserved region found in all HPVs varies by more than 10% from that in all other known HPVs, the isolate is defined as a new type, or more accurately, as a new genotype
what’s the difference between serotype and genotype?
a serotype is based on antibody recognition of the virus during the infection
the antibodies can be used to recognize the virus if we purify them
however, antibdoes can recognize multiple viruses so you won’t be able to differentiate closely related viruses
genotyping on the otherhand is very specific and you can differentiate
which HPV strains are high risk?
16 18 31 33 35 45 52 58
which HPV strains cause plantar warts? is there a risk of cancer?
1 and 4
no risk of cancer
plantar warts on sole and palm
which HPV strains cause common warts? is there a risk of cancer?
2 and 57
no risk of cancer
cutaneous and genital warts
which HPV strains cause flat warts? is there a risk of cancer?
3 and 10
no risk of cancer
cutaneous and gential warts
which HPV strains cause epidermodysplasia verruciformis? is there a risk of cancer?
5,8 and 47
super high risk of cancer!!!
epidermodysplasia verruciformis on the face, trunk and esophagus
which HPV strains cause benign warts? is there a risk of cancer?
6 and 11
low risk of cancer
anogenital and larynx benign warts!!
larynx benign warts = laryngeal papillomatosis (acquired during childbirth)
anogenital benign warts = condyloma acuminata (acquired during sex)
which HPV strains cause flat condylomata or carcinoma? is there a risk of cancer?
16 and 18
high risk of cancer
anogenital and esophagus cancer
HPV 16 and 18 cause anogenital squamous cell carcinoma bceause HPV infects squamous cells found in the skin and anus and cervix
what’s important about HPV 6 and 11?
- can cause laryngeal papillomatosis = recurrent respiratory papillomatosis which is when tumors develop in the airways, usually of children (acquire
- they are also found in pre-malignant lesions of the cervix -the so-called cervical intraepithelial neoplasia (CIN) which are graded I to III
however, neither HPV 6 nor 11 have been found in malignant lesions of the cervix
what’s important about HPV 16, 18, 31 and 33?
they are frequently found both in CIN and invasive squamous cell carcinomas of the cervix!
we are most concerned about these strains!!
infections by type 18 are less common than type 16 but more aggressive
why do we care which HPV genotypes are associated with malignancy?
because these are the strains that we are going to develop drugs for!
how do you make an HPV vaccine?
we make vaccines from the capsid of the HPV virus!
if you take the capsid proteins from a virus and put them in a tissue culture, the capsid proteins will spontaneously crystallize – you can then turn this into a vaccine because when you inject the capsid proteins into us, our body will develop antibodies against the capsid proteins without actually infecting us with the virus
so then when we are exposed to the real virus, we will recognize its capsid proteins and be able to fight it
what is the most common STD in the US?
HPV
how common is HPV?
it’s the most common STD in the US
but most infections are latent or subclinical
25-45% of sexually active women are positive by PCR for HPV but only 10% of HPV-positive women show signs of infection by Papanicolaou (PAP) smears
how do you prevent HPV?
- Gardasil
2. Cervarix
which HPV strains does Gardasil protect against?
HPV 16, 18 (70% of cervical cancers)
HPV 6, and 11 (90% of genital warts)
it’s made from non-infectious HPV-like particles (VLP) and is an inactivated subunit vaccine!
it doesn’t contain thimerosal/mercury
doesn’t cover 31 and 33 but we’re working on it
which HPV strains does Cervarix protect against?
HPV 16 and 18
what are the two subfamilies of the poxviridae family?
- entomopoxvirinae = poxviruses of insects
2. chordopoxvirinae = poxviruses of vertebrates
what are the general characteristics of the poxvirus?
- largest and most complex animal viruses
- virions are complex, oval or brick shaped, with a core and lateral bodies
- linear dsDNA genome
- replicates in the CYTOPLASM
where does poxvirus replicate in the cell?
the cytoplasm!!!
even though it’s a DNA virus, it replicates in the cytoplasm because it’s so huge it can afford to make its own machinery and doesn’t need the nucleus
they have virion-associated DNA dependent RNA polymerase that does the replicating for the virus, they don’t need the host RNA polymerase
how many poxviruses infect humans? what are they?
- orthopoxviruses
- parapoxviruses
- yatapoxviruses
- molluscipoxvirus
which viruses are orthopoxviruses?
- variola virus
- vaccinia virus
- cowpox virus
- monkeypox virus
which virus causes smallpox?
variola virus
variola is an orthopoxvirus aka a poxvirus
which viruses are parapoxviruses?
- Orf virus
- pseudocowpox
- bovine papular stomatitis virus
which viruses are yatapoxviruses?
- tanapox virus
- yaba monkey tumor virus
both cause fever and localized single or multiple lesions
transmission from infected African primates
which poxviruses are strictly human pathogens?
- variola virus (type of orthopoxvirus)
2. molluscipoxvirus
what is the course of smallpox?
first you inhale air droplets or aerosols with initial infection of mouth, trachea and lungs but there’s no lesions or symptoms at this point
then the cells of the lungs/trachea get infected and the macrophages of the area will carry the virus to the lymph nodes which will cause the virus to infect the lymph nodes (˜day 4)
early replication in the lymph nodes produces flu like symptoms with a super high fever
then as the fever goes down, you get a huge rash in your mouth called an enanthem
then the enanthem goes away and it becomes an exanthem = a rash all over the outside of your body that’s super infectious; the rash will show up everywhere all at the same time
the infection is NOT contagious during the 1-2 weeks of incubation before the enanthem and exanthem
the rash then develops into pustules all ove
eventually the pustules dry up and scab over
then all the scabs fall off at the same time which is a problem because you’re basically losing all your skin at the same time and you die from infections..
what does smallpox look like?
like little bubbles literally all over your entire body
why is the smallpox vaccine so effective?
- humans are the only host - there’s no hidden population
- you’ll have lifelong immunity
- smallpox is a transient, not persistent infection
- vaccine is inexpensive
what’s the risk with a smallpox vaccine?
it’s a live vaccine so they used to have really bad sores and stuff developing at the site of the smallpox vaccine
- encephalitis
- necrosis
- vaccine blisters spread all over the body
- accidental autoinnoculation
- death
what is autoinoculation?
when the virus is spread from the fingertips to eyes or mouth
like if you scratch the vaccine site then touch your eyes….
what is the vaccinia virus?
a type of orthopoxvirus
subspecies of buffalo pox virus
mainly in the indian subcontinent
what is the cowpox virus?
a type of orthopoxvirus
rodent-borne and indigenous to rodents in europe/asia
what is the monkeypox virus?
a type of orthopoxvirus
rodent-borne virus
reported in 9 west and central african rainforest countries
what is the Orf virus?
a type of parapoxvirus
transmitted by infected sheep, goats, or wild artiodactyls
what is the pseudocowpox virus?
a type of parapoxvirus
transmitted by infected dairy cows “milkers nodules”
Bovine papular stomatitis virus - transmitted by cattle
what is bovine papular stomatitis virus?
a type of parapoxvirus
transmitted by cattle
what are the two virus subfamilies associated with the parvovirus?
- aleutian mink disease
2. canine parvovirus
what is the structure of parvoviruses?
2-3 capsid proteins
linear, single-stranded naked DNA
what is AAV?
AAV = adeno-associated virus
it doesn’t cause any known disease in humans
its DNA integrates into a single site in human chromosome 19
it is used as an experimental gene therapy vector
what are bocaviruses?
human bocaviruses are related to bovine (bo) and canine (ca) parvoviruses
what are the clinical features of parvoviruses?
- seasonal infections = december - april
2. infections are respiratory diseases especially in kids
what is B19?
the full name of parvovirus is parvovirus B19!!!
what is the clinical presentation of B19?
it’s a parvovirus
presents as “slapped cheeks”
the mouth and nose area DON’T get red
who gets infected with B19?
it is a global and common infectious pathogen in humans
common in kids but adults can also get it
which type of antibody is directed against B19?
IgG
how does B19 infect cells?
B19 virus infects cells expressing globoside (P-antigen) on their surface but it only replicates in proliferating cells such as RBC precursors
**B19 infects and kills the precursors to RBCs
temporary depression of erythropoiesis is likely a feature of all transient B19 infections, and usually not significant if no underlying hemolysis or erythroid compartment stress
transient aplastic crisis (TAC) results only when a shortened red-cell life span is coupled with failed erythropoiesis – TAC is self-limiting but the patient may be acutely ill and severly anemic
pure red cell aplasia and chronic anemia occur only when the patient cannot make neutralizing antibodies to clear B19 virus and stop loss of RBC precursors
what is erythema infectiosum?
this is a low grade fever that lasts a week and then when the fever breaks the kid gets the slapped cheek rash on their face which then progresses to lacy reticular pattern that travels down the body
this is an innocuous rash illness with a mild fever
this happens during parvovirus B19 infection!
what can B19 cause in adults?
occasionally, B19 is associated with an acute symmetric polyarthropathy that may mimic rheumatoid arthritis!
when would parvovirus B19 cause TAC?
TAC = transient aplastic crisis
TAC can happen in patients infected with B19 if they have an underlying hemolytic disorder, such as sickle cell anemia, hereditary spherocytosis, enzymopathies or thalassemias, and acquired hemolytic anemias
when BM is depleted, the cell lines get depleted and the BM is only left with adipocytes – this is usually transient and the BM goes back to normal as the virus fades out
conditions of erythroid stress, such as hemorrhage and iron deficiency or bone marrow transplantation, can also be associated with TAC
what happens if an immunocompromised person gets a B19 infection?
they can develop persistent B19 infections which cause pure red cell aplasia and chronic anemia
what happens when a baby in utero is exposed to parvovirus?
fetal B19 infection causes death in utero, hydrops fetalis, or development of congenital anemia because of the immature immune status
if B19 is contracted during 1st 2 trimesters = hydrops fatalis = severe fetal anemia
what are the 5 syndromes caused by parvovirus B19?
- Fifth disease
- anthropathy
- TAC
- persistent anemia
- hydrops fetalis and congenital anemia
how can you diagnose B19?
children will have erythema infectiosum and exhibit a bright red rash on their cheeks (slapped cheek syndrome), lacy rash on trunk and limbs
you can also detect specific antibodies by ELISA or viral DNA by PCR
how do you treat B19?
treatment of persistent B19 infection with immunoglobulin reduces viral load and results in a marked resolution of anemia
what do you need for recovery from B19?
neutralizing antibodies
neutralizing antibodies bind to B19 virus and prevent the uncoating of virions – a single antibody will act to stabilize the virion so the capsid cannot open, trapping the genome
antibodies that bind to the virus may not neutralize virus infectivity so iff you are unlucky and make only non-neutralizing antibody, B19 will cause a fatal persistent infection unless immune immunoglobulin is administered
in such a patient, immunoglobulin must be given life-long; otherwise the virus will start replicating again
what wart is associated with HPV 1-4?
verruca vulgaris = cutaneous common wart
transmission of warts is through physical contact
how is parvovirus transmitted?
respiratory droplets
also it can be transmitted vertically from mother to child
do poxviruses bud?
no, they make their own envelopes!!
what are Guarniari bodies?
poxviruses replicate in the cytoplasm and they form inclusion bodies called Guarniari bodies!
these are diagnostic for poxviruses!!
what does the core of a poxvirus look like?
dumbell
what’s the difference between smallpox and chickenpox?
lesions are of the SAME age for smallpox (variola)
chickenpox will have a mixture of new ulcers, blisters and scabs (varicella)
