DNA viruses Flashcards
What is the morphology of human herpes viruses
- envelope:
- lipoprotein: sensitive to detergents
- derived from host nuclear membrane
- glycoprotein spikes - more numerous and shorter than other enveloped viruses - Tegument: contains many viral enzymes
-thymidine kinase
-ribonucleotide reductase
-DNA synthesis machinery
-protein kinase
VHS - virion host shut off protein - turns off host protein synthesis
aTIF - trans inducing factor (transported to nucleus, initiates transcription of early genes) - Capsid
- Core: linear dsDNA
DNA and protein give a toroid shape
What is the steps of herpes virus replication and viral gene expression
Coordinately regulated by viral proteins Sequentially ordered in a cascade fashion
1. Attachment of viral glycoproteins to cell receptors
2. Fusion of envelope with plasma membrane
3. Viral proteins released from tegument
VHS - virion host shut off protein (turns off host protein synthesis) αTIF - trans inducing factor (transported to nucleus; initiates transcription of Immediate Early genes)
4. Capsid migrates to nuclear pore
5. Release of viral DNA; enters nucleus and circularizes
6. Transcription of viral Immediate Early genes Induced by
7. Immediate Early mRNAs transported to cytoplasm and translated
αTIF
Uses host RNA Pol II
8. Immediate Early proteins migrate back to nucleus
2-4 hr post infection Turns on transcription of Delayed Early genes
Early transcripts translated in cytoplasm; Delayed Early proteins return to nucleus Delayed Early proteins needed for replication of viral DNA
9. Delayed
Viral thymidine kinase Viral DNA polymerase
Delayed Early proteins induce transcription of Late Genes Rolling circle mechanism Head to tail concatemers
10. Replication of virus genome
11. γ proteins are transcribed/translated 12-15 hr post infection
Structural proteins of virus Viral envelope glycoproteins Late in infection: Late Gene proteins turn off synthesis of Immediate Early and Delayed Early
proteins
12. Assembly of capsid proteins 13. New viral DNA cleaved into unit length pieces and packaged 14. Accumulation of viral glycoproteins and tegument proteins in nuclear membrane 15. Capsids bud out of nuclear membrane and become enveloped 16. Progeny virions travel to extracellular space via ER
Virus not released efficiently into extracellular space Immediate attachment and penetration of adjacent cells
How do herpes avoid the immune system?
Some Herpes viruses produce proteins inhibiting production and activity of cytokines The viruses code for homologs of cellular cytokines that bind chemokine receptors but do not elicit responses Herpes viruses encode many proteins that function to decrease MHC class I proteins receptors, displayed on cell surfaces, evading CTLs. The viral proteins do this by various mechanisms: 1. Binding and retaining MHC class I chains in ER (CMV) 2. Dislocating class I chains from ER and directing them into cytoplasmic proteosomes (CMV) 3. Inhibiting peptide transfer mechanisms involved in antigen presentation (CMV, HSV) 4. Shunting newly assembled class I chains into endolysosomes for degradation (CMV) 5. Promoting endocytosis of MHC I chains from the cell surface leading to degradation in cellular endolysosomes (KSHV)
• HHV-8 (KSHV) encodes protein homologs of cellular transcription factors of the interferon regulatory factor (IRF) family. They inhibit virus-mediated transcriptional activity of the IFNα promoter, and thus, inhibit virus-mediated synthesis of biologically active interferons. This undermines the functions of IRFs and lowers the amount of interferon, important to host immunity.
Compare HSV1 to HSV2 in clinical manifestations and transmission
HSV 1
Herpetic Gingivostomatitis: Cold sores, fever blisters, multiple painful vesicles of mucous membranes; usually in mouth, can be in nostrils, genitalia, and cornea. Can present with fever. Very often asymptomatic.
Herpetic Keratoconjuntivitis: Herpes virus infection of conjunctiva and cornea;
swelling and inflammation of superficial tissue of anterior eye; potential scarring and loss of vision.
Herpes Simplex Encephalitis: A rare complication in HSV 1 infections. One of the most common severe, sporadic viral diseases of brain. Believed to spread along neurons to brain in either primary or recurrent infections, leading to necrotizing hemorrhagic encephalitis. If untreated results in coma or death.
HSV2:
Genital Herpes: Genital sores, painful pustules and ulcers accompanied by fever and malaise. Urethra and cervix can also be infected.
Neonatal Herpes: Mothers infected with HSV-2 (even asymptomatically) shed virus in vaginal track and can infect neonates during birth. Very severe CNS infections; often fatal.
HSV 1 - oral-oral; oral-genital
HSV 2 - primarily genital-genital; also oral-oral; oral-genital
Hbv structure
HBV virions contain only three proteins: (1) envelope (Hbs or surface) glycoprotein
, (2) Hbc or core protein of the icosahedral nucleocapsid, and (
3) a non-structural protein, the viral replicase. The genome is circular DNA, partly single- stranded and partly double-stranded. The genome encodes only four open reading frames, which encode the three proteins described previously plus ORF X, a transactivator of transcription.
how is Hbv a retrovirus in disguise
Although HBV virions contain a DNA genome, HBV is in fact a retrovirus. The viral replicase is a reverse transcriptase. HBV differs from other retroviruses in the time and place of reverse transcription. Conventional retroviruses reverse- transcribe genomic RNA after a virion has infected a cell. HBV reverse transcribes its genome prior to release of progeny virions from the infected cell. Second-stand synthesis is not completed; this is why virion genomes are only partly double-stranded. After infection of a cell, these genomes are converted to fully double- stranded DNA, which is transcribed to produce both mRNA’s and genomic RNA’s to be incorporated into new virions.
delta agent
Delta agent: A virus dependent on HBV for its replication. The genome is a small circular (-) strand RNA, highly self- complementary, which base-pairs to itself to form a rod-like structure. It encodes a single protein, delta antigen. The genome is transcribed by host-cell RNA polymerase II. Delta antigen binds to genomes; as its concentration increases replication is suppressed and incorporation of genomes into envelopes is promoted.
Delta agent produces progeny only in cells infected with HBV. Virions are enveloped; the envelope contains HBV envelope protein and encloses the genome bound to delta antigen. Infection with Delta agent can take place simultaneously with infection with HBV or by super-infection later. Presence of Delta agent increases the severity of HBV disease.
transmission of hbv
Exposure to blood or blood products. There is a high prevalence among users of IV drugs, transfusion recipients, hemo- philiacs, renal dialysis patients, and health care workers. Immunization, screening and testing of blood donors, and universal precautions have reduced the incidence in some populations, but it remains high in others. In some urban populations
prevalence of HBV is about 1%; many of the infections are asymptomatic.
During acute infection blood contains very large amounts of HBV and is highly infectious - less than one microliter
is sufficient to transmit infection. Before immunization many health care workers became infected. The high prevalence of
HBV and HIV and the high infectivity of HBV lead to the institution of ‘Universal Precautions’ when handling patients,
contam-inated material, and clinical specimens.
From mother to infant, mostly by exposure to maternal blood during delivery. Highly efficient; nearly all infants of infected mothers become infected.
By sexual intercourse.
Household contacts of persons with HBV often become infected; the route of transmission is sometimes not obvious.
acute hbv disease
Acute HBV disease.
There may be a prodromal period of non-specific symptoms such as fever, nausea,/vomiting, anorexia, before development of jaundice (from decreased liver function and increase in plasma bilirubin) and elevated plasma levels of liver-specific enzymes. Later, after an immune response begins, there may be so much circulating HBV antigen as to produce serum
sickness and/or glomerulonephritis.
Fulminant hepatitis (rare, often associated with HDV infection) with massive/total liver destruction produces neurological disease ranging from encephalopathy to coma or death and requires hospitalization and intensive supportive care. Mortality is high; survivors usually regain normal liver function.
chronic hbv disease
Chronic HBV disease.
Disease varies widely in severity: from asymptomatic carriage, to chronic hepatitis with elevated liver enzymes, to
widespread cirrhosis and liver failure.
HBV and Hepatocellular Carcinoma (HCC). Nearly all HCC patients are HBV-positive and the prevalence of the two diseases is strongly correlated. Exposure to HBV early in life leads to chronic low-level infection, chronic hepatitis, and
cirrhosis, with HCC developing 30-50 years after infection.
In 80-90% of tumors, HBV is integrated into host-cell DNA. However, viral DNA is extensively rearranged and
fragmented and there is neither any viral gene expression, a consistent structural pattern to the integrated viral sequences
or a consistent site of integration. HBV’s role may be indirect, with a long period of inflammation and cell death and
replacement setting the stage for genetic changes in proliferating hepatocytes.
HbC doesnt have a vaccine but A and B do: describe them and the treatment of Hav and hbv
Vaccines exist for HAV and HBV and are highly recommended.
HAV vaccine contains killed virus.
HBV vaccine contains surface antigen produced in yeast cells by genetic engineering.
Human immune globulin (HAIG, HBIG) is used for prophylaxis of non-immune contacts (especially in HAV outbreaks).
α -Interferon and the reverse-transcriptase inhibitor 3TC (developed for use against HIV) are used to treat chronic HBV disease. The virus is usually not completely eliminated but viral load declines and liver function improves. In most patients viral levels return to pre-treatment levels if therapy is discontinued.
How to diagnose Hepatitis B?
Serology is the mainstay of diagnosis: acute viral hepatitis caused by different viruses cannot reliably be distinguished on clinical grounds. Serological tests identify HAV, HBV, HCV, Delta agent, and HEV.
Three HBV antigens, and antibodies to them, are important in diagnosis.
Surface antigen -
HbsAg - Present in both infectious virions and empty particles. (measure of immunity)
Core antigen -
HbcAg - Only in infectious virions.
Hbe antigen [translational variant of Hb core Ag with N- terminal extension]
HbeAg - Only in infectious virions; also present free in serum.
For serological testing, prepared by extraction of viral cores with detergent. **Plasma HbeAg correlates with viremia, infectivity.
When antibodies first appear, circulating viral antigen is present at so high a concentration that the antigen-binding sites of all anti-HBV antibody molecules are saturated with antigen and cannot be detected in laboratory tests (which rely on antigen binding by free antibody). The amount of circulating immune complexes can be so high as to produce serum sickness. Only after most antigen has been cleared from the blood do free antibodies become detectable. Antigens and antibodies to them appear with a characteristic time course - this is used clinically to establish the stage of infection.
TORCHeS stands for things that can cross the placenta and infect the neonate what are they?
TO: toxoplasma gondhi R: rubella C: CMV H: HIV, HSV S: syphillus
also Varicella zoster and parvo.
smallest pathogenic virus - slapped cheek rash on face with lacy red rash on trunk and limbs.
There is transient deficiency of red cell production.
Maternal to fetal infection can cause serious disease and is fatal if its early in pregnancy 10%
Parvovirus B19 - linear (-) single stranded DNA) Replicates only in dividing cells
Heeds host cell replication machinery. Replicates in the nucleus of epithelial cells. Cells must differentiate for virus to go through full replication cycle so viral proteins keep infected cell in division cycle.
Proliferative lesions = warts.
Propensity to develop cervical cancer because infection is most common in sexually active young women.
HPV - early viral proteins E6 - binds to p53 and blocks apoptosis
E7- binds to Rb which sequesters transcription factor E2F. Binding releases E2F from inhibition and promotes cellular division.
Treatment is via surgical removal or killing of infected tissue
What are E6 and E7
HPV - early viral proteins
E6 - binds to p53 and blocks apoptosis
E7- binds to Rb which sequesters transcription factor E2F. Binding releases E2F from inhibition and promotes cellular division.
What are E1A and E1B?
They are Adenovirus viral proteins. E1A binds and sequesters Rb like E7 of HPV. E1B binds p53 and blocks site required for activation of transcription.
Although adenoviruses don’t cause tumors.
This causes aspectic pharyngitis with conjunctivits.
Adenovirus: infection is created by propensity of virus to infect and kill epithelial cells of the respiratory, GI and urinary tracts and of the cornea and conjunctiva.
The only DNA virus that transcribes in the cytoplasm forming brick shaped cytoplasmic inclusion bodies
Smallpox - the largest and most complex- respiratory or on fomites.
Has two forms: Variola major - severe and more common form with more extensive rash and higher fever
Variola minor - less common and much less severe.
*distinguishing feature from chicken pox: chicken pox comes in waves, in smallpox all lesions evolve from macules to papules to vesicles to pustules which scab over and ultimately heal. In lesions there is dermal necrosis and after healing each leaves a small scar or pock .
What is one of the most common severe, sporadic viral diseases of the brain?
HSV encephalitis caused by HSV1 of the alphaherpesvirus group.
Intra-nuclear inclusion bodies
Multinuclear giant cells
Focal necrosis
You see these on the microscope, how would you treat?
Sounds like the host cell of an alphaherpesvirus infection.
Acyclovir for Alphaherpes.
How do alphaherpes virus evade the immune system?
They remain latent in the sensory ganglion. During that time there is no virus replication and the virus avoids immune recognition. The myelin sheaths protect the virus because neurons do not express MHC antigens for T cell recognition.
Some viral mRNA transcripts - Latency associated transcripts (LATS) - found in latently infected sensory neurons and are viral mRNA transcripts. They are antisense to the viral gene ICPO (infect cell protein alpha O), mRNA binds to it and turns off infection so that cell will remain in latency.
Where the Varicella Zoster hide in?
It stays latent in MULTIPLE sensory ganglia. There live attenuated vaccine for it.
Treatment for alpha viruses is still acyclovir.
DNA virus: Usually asymptomatic infection.
The serious complications is in children younger than 2 yrs and immunocompromised.
Fatal is 20% of infected children and can cause severe congenital abnormalities including motor and mental retardation, and deafness.
For immunocompromised RETINITIS is very common.
For young adults can cause mononucleosis-like disease (fever, pharyngitis and lympadenopathy)
Cytomegalovirus - betaherpesvirus
latent in neutrophils and monocytes, the mechanism of viral latency unlike ALPhaherpes has nothing to do with viral proteins.
Infectious mononucleosis - (fever, pharyngitis, and lymphadenopathy, and SPLEEN enlargement:
on microscope no cytopathic effects, no inclusion bodies
Atypical lymphocytosis with reactive lymphocytes in blood (downey cells)
Heterophile antibodies - polyclonal immunoglobulins which agglutinate RBCs and can be detected by Paul-Bunnel Test
Epstein Barr Virus
What kind of EBV does this patient have?
Anti EBV nuclear antigen: none
Anti VCA - IgM
Anti EBV nuclear antigen: High IgG
Anti VCA - IgG
Acute
Past
How does EBV and M. falciparum cause Burkitt lymphoma
THese are relevant because they are endemic to the same region.
It comes down to the c-myc gene which codes a TF.
A mutated version of Myc is found in many cancers, which causes Myc to be constitutively (persistently) expressed. This leads to the unregulated expression of many genes, some of which are involved in cell proliferation, and results in the formation of cancer
c-myc into Ig promotor leads to tumor
Malaria impairs the cellular immunity but also chronically stimulates it, thereby increase B cells which can carry EBV and also increases chances of translocation
What is reyes syndrome?
Characterized by acute brain damage. Liver dysfunction. It is caused by the use of aspirin following varicella or influenza. Primarily infects 4-12 yrs of age with a 40% mortality.
A distinguishing feature of influenza.
What is the morphology of pox viruses?
The virion is as large as a small bacterium and
(barely) visible in a light microscope.
Virions have a complex structure and contain >100 different proteins. Particles
are brick-shaped and enveloped.
The DNA-containing core is bi-
concave (like an erythrocyte) and flanked by two lateral bodies.
Compare the timing and distribution of small pox and Chickenpox lesions/
Smallpox
Distribution: first on face and extremities, then on trunk
Timing: lesions appear synchronously, all at same stage of development
Chickenpox:
Distribution: first on trunk, then on face and extremities
Lesions: appear in successive waves, can see all stages at once.
Structural qualities of
Poxvirus
Parvovirus
Papovirus
Adenovirus
Poxvirus: has envelope, dumbell shaped core
Parvovirus: no envelope, icosahedral, linear ssDNA.
Both papovirus and adenovirus have no envelopes and are icosahedral, with double stranded DNA.
