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Microbiology & Infectious Disease > Virology: Herpesviruses > Flashcards

Virology: Herpesviruses Flashcards

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1
Q

Describe the classification of Herpesviruses.

family, subfam etc

A 
Family: Herpesviridae 
Subfamilies: Alpha, Beta, Gamma herpesviridae 
Size: 180-200nm
Envelope: YEP
Genome: linear dsDNA (120kb to 230kb) 
Genome Replication: Nucleus 
Virus assembly: Nucleus
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2
Q

Describe the structure of herpesviruses.

glycoproteins, tegument etc

A
  • Glycoproteins: embedded in the lipid envelope. Receptor mediated entry into cells
  • Tegument: between envelope and capsid, induction of viral gene expression, shutoff of host protein synthesis, virion assembly
  • Icosadeltahedral capsid
  • dsDNA
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3
Q

What are the 8 Human Herpesviruses?

A
  1. Herpes simplex virus 1 (HSV-1)
  2. Herpes simplex virus 2 (HSV-2)
  3. Human cytomegalovirus (HCMV)
  4. Varicella-zoster virus (VZV)
  5. Epstein Barr virus (EBV)
  6. Human herpesvirus 6A/6B (HHV-6A/6B)
  7. Human herpesvirus 7 (HHV-7)
  8. Kaposi’s sarcoma-associated herpesvirus (KSHV/HHV-8)
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4
Q

What are the three subgroups of the Human Herpesviruses.

A
  1. Alphaherpesvirinae
  2. Betaherpesvirinae
  3. Gammaherpesvirinae
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5
Q

Human Herpesvirus Subgroups:

1. Alphaherpesvirinae?

A
  • HSV-1, HSV-2, VZV
  • variable host range
  • short replication cycle
  • rapid spread in culture
  • efficient destruction of infected cells
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6
Q

Human Herpesvirus Subgroups:

2. Betaherpesvirinae?

A
  • CMV, HHV-6, HHV-7
  • restricted host range
  • long replication cycle
  • slow spread in culture
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7
Q

Human Herpesvirus Subgroups:

3. Gammaherpesvirinae

A
  • EBV, KSHV
  • restricted host range
  • usually specific for B or T lymphocytes
  • Latent infection in lymphocytes
  • replication in culture is infrequent
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8
Q

Describe the cellular tropsim of the following herpesviruses:
HSV-1, HSV-2, Varicella Zoster virus (VZV), Cytomegalovirus (CMV), Human herpesvirus 6 (HHV-6), Human herpesvirus 7 (HHV-7), Epstein Barr Virus (EBV) and Kaposi’s Sarcoma-associated herpesvirus( HHV-8).

A
  • Mucoepithelial cells for both simplex viruses.
  • B lymphocyte and epithelial cells for VZV
  • Epithelial cell, monocytes and lymphocytes for CMV
  • T lymphocytes for both Human Herpesvirus 6 + 7
  • B lymphocytes and epithelial cells for EBV
  • B lymphocytes and endothelial cells for HHV-8.
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9
Q

What are the two parts of herpesvirus life cycles?

A
  1. Latency: no virus protein expression(modified protein expression), episomal DNA replicated with host DNA aka copies of viral genome is passed on to the daughter cells, it is immunologically silent. Once you are infected it is there for your entire lifespan.
  2. Lytic cycle: virus DNA replication, new progeny viruses made, full range of virus proteins expressed, highly immunogenic
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10
Q

Give a brief history of herpesvirus.

A
  • described since ancient Greece
  • herpes is derived from the greek word herpein which means to creep
  • hippocrates and other greek scholars used the word Herpes to describe spreading cutaneous lesions.
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11
Q

What glycoproteins are involved with entry of herpesvirus into host cells?(5)

A
  • five highly conserved glycoproteins
    1. Glycoprotein B (gB)
    2. Glycoprotein H (gH)
    3. Glycoprotein L (gL)
    4. Glycoprotein M (gM)
    5. Glycoprotein N (gN)
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12
Q

What are the two ways Herpesvirus can bind and enter host cells?

A
  • Receptor-mediated endocytosis -glycoproteins interact with receptors on cell and endocytosis occurs
  • Direct fusion with the plasma membrane - interaction with receptors triggers direct fusion of the viral envelope and host cell membrane; capsid is released into the cell
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13
Q

Explain how EBV enters epithelial cells.

A
  • a complex comprised of gp42, HLA, Class II, gH and gB is formed. This complex is called the fusion complex. It undergoes a rearrangement to bring VM into direct contact with the HCM for fusion to allow entry of the virus.
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14
Q

What are the steps for herpes simplex virus binding and entry into host cells?

A
  1. Pre-fusion
  2. Receptor binding
  3. Fusion triggering
  4. Fusion
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15
Q

Will all herpesviruses go lytic immediately following infection?Examples?

A
  • HELL NO
  • Ex:
    1. HSV/VZV infection —> Lytic replication latency. If it goes to lytic it will either cause cell death or cell to cell transmission Lytic replication Latency. If it goes to lytic it will either cause cell death or cell to cell transmission
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16
Q

Explain herpesvirus lytic replication cascade.

A
  • Immediate early : Immediate early transducers of lytic replication (alpha proteins) -> minimal number of proteins..interact with promoters for viral rep in lytic. Also interact with promotes of latent / structural genes.
  • Early: Virus DNA replication (beta proteins)
  • Late: Structural proteins (gamma proteins)
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17
Q

Do all herpesviruses encode their own protein which are necessary and sufficient for viral DNA replication?

A
  • yes. Herpes all express the proteins required for rep and do not need host proteins etc for rep.
  • This includes: ssDNA binding proteins, Origin binding protein, helicase-primase complex, DNA polymerase and polymerase processivity factor.
    L> homologues exist for these host cell proteins in alpha(ex:HSV) , beta(ex: CMV) and gamma herpesviruses (ex: EBV)
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18
Q

Explain herpesvirus DNA replication.

A
  • oriLyt
    L> Origin of replication region
  • Origin binding protein
  • DNA unwinding
  • Replication bubble formed from the unwinding of DNA
  • ssDNA binding protein stabilizes the replication fork
  • Helicase/Primase: origin binding proteins and ssDNA binding proteins recruit the viral DNA replication proteins to the replication forks.
  • synthesis of new DNA strand via poly/accessory factor on the leading strand occurs and discontinuous synthesis occurs on the lagging strand with RNA primer filling the gaps (okasaki fragments)
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19
Q

Herpesvirus DNA replication, rolling circle?

A
  • DNA is nicked to form a rolling circle.
  • cleavage /packing proteins
  • no one knows why this occurs.
  • one strand is nicked by endonuclease. The free 3’ end is extended by DNA poly (5’->3’) displacing the comp temp strand which is copied in short segs by DNA poly
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20
Q

What are the clinical manifestations of herpes simplex 1 infections?

A
  • Encephalitis
  • conjunctivitis
  • oropharyngeal herpes
  • mucocutaneous disease (immunocompromised)
  • primary genital herpes, recurrent herpes genitalis
  • herpes whitlow
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21
Q

What are the clinical manifestations of herpes simplex 2 infections?

A
  • meningitis
  • oropharyngeal herpes
  • perianal herpes
  • primary genital herpes, recurrent herpes genetalis
  • herpes whitlow
22
Q

By examining the clinical manifestations of both HSV-1 and HSV-2 what conclusion can be drawn?

A
  • that they have coevolved with us
23
Q

Clinical manifestations of herpes simplex infections:

  • Infection via what surfaces?
  • replication occurs where?
  • invasion?
A
  • mucosal surfaces
  • replication in oral or genital mucosa
  • invasion via sensory nerve endings
24
Q

Clinical manifestations of herpes simplex infections:

- what is HSV’s two unique properties? Explain them.

A
  1. Neurovirulence: Invade and replicate in the CNS, profound disease, severe neurologic devastation
  2. Latency: HSV-1: trigeminal ganglion and HSV-2: sacral ganglia.
    * *** goes latent in dorsal root ganglion and can travel along nerves and invade CNS
25
Q

Clinical manifestations of herpes simplex infections:

- Explain the immunocompromised situation.

A
  • Transplants: severity directly related to type of immunosuppressive therapy
  • pneumonitis, esophagitis and gastritis
  • HIV/AIDS: more exaggerated, more frequent and more resistant to antivirals.
    aka you can get diseases you would not normally see.
  • allows replication out of control.
26
Q

Clinical manifestations of herpes simplex infections:

  • Explain the following states:
    1. Healthy
    2. Congenital CMV
    3. Immunocompromised
A
  1. Usually clinically silent..up to 8% primary infection results in mononucleosis
  2. In utero infection of multiple systems
  3. Transplants (solid and hematopoietic stem cell) : Pneumonitis, Esophagitis, Gastritis, Enterocolitis, Hepatitis, Retinitis, Graft-Versus-Host Disease
    HIV/AIDS: Retinitis, Esophagitis, Gastritis, Enterocolitis, Peripheral neuropathy, Pneumonitis, Hepatitis.
27
Q

What is going on with CMV infection and pregnancy?

A
  • Primary maternal CMV Infection (when infected for the first time during life while PREGO))
  • 40% risk of transmission to fetus
  • 10-15% infected infants may have clinically apparent disease (mild to severe) -> 10% develop normally and 90% develop sequelae
    OR
  • 85-90% infected infants are asymptomatic –> 5-15% develop sequelae and 85-90% develop normally
28
Q

Explain the clinical manifestations present in symptomatic congenital CMV.

A
  • Petechiae 76%
  • Jaundice 67%
  • HSM 60%
  • Neurologic abnormality 68%
  • Microcephaly 53%
29
Q

Epstein Barr Virus Infection:

  • up to _% of the world population will be infected by adulthood
  • Infection is usually ___.
  • Delayed infection can result in____.
A
  • 95%
  • asymptomatic
  • infectious mononucleosis (glandular fever)
30
Q

Epstein Barr Virus Infection:

-B lymphotropic??

A
  • EBV maintains latency in memory B cells for the lifetime of the host
  • CD21 (gp350)) and HLA Class II (gp42)
31
Q

Epstein Barr Virus Infection:

- epithelial cells??

A
  • person to person transmission of EBV..virus is released into saliva
32
Q

Epstein Barr Virus Infection:

- T cells and NK cells

A
  • very rare.
33
Q

Epstein Barr Virus Infection:

- what are the three groups that can be infected?

A
  • B lymphocytes
  • Epithelial cells
  • T cells and NK cells
34
Q

Clinical manifestations of Epstein Barr infection:

- Wrt B cell manifestations?

A
  • Burkitt lymphoma -> tumour can double in size every two hours
  • Hodgkin lymphoma
35
Q

Clinical manifestations of Epstein Barr infection:

- Wrt Epithelial cell malignancies ??

A
  • Nasopharygneal carcinoma

- Gastric carcinoma (10%)

36
Q

Clinical manifestations of Epstein Barr infection:

- Wrt T and NK cell malignancies ??

A
  • Extranodal NK/T cell lymphoma *** very serious and particularly necrotic
  • NK leukaemia
37
Q

What three ways are latent infections characterized?

A
  1. Viral gene products that promote productive replication are not made.
  2. Cells harbouring latent genome are poorly recognized by the immune system.
  3. The viral genome persists intact so that productive infection can be initiated to ensure spread to new hosts.
38
Q

Explain herpesvirus cellular tropism and latency of:

  • HSV-1/2
  • Varicella Zoster Virus (VZV)
  • Cytomegalovirus (CMV)
  • Human Herpesvirus 6 (HHV-6)
  • Human Herpes virus 7 (HHV-7)
  • Epstein Barr Virus (EBV)
  • Kaposi’s Sarcoma-associated herpesvirus (HHV-8)
A
  • Target cell for HSV-1/2 and VZV= mucoepithelial cell and it goes latent in neurons.
  • Target cell for CMV is epithelial cell, monocytes and lymphocytes. Latency = CD34 +HSC, Monocytes and Dendritic cells
  • Target cell for HHV-6 and 7 = T-lymphocytes. Latency for HHV-6= CD34 + HSC monocytes. Latency for HHV-7= T-lymphocytes.
  • Target cell for EBV is B-lymphocytes and epithelial cells. Latency= B-lymphocytes.
  • Target cell for HHV-8 is B-lymphocytes and epithelial cells. Latency = B-Lymphocytes.
39
Q

Explain the factors involved with inducing virus reactivation in:

  • HSV-1/2
  • Varicella Zoster Virus (VZV)
  • Cytomegalovirus (CMV)
  • Human Herpesvirus 6 (HHV-6)
  • Human Herpes virus 7 (HHV-7)
  • Epstein Barr Virus (EBV)
  • Kaposi’s Sarcoma-associated herpesvirus (HHV-8)
A
  • Latency in HSV 1/2 = neuron…reactivation can occur via stress, UV and immune suppression
  • Latency for VZV occurs in neuron and can be reactivated by stress, UV and immune suppression.
  • Latency for CMV occurs in CD34 +HSC, Monocytes, dendritic cells and can be reactivated by cell differentiation (pro-inflammatory cytokines)
  • Latency for HHV-6 occurs in CD34 + HSC, monocytes and can be reactivated by cell differentiation ( pro inflammatory cytokines).
  • Latency for HHV-7 occurs in T- lymphocytes and can be reactivated by pro inflammatory cytokines
  • Latency for EBV occurs in B lymphocytes and can be reactivated by cell differentiation (pro inflammatory cytokines.germinal centre reaction).
  • Human Herpes virus goes latent in B lymphocytes and can be reactivated by cell differentiation
40
Q

Explain the stages of herpes simplex (HSV) infection of the host.

A
  1. primary site of infection = productive infection of epithelial cells.
    - infection by retrograde transport…viral DNA in latent state
  2. Secondary sites of infections and site of latent infection sensory neuron …goes latent in the sensory ganglion
    - infections by antereograde tranpost
  3. Site of recurrent infection: productive infection of epithelial cells
41
Q

What benefit does the herpes simplex virus get from going latent vs not?

A
  • if it didn’t go latent it would be attacked cytotoxic T cells and Natural Killer cells while they are active in the epithelial cells.
  • By going latent in the sensory ganglion it is protected from the T cells and Natural Killer cells
42
Q

Explain the stages of Epstein Barr Virus (EBV) infection of the host.

A
  • virus leaves infection site in the epithelial cells and goes latent in a naive b cell.
  • downregulation of gene expression occurs to stop protein expression initiating this migration into b cells (memory cells).
  • the memory cell will differentiate into a plasma cell which pumps out antibodies in the presence of antigens. This differentiation will reactivate the virus.
    • the plasma cell that the virus becomes reactivated in can become a target of lytic Ag specific T cell Responses and NK cell receptors
43
Q

Explain the herpesviral latency products for:

  • HSV 1+2
  • VZV
  • CMV
  • HHV 6
  • HHV 7
  • EBV
  • KSHV
A
  • latent in dorsal root ganglion…latency transcript/protein = LAT(antisense ICP0)
  • latent in trigeminal, dorsal root, geniculate, celiac and vagal ganglia…latency vIL-10, UL82-82ast.
  • latent in monocytes/ macrophages/ CD34+ stem cells and the latency transcript/protein = IE region and U94
  • latent in CD4+ T cells….latency transcript/protein = IE region and U94
  • latent in B cells and the latency transcript/protein = EBER 1 and 2, miRNA
  • latent in b cells and the latency transcript/protein = LANA
  • ***** HOWEVER, the gammaherpesviruses are associated with cancers and their latency profiles consequently change.
44
Q

Clinical manifestations of Epstein Barr infection:

  • B cell malignancies
  • Epithelial cell malignancies
  • T and NK cell malignancies
A
  • Burkitt lymphoma, hodgkin lymphoma
  • Nasopharyngeal carcinoma, Gastric carcinoma (10%)
  • Extranodal NK/T cell lumphoma, NK leukaemia
45
Q

EBV is a potent transforming agent for what?

A
  • B lymphocytes
46
Q

EBV is a potent transforming agent for B lymphocytes:

- How many growth transforming proteins are there?

A
  • nine
  • EBNA-LP
  • EBNA1
  • EBNA2
  • EBNA3A
  • EBNA3B
  • EBNA3C
  • EBERs
  • miRNAs
  • above are all grouped together
  • LAP1
  • LAP2A
  • LAP2B
47
Q

EBV is a potent transforming agent for B lymphocytes:

- What do the nine growth transforming proteins do?

A
  • they drive b lymphocytes into cycle (normally they are in blood and not cycling..now they will not stop cycling/growing)
  • generates continuously proliferating lymphoblastiod cell lines.
48
Q

Mechanisms of EBV induced tumourgenesis, explain it.

A
  • EBV infection is not sufficient to induce tumours: cofactors include immunosuppression and additional cellular genetic changes
  • rare accidents of persistent virus infection
  • in each tumour, EBV expresses different patterns of virus gene expression which complement genetic changes within the cell to initate and maintain the tumour phenotype.
49
Q

Do viruses want to cause cancer?

A
  • no - viruses want to remain latent and cancer is an accidental byproduct in the right circumstances.
50
Q

Explain the three latency phenotypes in EBV associated malignancies.

A
  • Burkitt lymphoma (Latency 1): involves EBA1, EBERs, miRNA
  • Hodgkin lymphoma, Nasopharyngeal carcinoma and T/NK cell lymphomas (Latency2): involves EBNA1, EBERs, miRNA and LAMP1, LAMP2A
  • PTLD in immunocompromised patients (Latency3): involves all nine proteins
  • *EBNA1 tethers viral DNA to human DNA so it is not lost.
51
Q

Multiple EBV proteins are involved in tumourgenesis. Explain the following proteins f(x):

  • EBNA2
  • EBNA1
  • EBNA3A and 3C
  • LAMP1
A
  • TF, interacts with notch signalling pathway…inducing proliferation
  • TF, activates viral and cellular genes…tumours in trangenic mice
  • TF, chromatin remodelling and changes in cellular gene expression
  • mimics constitutive TNFR signalling..activates cellular genes..transforms mouse fibroblasts.

Microbiology & Infectious Disease (27 decks)

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