Herpes I and II- Ornelles

Question 1

Alpha group HHV’s are
- highly ___, and grow ___ in culture.
They reside in ___ during latent stages.
Examples are:

Where do these replicate?

Answer 1

Alpha group HHV’s are highly cytolytic, and grow rapidly in culture. They reside in neurons during latent stages.
Examples are:
HHV 1 - HSV -1
HHV 2 - HSV-2
HHV 3 - VZV
They all replicate in muco and epithelial cells and in T cells for VZV

Question 2

Beta group HHV’s are
____ growing, laarge, and mostly associated with CD___ cells.
Examples are:

Answer 2

HHV V - CMV
HHV 6A
HHV 6B
HHV 7

HHV 6A , 6B and 7 replicte in t cells and the lymphoid.

Question 3

gamma Herpes virus are __ and __.

Answer 3

EBV (HHV 4)

Kaposi’s Sarcoma (HHV 8)

Question 4

All herpes viruses establish __ and __ stages

Answer 4

Lytic and Latent

Question 5

Latent phase HHV is a life-long, asymptomatic carrier stte. Cell express few, if any viral gene product. Ideally, there i little consequence to host cell and subclinical presentation, with the exception of ___ viruses.

Answer 5

gamma (EBV and Kaposi’s)

Question 6

Which viruses establish latency in lymphoid or myeloid lineage?

Answer 6

HHV 5, 6A, 6B, 7, and 8.

Question 7

During herpes latency phase, there is absence of viral __, the genome persists as an ___ and not usually integrated. Herpes virus gets converted from a __ to a __ genome (less offensive to the host).
There is highly ___ gene expression. __ to __ genes are expressed. __ __ and ___ are expressed.
Latency is maintained in part by the ___ __. All herpes viruses have a constellation of genes to __, __ or __ with the host immune system.

Answer 7

During herpes latency phase, there is absence of viral replication, the genome persists as an episome and not usually integrated. Herpes virus gets converted from a linear to a circular genome (less offensive to the host).
There is highly restricted gene expression. Little to no genes are expressed. Regulatory RNA (miRNA) molecules and LAT (latency associated transcript) are expressed.
Latency is maintained in part by the immune system. All herpes viruses have a constellation of genes to mimic, subvert or cooperate with the host immune system.

Question 8

Herpes virus structure:
genome:
capsid:
envelope:
tegument?

Answer 8

Herpes virus structure:
genome: dsDNA
capsid: icosahedral
tegument: yes, has tegument proteins
This is unique to the herpes virus.

Question 9

What are the tegument proteins? There are two.

Answer 9

Tegument proteins are unique to the herpes virus. The tegument proteins present between the capsid and envelope and include:
VP16 (viral transcription factor)
VHS (ribonuclease)

Question 10

Which nerve does the HSV-1 latently reside in? Which nerve does the HSV-2 latently reside in?

Answer 10

Which nerve does the HSV-1 latently reside in? Which nerve does the HSV-2 latently reside in?
HSV - 1 –> trigeminal ganglia
HSV - 2 –> sacral ganglia

Question 11

What is VP16 and VHS?

Answer 11

VP16 - viral protein 16 –> enters nucleus. a key activator of immediate early viral gene associates with host cell factor (CF1 and CF2)

VHS - virion host shut off protein. These protein remains in the cytoplasm, degrades host mRNA. It is a nonspecific ribonuclease (RNase) that degrades mRNA.

Question 12

What are some characteristics of a latent infection by any herpesvirus?

1. Absence of viral ___
2. Maintenance of the __ __ in the nucleus
3. Expression of viral genes is __ __.
4. ___ of viral replication must be possible

Answer 12

What are some characteristics of a latent infection by any herpesvirus?

1. Absence of viral replication
2. Maintenance of the viral genome in the nucleus
3. Expression of viral genes is highly limited (it can still express LAT and miRNA)
4. Reactivation of viral replication must be possible

Question 13

Herpes simplex virus 2 most typically initiates infection in the ___

Answer 13

urogenital epithelium.

Question 14

___ and __ viruses establish latency in the neurons. Which group of herpes viruses are these in?

Answer 14

VZV and HSV

These are the alpha herpes viruses

Question 15

EBV most typically initiates infection in the __

Answer 15

oral epithelium

Question 16

Latent HSV - 1 virus:
preceded by viral replication in the __ ___.
infection of __ ___
establishes latency in __ ___ of __

Latent HSV - 2 virus
preceded by replication in __ __ epithelium
infection of __ __
establishment in __ __

Answer 16

Latent HSV - 1 virus:
preceded by viral replication in the oral epithelium.
infection of sensory neurons
establishes latency in trigeminal ganglia of CN V

Latent HSV - 2 virus
preceded by replication in urogenital epithelium
infection of sensory neurons
establishment in sacral ganglia of sacrum

Question 17

For both HSV 1 and 2, lytic replication occurs in the epithelial cells. But infection of __ __ delivers __ proteins insufficiently, or not at all. Retrograde transport moves capsid up an axon. Since tegument proteins (__ and ___) don’t make it to the nucleus, only the HSV episomes stays (____ infection). There are no tegument proteins to help with transcription/translation.

Answer 17

For both HSV 1 and 2, lytic replication occurs in the epithelial cells. But infection of sensory neurons delivers tegument proteins insufficiently, or not at all. Retrograde transport moves capsid up an axon. Since tegument proteins (VP16 and VHS) don’t make it to the nucleus, only the HSV episomes stays (latent infection). There are no tegument proteins to help with transcription/translation.

Question 18

Latent infection of HHV 3 (___)
Neurotropic like HSV, but involves viremia.
Secondary infection occurs primarily in __ __ (__ cells)
Replication in other organs produce secondary viremia.
___ infection of skin and follows appearance of a rash (__ __)

Answer 18

Latent infection of HHV 3 (VZV)
Neurotropic like HSV, but involves viremia.
Secondary infection occurs primarily in lymph nodes (T cells)
Replication in other organs produce secondary viremia.
Secondary infection of skin and follows appearance of a rash (chicken pox)

Question 19

Viral __ __ is much less discriminating than cellular __ __ at initial phosphorylation (RLS).

Answer 19

Viral TK is much less discriminating than cellular TK at initial phosphorylation (RLS)

Question 20

Herpes viral replication can be targeted by nucleoside analogs. Neurotropic herpes viruses must mobilize ___ ____ in order to replicate their DNA. Successful drugs that target this are:
Acyclovir, Famciclovir, Penciclovir, Valcyclovir, Ganciclovir, Valganciclovir, Adefovir.
What is the MOA of these drugs?

Answer 20

Herpes viral replication can be targeted by nucleoside analogs. Neurotropic herpes viruses must mobilize nucleoside metabolism in order to replicate their DNA. Successful drugs that target this are:
Acyclovir, Famciclovir, Penciclovir, Valcyclovir, Ganciclovir, Valganciclovir, Adefovir.
What is the MOA of these drugs?
They stop DNA polymerase

Question 21

Gamma herpes viruses present with mild illness when contract in ___. More severe illness presents if the __ infection in acquired later in life. __ __ from VZV shows an age-dependent pathogensis. ___ (HHV ___) is more severe in adults than teens.

Answer 21

Gamma herpes viruses present with mild illness when contract in children. More severe illness presents if the primary infection in acquired later in life. Chicken pox from VZV shows an age-dependent pathogensis. EBV (HHV 4) is more severe in adults than teens.

Question 22

Post-mitotic neurons are a nucleotide-___ environment, thus, __ __ may be required for reactivation of latent herpes infections.

Answer 22

Post-mitotic neurons are a nucleotide-___ environment, thus, __ __ may be required for reactivation of latent herpes infections.

Question 23

Thymidine kinase mutants are __ recovered from latency

Answer 23

seldom

Question 24

Neurotropic herpesviruses must mobilize __ __ in order to replicate their DNA.

Answer 24

nucleotide metabolism

Question 25

EBV is a ___ group Herpes Virus. It is __ causing. The lytic infection primarily affects the __ __. There is profound replication in the __ __. Viral DNA is replicated by ___ ___ __. Latency in ___ cells is described by three different patterns believed to reflect stages in progression of latency. __ and __ tumors are made up of latent infected cells. In latent infected cells, __ __ is replicated by ____ ___ DNA Pol, along with ___ , a viral factor that promotes it.

Answer 25

EBV is a gamma group Herpes Virus. It is cancer causing. The lytic infection primarily affects the oral mucosa. There is profound replication in the oral epithelium. Viral DNA is replicated by viral DNA pol. Latency in B cells is described by three different patterns believed to reflect stages in progression of latency. EBV and KSHV tumors are made up of latent infected cells. In latent infected cells, viral genome is replicated by host cell DNA Pol, along with EBNA-1, a viral factor that promotes it.

Question 26

Drugs can usually take advantage of the sloppy nature of viral TK in EBV. However, if the virus is using __ __ __ antivirals won't work (i.e. latent infections).

Answer 26

Drugs can usually take advantage of the sloppy nature of viral TK in EBV. However, if the virus is using host cell DNA pol, antivirals won't work (i.e. latent infections).

Question 27

Progression to Latency in EBV: As the initial infection progresses towards latency, if you take peripheral blood and add EBV, you will ___ B cells. This uncontrolled growth is recognized by __ cells. The proliferation of __ cells leads to ___, and associated diseases. As we progress, the number of viral genomes decreases, and the latent infection causes __ carcinoma and __ adenoma. Finally, the latency progresses to a point where only ___ viral genome is expressed. This causes __ _and __ lymphoma. Note ___ is present in all 3 stages It binds to the origin or viral DNA and ensures that viral DNA segregates and replicates in sync with the ___.

Answer 27

Progression to Latency in EBV: As the initial infection progresses towards latency, if you take peripheral blood and add EBV, you will immortalizes B cells. This uncontrolled growth is recognized by T cells. The proliferation of T cells leads to mononucleosis, and associated diseases. As we progress, the number of viral genomes decreases, and the latent infection causes nasopharyngeal carcinoma (common in asian people) and gastric adenoma. Finally, the latency progresses to a point where only ONE viral genome is expressed. This causes BURKITTS and HODGKINS lymphoma. Note EBNA-1 is present in all 3 stages It binds to the origin or viral DNA and ensures that viral DNA segregates and replicates in sync with the HOST.

Question 28

In EBV infected B cells, ___ prevents apoptosis, and EBNA-2 promotes B cell formation. EBV proteins are essentially __ and anti___factors.

Answer 28

In EBV infected B cells, LMP1 prevents apoptosis, and EBNA-2 promotes B cell formation. EBV proteins are essentially oncogenes and anti-apoptotic factors.

Question 29

Infectious mononucleosis (primary manifestaion of __). Symptoms are: fever, sore throat, adenoapthy, hepatitis, __ (avoid contact sports). Cytology shoes __% of ___ that are atypical. There is an increase in ______ cells because they are trying to clear the infected ___ cells. Serology shows anti-___ Ig__ in an early infection, and anti-___ Ig__ in a late infection. Resolves, with most but not all latently infected cells eliminated. A number of cells become __ cells.

Answer 29

Infectious mononucleosis (primary manifestation of EBV). Symptoms are: fever, sore throat, adenoapthy, hepatitis, SPLENOMEGALY (avoid contact sports). Cytology shoes 50% of lymphocytes that are atypical. There is an increase in CYTOTOXIC T CELLS cells because they are trying to clear the infected B cells. Serology shows anti-EBV IgM in an early infection, and anti-EBV IgG in a late infection. Resolves, with most but not all latently infected cells eliminated. A number of cells become MEMORY cells.

Question 30

Reactivation of EBV typically occurs in the ___ __. Usually it is b/c B cells are stimulated by a T cell or antigen. They can also be stimulated by an adhesion protein on the oral mucosa. They can also be reactivated by the removal of an epigenetic control.

Answer 30

Reactivation of EBV typically occurs in the oral mucosa. Usually it is b/c B cells are stimulated by a T cell or antigen. They can also be stimulated by an adhesion protein on the oral mucosa. They can also be reactivated by the removal of an epigenetic control.

Question 31

EBV cancers: ___ lymphoma (B cell origin) -endemic in __-___ ___ in malaria co-infected children. Translocation of ___ gene, a gene that encodes for a transcription factor for growth) under control of IgG heavy chain promoter. __ gene is now being expressed under the control of IgG. Viral anti-apoptotic (__1), proteins "rescue" cells with translocation and permit tumor growth. ____ lymphoma (50% have EBV present) ___-___ ____ disease - T cell respond to EBV infected cells is suppressed. This is generally seen if a person has an organ transplant who takes immunosupressants. This dampens the immune response and lets the latent EBV run wild. __ carcinoma -Tumor of epithelial origin. ___ carcinoma has a concentration in Asia (could be the from high cooking temps of oils)

Answer 31

EBV cancers: Burkitt's lymphoma (B cell origin) -endemic in Sub-Saharan Africa in malaria co-infected children. Translocation of C-MYC gene, a gene that encodes for a transcription factor for growth) under control of IgG heavy chain promoter. C-MYC gene is now being expressed under the control of IgG. Viral anti-apoptotic (LMP1), proteins "rescue" cells with translocation and permit tumor growth. Hodgkin's lymphoma (50% have EBV present) Post-Transplant Lymphoproliferative disease - T cell respond to EBV in infected cells is suppressed. This is generally seen if a person has an organ transplant who takes immunosupressants. This dampens the immune response and lets the latent EBV run wild. Nasopharyngeal carcinoma -Tumor of epithelial origin. NP carcinoma has a concentration in Asia (could be the from high cooking temps of oils)

Question 32

__ is a HHV-5 virus (a BETA herpes virus). It is the ___ herpes virus in terms of size and genome. Lytic infection: acquired by blood, tissue, bodily secretions. It is often acquired during organ transplants. It replicates in many cells (epithelial, fibroblasts, lymphoid). It is a ___ proccess (hint: it is a beta group Herpes virus). It is chronic in epithelial and endothelial cells. It is a sustained, long-term production (not cytolytic, like in __ group herpes viruses). Viral DNA is replicated by __ ___ __. It is a largely inapparent disease. Latent infection: circulates in peripheral blood in CD__+ hematopoetic cells Reactivation may be linked to myeloid differentation. Histologically, it looks like __ eyes.

Answer 32

CMV is a HHV-5 virus (a BETA herpes virus). It is the largest herpes virus in terms of size and genome. Lytic infection: acquired by blood, tissue, bodily secretions. It is often acquired during organ transplants. It replicates in many cells (epithelial, fibroblasts, lymphoid). It is a slow proccess (hint: it is a beta group Herpes virus). It is chronic in epithelial and endothelial cells. It is a sustained, long-term production (not cytolytic, like in alpha group herpes viruses). Viral DNA is replicated by viral DNA pol. It is a largely inapparent disease. Latent infection: circulates in peripheral blood in CD34+ hematopoetic cells Reactivation may be linked to myeloid differentiation.

Question 33

An effective vaccine for chicken pox and VZV is available in a __ and __ form, called __ and ___. __ is for chicken pox. __ is also for chicken pox but is at a __x stronger dose and for adults greater the __ years old. This vaccine seems to be safe and effective, but there are concerns over these vaccines. What are the concerns?

Answer 33

An effective vaccine for chicken pox and VZV is available in a live and attenuated form, called Varivax and Zostavax. Varivax is for chicken pox. Zostavax is also for chicken pox but is at a 14x stronger dose and for adults greater the 50 years old. This vaccine seems to be safe and effective, but there are concerns over these vaccines. What are the concerns? - Immunity from vaccine can wane - Repeated immunization recommended - Breakthrough and much more severe chicken pox can arise later. - Consequence for loss of herd immunity

Question 34

Latency requires continuous immuno-surveillance to prevent reactivation. __ to ___% of all circulating cells are ____ specific killer or memory cells. In a typical latent infection, the virus first finds and enters a host to establish an ___ infection which may or may not manifest in the form of a disease. For latent infections, there is a long period with___ effect. For whatever reason, aging or intentional, immune suppression results in a quick ___ of the virus, often followed by expression of a severe disease. This is implies that there is something going on in the form of __ __ continually during the latent infection period.

Answer 34

Latency requires continuous immuno-surveillance to prevent reactivation. 20 to 30 % of all circulating cells are herpesvirus specific killer or memory cells. In a typical latent infection, the virus first finds and enters a host to establish an acute infection which may or may not manifest in the form of a disease. For latent infections, there is a long period with no effect. For whatever reason, aging or intentional, immune suppression results in a quick reactivation of the virus, often followed by expression of a severe disease. This is implies that there is something going on in the form of immune surveillance continually during the latent infection period.

Question 35

The most common disease caused by CMV is ____.

Answer 35

Mononucleosis

Question 36

Proteins found in the virion that contribute to efficient immediate early gene expression during a productive alpha herpes virus infection is ___.

Answer 36

VP16

Question 37

* Herpes virus are unique by having a tegument (protein cluster b/t envelope & nucelocapsid containing viral TF (___), ribonuclease (___) and sometimes mRNA), have nuclear or Golgi derived envelope * Immediate early gene expression requires ____(trans-inducing factor) to associate with host CF1 & 2 before gene activators and early products (DNA replication enzymes) can be made, and finally structure and tegument proteins * HHV 1-3 are alpha (alpha’s have to be first): highly cytotoxic, rapid growth in culture, neurotropic (viral thymidine kinase uses host ATP to phosphorylate dNTs for DNA synthesis to overcome neuron’s NT-poor environment) * Non-latent neurotropic herpes can be blocked from mobilizing NTs/DNA synthesis by nucleoside analogs * HSV-1 is transmitted by saliva, replicates in oral epithelium to cause gingivostomatitis, orolabial ulcers (lytic), and establishes infection in trigeminal sensory ganglia w/ circularized genome (latent), point mutations responsible for resistance to acyclovir * HSV-2 is transmitted by sexual contact and saliva, replicates in urogenital epithelium to cause ulcers (lytic), and establishes infection in sacral sensory ganglia w/ circularized genome (latent) * HHV-3 has effective live/attenuated vaccines (Varivax, Zostavax)—preventive but can limit severity if it breaks through, initially infects oral epithelium * HHV 5-7 are beta (and a 5, 6, 7, β!): slow growth in culture, create large cells during replication, transplant disorders, latent in leukocytes * CMV replicates in many cells but is chronic in epithelial and endothelial cells, latent in blood stem cells (CD34+) * HHV 4 and 8 are gamma: tumorigenic * EBV replicates in oral epithelial cells with cell DNA pol (with EBNA1) to cause mononucleosis and is latent in submucosal B cells, where it can stimulate B cell activation and differentiation (T cells, Ags, removal of epigenetic controls) * Lytic alpha HHV causes inflammation and tissue damage d/t replication, while latent alpha HHV have a genome that exists as an episome (not integrated) that is maintained in the nucleus, and sparsely expressed (LATS gene suppresses virus), and is transported along axon to epithelial sites when reactivated * Maintained latency requires continuous immune surveillance to prevent reactivation (represent 1/3 of circulating T cells)

Answer 37

* Herpes virus are unique by having a tegument (protein cluster b/t envelope & nucelocapsid containing viral TF, ribonuclease and sometimes mRNA), have nuclear or Golgi derived envelope * Immediate early gene expression requires VP16 (trans-inducing factor) to associate with host CF1 & 2 before gene activators and early products (DNA replication enzymes) can be made, and finally structure and tegument proteins * HHV 1-3 are alpha (alpha’s have to be first): highly cytotoxic, rapid growth in culture, neurotropic (viral thymidine kinase uses host ATP to phosphorylate dNTs for DNA synthesis to overcome neuron’s NT-poor environment) * Non-latent neurotropic herpes can be blocked from mobilizing NTs/DNA synthesis by nucleoside analogs * HSV-1 is transmitted by saliva, replicates in oral epithelium to cause gingivostomatitis, orolabial ulcers (lytic), and establishes infection in trigeminal sensory ganglia w/ circularized genome (latent), point mutations responsible for resistance to acyclovir * HSV-2 is transmitted by sexual contact and saliva, replicates in urogenital epithelium to cause ulcers (lytic), and establishes infection in sacral sensory ganglia w/ circularized genome (latent) * HHV-3 has effective live/attenuated vaccines (Varivax, Zostavax)—preventive but can limit severity if it breaks through, initially infects oral epithelium * HHV 5-7 are beta (and a 5, 6, 7, β!): slow growth in culture, create large cells during replication, transplant disorders, latent in leukocytes * CMV replicates in many cells but is chronic in epithelial and endothelial cells, latent in blood stem cells * HHV 4 and 8 are gamma: tumorigenic * EBV replicates in oral epithelial cells with cell DNA pol (with EBNA1) to cause mononucleosis and is latent in submucosal B cells, where it can stimulate B cell activation and differentiation (T cells, Ags, removal of epigenetic controls) * Lytic alpha HHV causes inflammation and tissue damage d/t replication, while latent alpha HHV have a genome that exists as an episome (not integrated) that is maintained in the nucleus, and sparsely expressed (LATS gene suppresses virus), and is transported along axon to epithelial sites when reactivated * Maintained latency requires continuous immune surveillance to prevent reactivation (represent 1/3 of circulating T cells)