DNA Viruses

Question 1

“Shock and kill” method for treating latent virus

Answer 1

Shock = give drugs to reactivate viral transcription

Kill = sensitize against the virus and destroy cells it appears in

This method is currently under development and is believed to be the future of antiviral treatment for latent viruses (HIV, Herpesviruses, HPV, Varicella Zoster, Hep B, etc.)

Question 2

Herpesviruses are divided into. . .

Answer 2

α Herpesviruses

β Herpesviruses

γ Herpesviruses

Question 3

α Herpesviruses (list)

Answer 3

Herpes simplex virus-1

Herpes simplex virus-2

Varicella-zoster virus

Question 4

β Herpesviruses

Answer 4

Cytomegalovirus

Human herpesvirus-6

Human herpesvirus-7

Question 5

γ Herpesviruses

Answer 5

Epstein-Bar virus (the kissing virus)

Human herpesvirus-8

Question 6

Herpes virus viral taxonomy

Answer 6

Encapsulated linear dsDNA, icosahedral nucleoplasmid

Question 7

An important biological characteristic of all herpesviruses is the capacity to establish ____.

Answer 7

An important biological characteristic of all herpesviruses is the capacity to establish lifelong latent infections

Question 8

Herpesviruses are ___.

Answer 8

Herpesviruses are fragile

They are and susceptible to drying and inactivation by heat, mild detergent, and solvents. Their susceptibility is imposed by their membrane envelope

Question 9

VZV is usually acquired from an infected person by the ____ route.

Answer 9

VZV is usually acquired from an infected person by the respiratory route,

but infection by direct contact with vesicular fluid or secretions also can occur

Question 10

Primary disease caused by VZV is ___ contagious

Answer 10

Primary disease caused by VZV is highly contagious

Question 11

Chickenpox

Answer 11

aka Varicella

systemic febrile disease with mucocutaneous lesions

Question 12

Complications of chickenpox

Answer 12

Cerebellar ataxia in otherwise healthy children and encephalitis in immunocompromised persons.

Question 13

How varicella diseminates

Answer 13

Cells of the lymphatic system are infected at the site of entry in the respiratory tract. Spread of virus-infected leukocytes throughout the lymphatic system induces cytokine responses that result in fever, malaise, and headache. Circulating leukocytes transmit the virus to epithelial cells of the skin and mucosa, and the characteristic lesions of chickenpox occur.

ie, primary infection in lung, secondary in epithelia via lymphatics

Question 14

Latent infections of varicella are established in. . .

Answer 14

Latent infections of varicella are established in peripheral ganglia

Question 15

Zoster

Answer 15

aka Shingles

similar to the vesicular lesions of chickenpox except that they are clustered on skin along the dermatome innervated by the nerve from which VZV was reactivated. Associated with severe pain, may be disseminated in immunocompromised individuals, and likelihood of reactivation increases linearly with age.

Question 16

Gene regulation in varicella zoster

Answer 16

During viral replication, immediate-early genes are transcribed with the assistance of transcription factors carried in the virus. Proteins encoded by immediate-early genes activate expression of about a dozen early genes whose protein products are required to replicate the viral DNA. Next, the late genes are expressed. Late genes encode proteins that assemble and compose the progeny virions.

Question 17

Varicella zoster lifecycle

Answer 17

Question 18

The membrane around a varicella zoster virion comes from. . .

Answer 18

the trans-Golgi network vesicles of a previous host cell.

Question 19

In latently infected cells, the varicella zoster genome. . .

Answer 19

. . . persists as an episome within the nucleus of the infected host cell, with minimal transcription of viral genes.

Question 20

Diagnosing varicella zoster

Answer 20

The patient’s clinical presentation and history are usually sufficient to lead to a diagnosis. To confirm, the presence of virus in active lesions can be detected by polymerase chain reaction or immunoassays.

VZV is difficult to propagate in cell culture and so this is an insensitive test.

Question 21

When are antiherpesvirus medications indicated for infected individuals?

Answer 21

Importantly, NOT for childhood varicella in an otherwise healthy child.

However, antiviral therapy is indicated in severe cases of chickenpox, chickenpox in immunosuppressed children or adults, shingles, and VZV infections associated with meningitis, encephalitis, or any other neurological manifestation.

Question 22

Antiherpesvirus medications cannot. . .

Answer 22

. . .effect a “cure”, because they does not prevent entry of virus into neurons and cannot eliminate latent viral genomes.

Question 23

Acyclovir

Answer 23

Inhibits HSV and VZV polymerases. Must first be phosphorylated by a virus-derived thymidine kinase, then twice by host kinases, to generate its active form.

Question 24

Valacyclovir

Answer 24

prodrug of acyclovir has improved oral bioavailability

Question 25

Prevention of varicella zoster virus

Answer 25

A live, attenuated VZV vaccine prevents chickenpox with 80% efficacy overall, and 99% efficacy in preventing severe disease. People with chickenpox should be isolated and vaccination offered to family members or other contacts. **Virus can be transmitted via the aerosol route**.

Question 26

Infection with ____ by adulthood is nearly universal in the developing world.

Answer 26

Infection with **Epstein-Barr virus** by adulthood is nearly universal in the developing world.

Question 27

Transmission of Epstein-Barr virus

Answer 27

EBV spreads most commonly through **bodily fluids**, especially **saliva**. However, EBV can also spread through blood and semen during sexual contact, blood transfusions, and organ transplantations. EBV can be spread by using objects, such as a toothbrush or drinking glass, that an infected person recently used. ## Footnote **Intermittent excretion of EBV on mucosal surfaces in the absence of clinical symptoms is common**

Question 28

EBV-mediated disease

Answer 28

**Primary infection** in young adults can be associated with an **acute mononucleosis syndrome** that consists of **low-grade fever**, **fatigue**, **pharyngitis**, **cervical lymphadenopathy**, **splenomegaly**, and **peripheral blood monocytosis** with **atypical or reactive lymphocytes**.

Question 29

Posttransplant lymphoproliferative disease

Answer 29

Following reactivation, lytic EBV infection in an **immunosuppressed transplant recipient** can induce lymphoproliferation. In its most benign form, the virus produces an **acute mononucleosis-like syndrome** with lymphoid proliferation. Untreated, this initially benign lymphoproliferation can evolve into an **oligoclonal neoplasm** that in some cases subsequently develops into a **lymphoma**.

Question 30

EBV and Lymphomas

Answer 30

EBV is associated with **Hodgkin lymphoma**, **Burkitt lymphoma**, **nasopharyngeal carcinoma**, and more recently **gastric carcinoma**.

Question 31

EBV is present in about \_\_\_\_% of Hodgkin lymphomas.

Answer 31

EBV is present in about **40%** of Hodgkin lymphomas.

Question 32

Burkitt lymphoma

Answer 32

IGH promoter, c-Myc sequence. The **mechanism** by which EBV contributes to neoplasia in these cells is **poorly understood**

Question 33

Nasopharyngeal carcinoma

Answer 33

Endemic in southern China and some parts of Africa. EBV is consistently found in the cancerous cells, and these patients have high levels of antibodies to some EBV proteins. Viral **latent membrane protein 1 (LMP-1)** in the cancerous cells **activates** the **NF-kB pathway**. This contributes to **neoplasia**, although the precise mechanism by this occurs is not well understood.

Question 34

EBV-mediated damage

Answer 34

* initially infects **oropharyngeal epithelial cells**, and then spreads to nearby **B cells** in the **tonsils and adenoids**. * At some point switches from **latency to lytic** within B cells * In most infected B-cells, EBV establishes latent infection * Minimal number of viral genes expressed in most cells to maintain **viral reservoire** * **Splenomegaly and lymphadenopathy** from intense lymphocyte proliferation (B cells, CD8 cells) * **Fever, malaise** from large amounts of cytokine produced by the response

Question 35

Regulation of genes throughout EBV's lifecycle

Answer 35

In initial phases, viral genes such as **Epstein-Barr nuclear antigen-1** are expressed to insure **maintenance and partitioning of the viral episome**. Expression of the **latent membrane proteins**, **LMP1 and LMP2a**, provides growth signals to infected cells that drive **cellular proliferation**. **Reactivation** of EBV from latency occurs **sporadically**.

Question 36

Mononucleosis occurs ___ during EBV infection

Answer 36

Mononucleosis occurs **early** during EBV infection associated with the strong host immune system response to initial infection. Large numbers of activated **CD8+ cytotoxic T-lymphocytes** specific for EBV are generated. These are seen as “**atypical lymphocytes**” in the peripheral blood film, and are the mononuclear cells from which this illness takes its name. Activation and proliferation of these lymphocytes is what induces **splenomegaly and lymphadenopathy**.

Question 37

Diagnosing EBV

Answer 37

1. **Seroconversion** (IgM measurement) 2. "**Monospot**" test for clonal plasma cells / monoclonal antibody production 3. **PCR** is sensitive and specific for **secondary infection or progressive primary**, but **_not_ resolving primary infections**.

Question 38

Treatment of EBV

Answer 38

EBV infections in normal immunocompetent individuals are almost always **self-limited** and thus, rarely, if ever, require treatment. Treatment of EBV infections in the immunocompromised host is difficult. Although **acyclovir** and related **gancyclovir** have some activity against EBV, treatment of **PTLD** in EBV-infected transplant recipients with these agents has **minimal, if any, efficacy.**

Question 39

Upon reactivation, a herpesvirus. . .

Answer 39

Upon reactivation, a herpesvirus **mediates lytic infection of the same cell in which it was previously latent.**

Question 40

\_\_\_\_ are the only DNA viruses with their own encoded DNA-dependent RNA polymerase.

Answer 40

**Poxviridae** are the only DNA viruses with their own encoded DNA-dependent RNA polymerase.

Question 41

\_\_\_ all utilize their own DNA polymerase rather than the cell's.

Answer 41

**Hepadnaviridae, adenoviridae, herpesviridae, and poxviridae** all utilize their own DNA polymerase rather than the cell's.

Question 42

Bell's palsy

Answer 42

**Palsy of the facial nerve**, often unilateral. **Suggestive for α-herpesvirus** infection in the absence of trauma.

Question 43

In latent viral episomes, DNA is \_\_\_\_.

Answer 43

In latent episomes, DNA is **epigenetically silenced**. In HSV, this is mediated by LAT.