3 - Viral Lifecycles II - latent and persistent infections

Question 1

What are characteristics of an acute viral infection?

Answer 1

Rapid onset of disease and relatively brief period of symptoms (days to a few weeks) and results in elimination of either the virus of the host.

Question 2

What occurs with the virus and the host during an acute viral infection?

Answer 2

Active viral replication followed by generation of specific adaptive immune responses that clear the pathogen and the establishment of immune memory.

Overactive immune response can induce tissue damage.

Question 3

What are the initial steps of a chronic viral infection?

Answer 3

Initial steps similar to acute: infection of naive host, replication, immune response.

Question 4

How does a chronic viral infection differ from an acute viral infection?

Answer 4

1. Virus not cleared
2. Host not eliminated (usually, or not for a long time)
3. Initial immune response is subdued to prevent immunopathology (immunoregulation) while maintaining control of the virus activity
4. Immune response of host is on alert (increased systemic cytokine levels)

Question 5

Is it possible to be virus-free?

Answer 5

No!

Everyone has chronic virus infections because we are all born with some endogenous retroviruses.

Question 6

What are the two types of viral life styles during chronic infection?

Answer 6

Latent (quiescent) infection

Persistent replication

Question 7

What is a latent virus infection?

Answer 7

A viral life cycle characterized by minimal (if any)expression of a few viral genes and absence of lytic replication and infectious virion production.

Question 8

What is a prototype virus that causes a latent infection? What are the two distinct life cycles that it can have?

Answer 8

Herpesvirus

Lytic replication and latent infection

Question 9

What are the first three steps of herpesvirus lytic replication?

Answer 9

1. Binding, fusion, trnasport of DNA into nucleus
2. Degradation of host mRNA and viral transcription of VP16 to localize to nucleus.
3. Viral DNA circularizes; early/alpha genes are transcribed by host RNA Pol II

Question 10

What are the last three steps of herpesvirus lytic replication?

Answer 10

4. Products activate transcr. of early/beta viral genes.
5. Viral DNA synthesis triggers expression of late/gamma genes which are structural components.
6. Viral DNA packaged into capsid and buds through host membrane to make mature virion that exits cell

Question 11

What are the initial steps of the latent life cycle of herpesvirus?

Answer 11

Same as lytic: viral attachment and entry, transport of DNA in the nucleus, and viral DNA circularizes and associated with host nucleosome.

Question 12

How does the latent life cycle of herpesviruses occur after the initial steps that were similar to the lytic replication?

Answer 12

Viral lytic program is halted and instead viral DNA is maintained by the cell as an extra chrom (episome) which allows it to survive another division. Few viral proteins expressed.

Viral episome is replicated by cellular host DNA pol when latently-infected cell goes through the cell cycle.

Question 13

What are the advantages of latent virus infection from the perspective of the virus?

Answer 13

Stealth: very few if any viral genes expressed so infected cells are invisible to the immune response.

Virus relies on host mechanism to maintain viral genome so it’s very hard to make drugs that specifically target latently infected cells.

Question 14

What are the disadvantages of a latent infection from the perspective of the virus?

Answer 14

Spread to a naive host is limit because there’s no production of infectious virions.

Death of a latently infected cell is a dead end for the virus - virus genome is non-infectious unless it can be introduced directly into the nucleus of the cell.

Question 15

How does the virus overcome the limited transmission to a naive host in a latent infection?

Answer 15

Reactivation: switch from latent to lytic.

Dangerous endeavor; viral replication during reactivation occurs in face of robust adaptive immune response that may eliminate the reactivating cell before virions are made.

Question 16

How does a virus deal with the potential death of a latently infected cell? What are examples?

Answer 16

Viral latency is established in long-lived cells.

Herpesvirus is established in neurons, memory T and B cells, hematopoietic stem cells.

HIV is established in memory T cells.

Question 17

What are characteristics of a chronic persistent virus infection?

Answer 17

The virus is limited to a single lifestyle: lytic replication, which continues to many months to years.

During this time, specific T cells are constantly stimulated with high levels of viral antigens which prevents development of a robust memory T cell population and leads to T cell exhaustion.

Question 18

What is T cell exhaustion that occurs during a chronic persistent virus infection?

Answer 18

T cells up-regulate inhibitory receptors that attenuate signaling downstream of T cell receptor. Essentially, immunoregulation occurs because the host is trying to decrease it’s immune response.

Decreased TCR signaling eventually leads to loss of antiviral functions and death of T cells.

Question 19

What type of infection occurs with HIV?

Answer 19

Combo of latent and persistent virus infection.

Question 20

What cells does HIV infect?

Answer 20

CD4 T cell that has a resting memory phenotype (kind of a latent memory T cell that is in a latent phase).

This allows the virus to be in a longer living cell and avoid the cell dying.

Question 21

What can highly active antiretroviral therapy (HAART) given to pts with HIV lead to? What occurs upon discontinuation?

Answer 21

Undetectable virus loads in the blood, but latently infected T cells can persist in the tissues.

Discontinuation of HAART will allow reactivation and persistent replication leading to disease.

Question 22

What is the pathogenesis of chronic virus infection when its latent?

Answer 22

Very little if any disease is observed.

Because low level of immune stimulation occurs due to occasional reactivation, latent infections reset the baseline of immune response by increasing the systemic cytokine levels and decreasing activation threshold of the immuen system.

Question 23

What causes disease in latent infection? Give two examples of this?

Answer 23

Reactivation and/or expanded viral gene expression.

Herpesvirus react. induces mucosal and skin lesions, encephalitis, and cancer.

HIV react. can lead to AIDs.

Question 24

Describe the Epstein-barr (gammaherpesvirus) virus and its characteristics during latency?

Answer 24

Some of its gene products are part of expanded latency-associated gene expression and have oncogenic properties.

Continuous expression of these genes if not limited by host, contributes to the virus-induced cancer.

Question 25

What is one approach to eradicate and/or limit latent infection? Why has this proven to be tricky?

Answer 25

Inducing virus reactivation from latency with subsequent targeting of lytic virus processes.

This is tricky because all stimuli tried so far indue reactivation only in a small subset of latently infected cells.

Question 26

Why is vaccine development difficult for latent chronic virus infections?

Answer 26

Because latency establishment is efficient and sometimes independent of viral replication during the initial phase of infection.

Question 27

Whats a viable alternative to vaccine for chronic latent virus infections?

Answer 27

Because pathogenesis is driven by viral reactivation, prophylactic treatment of susceptible hosts with antivirals targeting lytic viral replication is a viable alternative.

Question 28

Describe the pathogenesis of chronic virus infections that are persistent- What are the two primary contributions?

Answer 28

1. Tissue and cellular damage associated with virus replication
2. Tissue damage associated with inflammation and excessive immune response
   - chronic inflammation is associated with development of cancer

Question 29

What therapy for overcoming the pathogenesis of chronic persistent virus infection is used to target the virus?

Answer 29

Targeting viral replication (retrovirals therapies)

• often admin as combination to limit resistant and for lifetime of infected individual
• recent development of highly effective hep C antivirals lead to viral clearance

Question 30

What is the downside to the highly effective hep C antiviral that can effectively cure someone of Hepatitis C?

Answer 30

A patient with a cleared infection is not protected against a new chronic infection with the same virus.

Resistance to drugs may develop in the future.

Question 31

What therapy for overcoming the pathogenesis of chronic persistent virus infection is used to target the host? What precautions must be taken?

Answer 31

Since much of the tissue damage is induced by the host immune system, mild immunosuppressive therapy can benefit pt.

• has to be balanced to maintain virus-specific immune response
• Therapies that aim to reverse T cell exhaustion are under development