12 - Persistent Viral Infections

Question 1

Persistent infections

Answer 1

Those in which the virus, its genome, or parts of its genome persists in its host for the long term (months, years, or lifetime)

Question 2

Two main types of persistent infection

Answer 2

Chronic and latent

Question 3

Chronic infections

Answer 3

• Lytic replication in a multicellular organism occuring at low levels and ongoing for longer than
  the duration of the cell division cycle of most host cells
• Immune system takes long time to eliminate

Question 4

Latent infections

Answer 4

• Virus exits the lytic cycle and persists in host cells, (in form of a few nucleic acids and
  proteins), without causing production of new virions.
• Viral genomes persist even when viral proteins are not detectable.
• Exit from latency and entry back into the lytic cycle typically occurs when the host cell encounters environmental stress.

Question 5

Alpha herpesvirinae

Answer 5

• HSV1
• HSV2
• Varicella zoster virus

Question 6

Beta herpesvirinae

Answer 6

• HCMV
• HSV6
• HHV7

Question 7

Gamma herpesvirinae

Answer 7

• EBV
• Kaposi’s sarcoma associated herpesvirus

Question 8

Where does human herpesvirus establish latent infection

Answer 8

Trigeminal ganglia

Question 9

Latent herpesvirus infections

Answer 9

• HSV-1 and HSV-2
• Begin with lytic infection of an epithelium
• Virus replicates in the epithelium and latency is initiated when some of the offspring virions infect the
  sensory neurons that innervate the epithelium
• Virions that enter the terminally differentiated neurons traffic along the cytoskeleton to the cell nucleus, in the spinal column
• Herpesvirus genome circularizes and persists as an episome in the nuclei of latently infected cells
  -Multiple copies of episomal viral DNA remain in nucleus

Question 10

What is needed to maintain latency in HSV

Answer 10

• Lytic gene expression must be blocked
• Apoptosis and innate immunity must be blocked

Question 11

How is latency maintain in HSV

Answer 11

• HSV encodes miRNAs that inhibit viral proteins that control transcription and replication
• HSV Encodes two LATs that inhibit apoptosis in neurons

Question 12

LATs

Answer 12

Latency associated transcripts

Question 13

What is Herpesvirus latency is influenced by

Answer 13

adaptive immune responses

Question 14

HSV-1-infected neurons surrounded by T cells in the TG

Answer 14

• Limits viral reactivation which would otherwise lead to lytic replication of the virus, thus hampering the generation of infectious virions from these cells
• HSV1 specific CD8 in contact with TG neurons were shown to block viral reactivation through the release of granzymes that degrade viral proteins

Question 15

Viral persistence in the ependymal zone of the brain

Answer 15

• Related to T cells expressing exhaustion markers (e.g. programmed death 1 - PD-1)
• Isolated T cells were unable to control HSV-1 infection ex vivo and secreted less interferon (IFN)-γ in
  comparison to T cells isolated from TG
• Reactivation is also triggered by weakening of immunity brought about by aging or by infections such as HIV

Question 16

Varicella–zoster virus, Epstein–Barr virus, cytomegalovirus, and Kaposi’s sarcoma-associated herpesvirus

Answer 16

• Also cause latent infections of host cells
• In general, these viruses replicate lytically when they first enter the human body and subsequently infect quiescent or terminally differentiated host cells where the viruses establish latency