Viral Lifecycles Flashcards
Characteristic of Acute virus infection: ______onset w/ brief period of sypmtoms—eliminate either host or virus
-ex: influenza, norovirus, rhinovirus
Rapid
—generate specific adaptive immune response to clear pathogen—establish memory
Active virus replication
Overactive immune response may result in ….
tissue damage (immunopathology)
Initial steps simular to acute: virus infects a naïve host, replicates, host mounts immune response w/ some difference (3 differences)
Virus not cleared (for months to a lifetime)
Start with robust immune response—subdued to prevent immunopath by maintain control on virus
Immune response of host is set to a higher activation state overall (increased systemic cytokine levels)
See 2 types of viral life cycles during chronic infection: Latent and persistent
Viral lifecycle see______ expression of subset of viral genes, absent lytic replication and infectious virion production
minimal
herpes virus is a prototype for a……
has both latent and lytic stages
latent virus infection
Viral________ degrades host mRNA
vhs
Viral transcription factor localizes to nucleus to initiate viral gene transcription
VP16
Viral DNA circularizes and HSV ______transcribed by host RNA II polymerase
alpha genes
Some alpha gene products transactivate transcription of
beta genes
Some beta gene products are necessary for _______
viral DNA synthesis
Viral DNA synthesis triggers expression of
gamma viral genes
Gamma gene products are
structual compoents of the virion
Viral DNA is packaged into a
capsid
Filled viral capsid bud through host membranes to form
a mature virion that exits the cell
Initial steps are shared btwn lytic and latent:
–viral attachment and entry→ this consists of
transport of DNA in the nucleus→ viral DNA circularizes and associates with host nucleosomes
Viral DNA is MAINTAINED ______(episome) to allow viral genome to survive cellular division
BY CELL as extra chromosome
Little if any of the viral genes are expresssed (don’t want to tip off immune system) during
lytic cylce
Few expressed viral proteins help maintain the viral episome and prevent…..
its loss during division
Advantages of lytic cycle
a. Stealth: few gene expressed to infected cells are invisible to immune system
b. Virus relies on host cell mechanisms to maintain viral genome—very difficult to design therapeutics that specifically target latently infected cells
few gene expressed to infected cells are invisible to immune system (advantage of lytic cycle)
Stealth
b. Virus relies on _______ to maintain viral genome—very difficult to design therapeutics that specifically target latently infected cells (advantage of lytic cycle)
host cell mechanisms
Disadvantages of lytic cycle:
a. Spread to naive host is limited bc no production of virions
b. Death of latently infected cell is a dead end for virus—genome is non infectious
Death of latently infected cell is a dead end for virus because:
genome is non infectious
Challnge of latent virus: limited transmission to naïve host
Solution:
reactivation-switch from latent→ lytic lifecycle
-dangerous for the virus to do this—viral replication during reactivation occurs in the face of a:
robuse and highly virus-spcific adaptive immune response that can eliniate reactivating cell b4 infectious virions are made
Challenge: Death of a latently infected cell
Solution:
viral latency is established in long lived cells
Herpesvirus—neurons, memory T and B cells, hematopoetic stem cells
HIV: memory T cells
Protype: Hep C virus
Only has a lytic life cycle and can’t shut itself off
Chronic Persistent Virus infection
________ continues for duration of chronic virus infection
Lytic replication
- In contrast to latent, during persistent virus replication ________cells are constantly stimulated with high levels of virus antiGs
virus-specific T
Constant stimulation prevents development of a robust memory T cell population… leads to immunological phenomenon called _______
T cell exhaustion
-T cells upregulate inhibitor receptors that attenuate signaling downstream of TCR
T cell exhaustion
T cell exhaustion:
Decreased TCR leads to ……
loss of antivirl fnxs and death of T cell
HIV is our prototype for:
Combinations of latent and persistent virus infection
If infected CD4 T cell has a memory T cell phenotype, viral replication
becomes very inefficient downstream of viral genome integration
__________may lead to undetectable virus loads in the blood—but latent infected T cells persist in tissues
HIGH active antiretroviral therapy (HAART)
What happens HIV pts discontinue HAART
Discontinue HAART in most cases will allow HIV reactivation and persistant replication, leading to disease
____ is quiescent, little disease is observed
Latent
Latent infection: Low level of immune stimulation…latent infections reset baseline of immune response by
increaseing systemic cytokine levels and decrease activation threshold of immune system
During a latent infection: Disease is primarily generated by
reactivation and/or expanded viral gene expression
Some Epstein Barr virus (gammaherpesvirus) gene products are part of expanded latency associated gene expression have _______ Continuos expression of these, if not limited by host.. can contribute to cancer
oncogenic properties.
Overcoming pathogenesis of chronic virus infection: latent infections
Elimination of latent infections is challenge as virus relies on
cell machinery to maintain genome—virus specific therapeutic targets are limited if present at all
- One approach to irradicate and/or limit latent infection is to
induce virus reactivation from latency w/ subsequent targeting of lytic virus process (see herpesivirs and HIV blocks for specific therapies)
-tricky as all known stimuli induce reactivation only in very small subset of latently infected cells
Vaccine devo is difficult bc latency establishment is
extraordinary efficient and often ind of viral replication during initial phase of infection
prophylactic tx of susceptible hosts w/ antivirals targeting lytic viral replication is viable alternative because
BC pathogenesis is driven by viral reactivation
-ex: gammaherpevirus-induced sarcomas and lymphomas in context of HIV infection
Pathogenesis of Chronic virus infection: persistent Pathogeneis of persistent virus infection stems form two primary contributions:
- tissues and cellular damage associated w/ virus replication
- depletion of CD4 T cells in Hiv infection
- hepatocyte death d/t replicating hep C virus - Tissue damage associated with inflammation and excessive immune reponse
- Chronic inflammation is associated with
devo of cancer
-hep B and C infection
Overcoming pathogenesis of chronic virus infection: persistent infection
1. Therapies need to target both______
viral and host processes that lead to disease
Overcoming pathogenesis of chronic virus infection: persistent infection
Viral: therapies specifically target ______
viral replication (like retroviral therapy against HIV) -often administered as combination (to limit devo of resistance) and for lifetime
Overcoming pathogenesis of chronic virus infection: persistent infection
Host: much of tissue damage induced by ________
–mild immunosuppresive therapies can work
-BUT immunosuppresion has to be carefully balanced to maintain _______
-Therapies aim to _____________
host immune system
virus-specific immune responses
reverse the T cell exhaustion associated w/ persisten viruses
