Persistent Infections
Steps for modulation of immune response (CTLs)
(1) Inhibition of degradation of viral products (2) Disrupted association of degraded viral products with MHC or (1) Inhibition of MHCI expression (2) Inhibition of nuclear export of MHCI complex (3) Interference with transport from ER to Golgi
How are persistent infections established?
(1) Modulation of immune response (2) CTL escape mutants (3) Killing activated T cells (4) Limited immune surveillance (5) Infection of immune cells
What happens in chronic HBV?
- CTL kill infected hepatocytes - T cell exhaustion may lead to T cell dysfunction - Fibrosis may lead to cirrhosis and liver failure
CTL escape mutant examples
- HSV - HCV
Examples of viruses that cause persistent infections
- Lymphocytic choriomeningitis virus - JC virus - HIV - HTLV - Measles virus SSPE
Viruses that infect immune cells in persistent infections
- Measles (APCs) - HIV
How is HSV reactivated?
- Small number of neurons in ganglion reactivate; virions appear in mucosal tissue innervated by latently infected ganglia, and blisters may ensue - Immune response is too slow to prevent shedding - Some reactivate every 2-3 weeks; other never
Describe VZV
- Upper respiratory tract infection - Replication in lymph nodes - Primary viremia - Reproduction in liver, spleen, etc - Secondary viremia brings virus to skin - Then virus enters sensory neurons to establish latency
Killing activated T cells process
- Variety of receptors of CTL surface (Tnf, Fas, Apo2D) - CTL membrane receptors Fas normally bind FasL on infected cells - Viruses induce over-expression of FasL on infected cells - FasL binds in great amounts to CTLs, which triggers CTLs system overload and apoptosis
What is latency?
- Viral gene products that promote productive replication are not made or found in low concentrations - Cells harboring the latent genome are poorly recongized by the immune system
What types of HSV exist, and what organs do they infect?
1 and 2 Type 1 is oral, type 2 is genital.
Most persistent infections probably begin as...
Acute infection
What is the difference between acute and persistent infections?
Acute infections are rapid and self-limiting, while persistent infections are long term, and may last the entire life of the host.
What types of cells are important for EBV latency?
B cells
Sites of persistence: EPV
B cells, nasopharyngeal epithelia
Does measles cause acute or persistent infections?
Both
What is a major problem for organ transplantation?
CMV infections; virus can cause severe multi-organ congenital defect, death
Sites of persistence: Measles
CNS
Persistent infections of immune-privileged tissues are...
Common
What are CTLs?
Cytotoxic T lymphocytes; recognizes infected cell and starts neutralizing it
Autonomous self-replicating DNA in dividing cell
EBV, CMV, HPV, HBV, KSHV
How are HBV and HCV transmitted?
Exposure to blood
Which virus causes jaundice?
HCV
What is the only known human herpesvirus that integrates its genome to chromosomal telomeres in germline?
HHV6
Non-replicating DNA in a non-dividing cell
HSV, VZV in neurons
What two viruses cause liver damage through persistent infection? What is the molecular difference between them?
Hepatitis B and C viruses HCV is a + strand RNA virus, while HBV is a dsDNA virus
Main target of HBV
Hepatocyte
Infection manner for HHV 6 and 7
Horizontal through respiratory secretions (parent to child)
Which immunoglobulins are produced in response to persistent infection later?
IgG
Which immunoglobulins are produced first in response to viral infection?
IgM
Sites of persistence: Polyomavirus BK
Kidneys
Sites of persistence: Polyomavirus JC
Kidneys, CNS
Sites of persistence: CMV
Kidneys, salivary gland, lymphocytes, macrophages, stem cells, stromal cells
After CMV is initially resolved by the cellular immune response, what happens?
Latently infected myeloid cells remain in bone marrow
Sites of persistence: HCV
Liver
Sites of persistence: HBV
Liver, lymphocytes
What is the MHC I system?
Major histocompatibility complex; present antigens to CTls (essential for adaptive immunity)
Main intervention route during persistent infections
Modulation of the CTL response
Are polyomaviruses dangerous?
Mostly in immunocompromised patients
What do CTL escape mutants cause?
Mutated viral peptide no longer "fits on MHCI complex or prevents association of MHCI with CTL; changes may also affect proteasomal processing
Is chronic HBV cytopathic for hepatocytes?
No
Is there a single mechanism for establishing persistent infections?
No
Are all inapparent infections persistent?
No; some persistent infections cause no symptoms (Herpes)
What is the "unusual strategy" for transmission of HHV?
Occasional integration (homologous recombination)
What are immune-privileged organs?
Organs which don't have very much CTLs; includes the CNS, vitreous humor of the eye, areas of lymphoid drainage devoid of initiators and effectors of immune response (eye, high FasL)
Where does CMV replicate?
Peripheral blood leukocytes, endothelial cells
How is CMV transmitted?
Respiratory routes, urine, sex
EBV DNA is...
Self-replicating episome that associates with nucleosomes or B cells
Sites of persistence: HSV 1 and 2
Sensory and autonomic ganglia
Sites of persistence: Varicella-zoster virus
Sensory ganglia
Persistent infections for each virus are...
Stable and characteristic
SSPE
Subacute sclerosing panencephalitis
What may cause HSV reactivation?
Sunburn, physical / emotional stress, nerve damage, hormone imbalance, steroids; all of which stimulate production of viral proteins needed to activate viral transcription program
Primary infection in immunocompetent host for CMV is...
Usually asymptomatic or febrile, mono-like illness
***What herpesviruses attach their episomes to human chromosomes?
VZV?
When is persistent infection likely?
When cytopathic effects are absent and host defenses are reduced
When do persistent infections occur? What happens?
When primary infection is not cleared by immune response. Virions, proteins, and genomes continue to be produced, and viral genomes may remain after proteins are not detected.
