Transcript Document

Human Herpesviruses:
An evolutionary wonder…although, not a simple one.
“Anything produced by evolution is bound to be a bit of a mess.”
- Sydney Brenner
“Around here, it takes all the running you can do just to stay in the same
place.”
-Lewis Carroll
QuickTime™ and a
TIFF (Uncompressed) decompressor
are needed to see this picture.
The Red Queen to Alice in Alice in Wonderland
Outline:
I. General Background
Coexisting with viruses: friends or foe in evolution?
Outcomes of Infection
DNA Virus evolution
II. Herpesvirus Background and Human Cytomegalovirus (HCMV)
III. Two examples of evolution: HCMV vs. Human host
Innate Host Response
Adaptive Host Response
IV. HCMV Latency: paradigms, trends, and work in progress
We live and prosper in a literal sea of viruses
Viruses don’t just impact our biology (disease), they are part of it.
You will encounter viruses:
Viruses are in everything we touch, eat, breathe: they even become part of our
genome!
Every milliliter of sea water has >1 million virus particles
There are 1030 bacteriophage in the world’s water supply, each particle
weighing a femtogram. Thus,the planet’s biomass of bacterial viruses alone
exceeds that of elephants by more than 1000-fold.
There are 1016 HIV particles on the planet.
A whale secretes 1013 Calciviruses (whale diarrhea) each day, and they can
infect humans!
So, now what?!?!
So, you encounter a virus
(and you are going to), what now?!
We encounter billions of virus particles everyday, the outcome is varied:
Nothing
Infection and clearance
Infection and latency
Infection and persistence
Infection and death
Cancer
So, you encounter a virus
(and you are going to), what now?!
Viruses are ideal and fascinating models for studying
evolution
Every infection results in many new viral genomes
Despite a minimal number of genes, viruses exhibit remarkable diversity
Phenomenal speed
Virus evolution is defined in terms of population of
viruses, not an individual virus particle.
No individual particle represents an average for any given population.
Every individual virus particle is a potential winner.
The most rare genotype in a population can become the most abundant
after a single selection event.
A few points unique to DNA viruses:
DNA viruses tend to have narrow host range
Persistent or latent infections common
-so replication is less
Replication of DNA virus genomes is less error-prone than that of
RNA viruses.
Errors in DNA replication can be corrected, although error rates for
viruses are higher than that of cellular DNA replication.
Human Herpesviruses
Ancient family of viruses with 9 members
Relatively large (largest known human pathogen), complex viruses
Double-stranded DNA genome
Three subfamilies of herpesviridae
Alpha (variable host range; short replicative cycle)
Herpes Simplex Type 1 and 2
Varicella Zoster Virus
Beta (restricted host range; long replicative cycle)
Cytomegalovirus (human herpes virus type 5)
Human herpes virus type 6 and 7
Gamma (lymphocyte associated)
Epstein-Barr Virus
Kaposi’s sarcoma-associated virus (human herpesvirus type 8)
A hallmark of all herpesviruses is the ability to establish latent infections
Why are herpesviruses (and especially
CMV) so fascinating from an evolutionary
standpoint?
1.
They are ancient
2.
Latency = highly evolved
3.
While many viruses deal with evolution “passively” (i.e. mutate),
herpesviruses “actively” target mechanisms
Cytomegaloviruses are over 200 million years
old...no wonder they are so good at what they do
Human CMV (HCMV) has evolved with us
since the beginning of our time (prior to
invertebrate-vertebrate split).
For every defense mechanism we have,
HCMV has at least one countermechanism…tit for tat
Unsuccessful viruses cannot overcome host
defenses.
Human Cytomegalovirus
A complex -herpesvirus
Large genome (230kb)
Slow replicating
Restricted host range
Infects 60-90% of the population worldwide, typically asymptomatic infection
Infection in immunocompromised individuals life threatening
Stem cell and solid organ transplant recipients
HIV infected individuals
Cancer patients receiving intensive chemotherapy regimens
Infection in utero: Leading cause of infectious disease related birth defects
1 in 100 infected; 1 in 1000 present symptoms/pathology
Mild to severe hearing loss
Cognitive deficits
Physical abnormalities
Human Cytomegalovirus
Latency is a hallmark of all herpesviruses
During LATENCY, viral genomes are maintained in the absence of viral
replication = No overt disease
The virus exits latency by REACTIVATION resulting from poorly
characterized stimuli = Disease in immunocompromised host
While once considered benign, the latent infection is associated with agerelated immune senescence and increased risk of atherosclerosis
Human Cytomegalovirus
Virion Structure
envelope
glycoproteins
200 nm
tegument
capsid
DNA core
INNATE Host Defense
To contain and alert
Early defense that takes care of most infections before we know what’s going on-most underrated arm of the immune system
Provides early warning to activate the adaptive defenses
MAJOR PLAYERS:
Toll receptors (recognize microbial macromolecular patterns)
cytokines/interferons (soluble messengers)
natural killer cells (eliminate infected cells by direct lysis)
complement (antibody-activated)
Viral infection stimulates the release of interferons and interleukins (cytokines)
that establish an antiviral state in the infected cell and neighboring cells
Type-I IFN Response
IFNR
2. Receptor Signal
Transduction
IFN/
HCMV
Tyk2
Jak1
Cytoplasm
STAT1
STAT2
P
p48
P
TLR?
3. IFN-induced Gene
Transcription
1. Induction NF B
IRF3
AP1
STAT1
IFN/
Production
STAT2
P
p48
P
ISRE
RIG-1
MAVS
Nucleus
PKR
OAs
MxA
IRF-7
Antiviral
Response
INNATE Host Defense
Interferons induce death of the infected cell and also ensure
that surrounding cells will die if they become infected
INNATE Host Defense
Viruses have evolved complex strategies to by-pass the innate immune
response (antiviral state)
-Block the trigger: make proteins that bind dsRNA
-Cytokine homologues (decoys)
-Cytokine receptors (bind up/inactivate IFN)
-Inhibition by viral proteins
-Inhibition by viral miRNAs…maybe
Type-I IFN Response
IFNR
2. Receptor Signal
Transduction
IFN
HCMV
Tyk2
Jak1
Cytoplasm
STAT1
STAT2
P
p48
P
TLR?
3. IFN-induced Gene
Transcription
1. Induction NF B
IE2
IRF3
AP1
STAT1
IFN
Production
STAT2
P
p48
P
IE1
ISRE
RIG-1
MAVS
Nucleus
PKR
OAs
MxA
IRF-7
Antiviral
Response
X
ADAPTIVE Host Response
T Cells (Cellular Immunity)
cytolytic T-cells (CTL)
helper T-cells
TH-1: activate CTL
TH-2: activate antibody production
B Cells (Humoral Immunity-Antibodies)
viremic infections
Cell-mediated defense is essential for clearing most viruses-downside is a lot of immunopathology
ADAPTIVE Host Response
Viruses have evolved complex strategies to by-pass the adaptive
immune response:
-Block MHC class I or II presentation
-Bind MHC in secretory pathway
-Degrade MHC
-Compete with MHC
-Prevent antigen loading onto MHC
-Block TH1 (B cell) activation with viral IL-10 homologue
When T cells attack – CD8 T cells kill
virus-infected cells and tumor cells
Video microscopy
T cell = blue
Infected cell = green
Red = toxic granules in
T cell delivered to infected cell
Elapsed time = 400 seconds
Quick Time™ a nd a
YU V4 20 co dec de co mpr es sor
ar e n eed ed to s ee thi s pi ctu re.
from Zweifach, et al. 2001. Immunity. 15:847
MHC Class I Assembly/Antigen Presentation
Extracellular
Matrix
Cytosol
Golgi
ERp57
ER
Lumen
calreticulin
calnexin
tapasin
Transport
class I
heterotrimer
class I
heterodimer
TAP1
2m
TAP2
Peptides
Protein
Proteasome
class I
H-chain
MHC Class I Assembly/Antigen Presentation
Extracellular
Matrix
Cytosol
Golgi
ERp57
ER
Lumen
calreticulin
US3
US8
calnexin
tapasin
US6
Transport
2m
US10
class I
heterotrimer
class I
TAP1
hetero-UL18
dimer
US2
US11
Protein
Proteasome
TAP2
Peptides
class I
H-chain
MHC Class I Assembly/Antigen Presentation
Extracellular
Matrix
Cytosol
Golgi
ERp57
ER
Lumen
calreticulin
US3
US8
calnexin
tapasin
US6
UL18
Transport
2m
US10
class I
heterotrimer
class I
TAP1
hetero-UL18
dimer
US2
US11
Protein
Proteasome
TAP2
Peptides
class I
H-chain
Virus Evasion of CD8+ T Cell Responses
HCMV (US6)
Surface
HSV (ICP47)
Folded
Protein
Adv (E3-19K)
Proteasome
TAP
TAP
TAP
TAP
Peptide
Dislocation
c
HCMV (US2, US11)
ER
ERGIC
m
t
GOLGI
MCMV (gp40)
KSHV (kK5/3)
Lysosome
Viral Latency and
Persistence
The reward for subverting detection and elimination
Herpesvirus evolution is a complex and
elegant example of molecular biological
warfare…
It’s just not always clear who’s winning!
In healthy individuals, herpetic pathologies are rarely fatal.
Herpes is forever…big bonus for the virus!
The better the virus, the less disease it causes, the more it is
“tolerated” by the host
Herpes B Virus
80% of untreated cases are fatal in humans
Why?
Herpes B Virus
80% of untreated cases are fatal in humans
22 reported cases, 20 developed encephalitis, 15
were fatal
…hmmmm, very rare…
Herpes B Virus
80% of untreated cases are fatal in humans
22 reported cases, 20 developed encephalitis, 15
were fatal
Herpes B virus infection occurs naturally in
Macaque monkeys, most with NO obvious signs of
infection. Those with signs of infection have small
blisters or ulcers on the mouth, face, lips, genitalia.
Reactivation/relapse can occur in stressed monkeys