Evolutionary origin on HIV - UCSBsites.me.ucsb.edu/~moehlis/APC591/martin2.pdfEvolutionary origin on...
Transcript of Evolutionary origin on HIV - UCSBsites.me.ucsb.edu/~moehlis/APC591/martin2.pdfEvolutionary origin on...
Evolutionary origin on HIV
zThe closest relatives of HIV-1 and HIV-2 are simian immunodeficiency viruses (SIV).zThere is evidence for multiple
transmissions from SIV into humans.zHIV-1 is very closely related to SIV from
chimpanzees.
Evolution of virulence
zAll SIVs appear to be apathogenic in their natural hosts.zSIV can be transferred to other species,
where it induces AIDS.z‘Short-sighted’ evolution of virulence.
HIV is a quasispecies
zViral replication is error prone.zHIV reverse transcriptase and RNA
polymerase have error rates of about 1E-4.zThe virus population in any one patient is
extremely heterogeneous.zHIV can escape from drug treatment.zHIV can escape from immune
responses.
Evolution toward disease
zEscape from immune responseszIncreasing viral diversityzFaster replicating strains
Diversity threshold
Time
Virusload
Antigenic variation
ni ,...,1=virus mutant i
immune responseagainst mutant i
Each mutant goes to equilibrium:
iii
iiii
bxcvxvpxrvv
−=−=
&&
pr
xcpbr
v ii ==
Add new mutants over time.
Antigenic variation
Total virus load is proportional to antigenic diversity.
cpbr
nvvi i == ∑:
Antigenic variation
ni ,...,1=
virus mutant i
specificimmune response
cross reactive immune response
bzkvzbxcvx
qzpxrvv
iii
iii
−=−=
−−=
&&& )(
kqncpbrn
v+
=
n
Virus load:
Antigenic variation of HIV
ni ,...,1=
virus mutant i
specificimmune response
cross reactive immune response
uvzbzkvzuvxbxcvxqzpxrvv
iiii
iii
−−=−−=−−=
&&& )(
nkqrucpbrn
v)( −−
=Virus load:
Antigenic variation of HIV
Virus load:
Diversity threshold:
nkqrucpbrn
v)( −−
=
kqrucp
nc −=
1. Disease after long asymptomatic period.
2. Indefinite virus control.
3. Immediate disease.
The ‘diversity threshold’ model has 3 possible outcomes
cpkqrukq +<<
rucpkq <+
kqru <
Immune responses to multiple epitopes
Immunodominance
breadth of the response is related to immune memory
Immune responses to multiple epitopes
Antigenic variation can lead toshifting immunodominance
HIV disease progression according to this model
zThere is a highly dynamic balance between the virus and the immune system with rapid virus turnover.zThe evolutionary adaptation of the virus
in individual patients is the mechanism of disease progression.
Three possible mechanisms of HIV disease progression
zEvolution of the viruszSlow break-down of the immune systemzAccumulation of opportunistic infections
The virus will return if therapy is withdrawn
Virus load
Anti-viral treatment
Detectionlimit
Time
Is it possible to treat and help the patient’s immune system to gain control of the virus?
A new theory of CTL memory
zThe primary role of CTL memory is to eliminate virus infections or to reduce virus load to low levels.
Dominik Wodarz
Contact with antigen
ActivatedCTLp
Differentiation
EffectorCTL
NaiveCTLp
Proliferation
CTL dynamics
c
bCTL memory is characterized by highly responsive and long-lived CTL precursors (high c and low b).CTL memory requires CD4 cell help
xydxx βλ −−=.
pyzayxyy −−= β.
( ) bwqcyww −−= 1.
hzcqywz −=.
The basic model with CTL
Time
-2.5
-2
-1.5
-1
-0.5
0
0.5
1
1.5
0 20 40 60 80 100
-2.5
-2
-1.5
-1
-0.5
0
0.5
1
1.5
0 20 40 60 80 100
Log
CT
L
CTLe
CTLp
Log
vir
us lo
ad
Extinction threshold
2 possible outcomes:1. Virus elimination
Log
vir
us lo
ad
-2
-1
0
1
2
0 100 200 300 400 500
Time
CTLp
CTLeLog
CT
L
-2.5
-2
-1.5
-1
-0.5
0
0.5
1
1.5
0 100 200 300 400 500
Detection limit
Extinction threshold
2. Persistent infection
xydxx βλ −−=.
pyzayxyy −−= β.
bwcqywcxyww −−=.
hzcqywz −=.
HIV specific model
HIV
zHIV kills CD4 cells which are needed for CTL memory.zFailure to establish a CTL memory
response leads to persistent infection, high virus load and rapid disease progressionzA good CTL memory response leads to
virus elimination (rare ?) or at least low virus load and slow disease progression
HIV: rate of disease progression
Fast progressors: high virus load
Slow progressors: low virus load
CTL memory makes the difference.
CTL Memory No CTL Memory
Initial rate of viral spread
CTL Memory
No CTL Memory
HIV replication and establishment of memory
CTL Memory No CTL Memory
Initial rate of viral spread
CTL Memory
No CTL Memory
Vaccination or early treatment
HIV replication and establishment of memory
Treatment during primary infection
No treatment Treatment
CTLp Virus
SIV: Jeff Lifson HIV: Bruce Walker
Time (weeks)
Virus
CD4 response
SIV infection, no treatment
Time (weeks)
CD4 response
Virus
4 weeks of treatment ; re-challenge
SIV primary infectionwithout treatment
Virus
Time
Jeff Lifson: 12 monkeys, 12 authors
Virus load in the firstweek of infectionis correlated withset-pointis correlated withsurvival.
Treatment during chronic HIV infection
Treatment Treatment with drug holiday(s)
CTLp Virus
Anti-viral treatment and immunotherapy
Immunotherapy
CTLp Virus
A new approach for HIV therapy
zFor primary infection: Use vaccination and early treatment to reduce the initial viral growth rate and bring patients into a state of long term non-progression. zFor chronic infection: Use treatment
and immunotherapy to switch patients into a state of long term non-progression.