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The virus will return if therapy is withdrawn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.