Transcript Models of HIV infection in which CD4 cells are both helpers

Polyclonality & Initial HIVspecific CD4 clone size
determine outcome of infection
Hester Korthals Altes
Lab. Immunologie Tissulaire et Cellulaire
Hôpital Pitié-Salpêtrière, Paris, France
Observations:

Early events in HIV infection determine viral
setpoint and subsequent disease progression
(Staprans et al. ‘99, Lifson et al. ‘97)

Breadth of CD8 T cell repertoire correlates
negatively with progression (Pantaleo et al. ‘97)
Model HIV infection to explore how
viral setpoint depends on:
 CD4 helper clone size at infection
 Polyclonality of the response
HIV-specific CD4: HIV targets and
mediators of immune response

Specific CD4 cells important targets of
infection
(Miedema et al. ’88, Laurence et al. ’89, and
Douek et al. 02)

Importance for priming and establishment of
memory CD8 response
(resp. Ridge et al. ‘98/ Livingstone & Kuhn ’99 and
Borrow et al.)

Association CD4 T helper response with
disease progression / control
(Rosenberg et al., Pitcher et al. ‘99)
The model
Non-specific CD4
and other
targets cells
Infected
CD4 T cell
T
Source
I
Virus
Infection
Lytic
Non-lytic
CTL response
proportional to
Th response
Infection
Hi
HIV- specific
CD4 T cells
(i clones)
The model / Mathematics
1
N
1  n1 H1  n2 H 2
dT
    T T  ITN ( H 1 , H 2 )
dt
dH 1
IH 1
2
H 
 H 1   H IH 1 N ( H 1 , H 2 )
dt
1  I
dH 2
IH 2
2
H 
 H 2   H IH 2 N ( H1 , H 2 )
dt
2 I
dI
 I [ T   H ( H1  H 2 )] N ( H1 , H 2 )
dt
  I I  K ( H1 , H 2 ) I
K  k1H1  k2 H 2
Characteristics of HIV-specific
CD4 clones

Clones differ in functional avidity:
1 = “responsiveness to Ag”
= amount of antigen needed for halfmaximum proliferation of H1.

Responsiveness H2 scaled to responsiveness
1 of H1 (2=g1). H1 is dominant, because g>1.

Competition within clones;
Competition between clones only indirectly,
through Ag stimulation
MONOCLONAL SYSTEM:
Virus infectivity and outcome of infection
No T helpers
Immune control:
1 non-lytic clone
Initial events crucial
High initial H0:
Immune control
Low initial H0:
No Immune control
=0.05; T0=40; I0=1
MONOCLONAL SYSTEM:
Th avidity and outcome of infection
No T helpers
Immune control:
1 non-lytic clone
2 LYTIC CLONES:
Th avidity and outcome of infection
No T helpers
1 lytic clone
2 lytic clones
2 DIFFERENT CLONES:
Th avidity and outcome of infection
No T helpers
1 lytic clone
1 non-lytic,
1 lytic clone
Conclusions I

Bistability: Initial race between CD4 T
helpers and HIV can determine the outcome
of infection; importance dual role CD4 H
- early therapy preserves CD4 and associated CTL response
against HIV (Oxenius et al., 2000);
- CD4 H induced by vaccination is beneficial (Heeney 2002).

Probability of n-stability occurring highest
with only non-lytic or with “specialised”
responses (high-avidity lytic, low-avidity
non-lytic)
Conclusions II

Variation in viral setpoints can be explained by:
– n-stability across patients with same HLA-type
– differences in avidity of clones across patients
with different HLA-type

Implications for structured therapy
interruptions: possible to stimulate extra
clones of intermediate avidity
Acknowledgements

Rob de Boer
Theoretical Biology, Utrecht University,
the Netherlands

Ruy Ribeiro
Theoretical Biology and Biophysics,
Los Alamos National Laboratories

Research supported by a Marie Curie Fellowship
under the European Community Programme Quality
of Life