1. Polyclonality & Initial HIV- specific CD4 clone size determine outcome of infection Hester Korthals Altes Lab. Immunologie Tissulaire et Cellulaire Hôpital Pitié-Salpêtrière, Paris, France

2. 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 Observations:

3. 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) HIV-specific CD4: HIV targets and mediators of immune response

4. The model Infection Virus Source T Non-specific CD4 and other targets cells I Infected CD4 T cell Lytic Infection HIV- specific CD4 T cells (i clones) HiHi Non-lytic CTL response proportional to Th response

5. The model / Mathematics

6. Characteristics of HIV-specific CD4 clones Clones differ in functional avidity:  1 = “responsiveness to Ag” = amount of antigen needed for half- maximum proliferation of H 1. Responsiveness H 2 scaled to responsiveness  1 of H 1 (  2 =g  1 ). H 1 is dominant, because g>1. Competition within clones; Competition between clones only indirectly, through Ag stimulation

7. MONOCLONAL SYSTEM: Virus infectivity and outcome of infection No T helpers Immune control: 1 non-lytic clone

8. Initial events crucial High initial H 0 : Immune control Low initial H 0 : No Immune control  =0.05; T 0 =40; I 0 =1

9. No T helpers MONOCLONAL SYSTEM: Th avidity and outcome of infection Immune control: 1 non-lytic clone

10. 2 LYTIC CLONES: Th avidity and outcome of infection 2 lytic clones 1 lytic clone No T helpers

11. 1 lytic clone 1 non-lytic, 1 lytic clone 2 DIFFERENT CLONES: Th avidity and outcome of infection No T helpers

12. 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)

13. Conclusions II Variation in viral setpoints can be ex- plained 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

14. 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