Polyclonality & Initial HIV-specific CD4 clone size determine outcome of infection

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. 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

3. 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)

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

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 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

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

8. Initial events crucial High initial H0: Immune control Low initial H0: No Immune control =0.05; T0=40; I0=1

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

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

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

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