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This study investigates the role of polyclonality and initial size of HIV-specific CD4 clones in determining the outcome of HIV infection. It explores the importance of CD4 helper cells as targets of infection and their association with disease progression. Mathematical modeling is used to examine viral setpoint dependence on CD4 clone size and the breadth of CD8 T cell repertoire. The study suggests that the initial race between CD4 T helpers and HIV can determine the outcome of infection, emphasizing the potential benefits of early therapy and vaccination-induced CD4 response. The findings have implications for individual variation in viral setpoints and structured therapy interruptions.
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Polyclonality & Initial HIV-specific 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)
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
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=g1). 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 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
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
