Polyclonality

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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

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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

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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)

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The model
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The model / Mathematics
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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 (?2g?1). H1 is dominant, because ggt1.
• Competition within clones
• Competition between clones only indirectly,
  through Ag stimulation

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MONOCLONAL SYSTEMVirus infectivity and outcome
of infection
No T helpers
Immune control 1 non-lytic clone
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Initial events crucial
High initial H0 Immune control
Low initial H0 No Immune control
?0.05 T040 I01
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MONOCLONAL SYSTEM Th avidity and outcome of
infection
No T helpers
Immune control 1 non-lytic clone
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2 LYTIC CLONESTh avidity and outcome of
infection
No T helpers
1 lytic clone
2 lytic clones
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2 DIFFERENT CLONESTh avidity and outcome of
infection
No T helpers
1 lytic clone
1 non-lytic, 1 lytic clone
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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)

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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

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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