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HIV

Rapid Progression to AIDS in HIV+ Individuals with a Structural Variant of the Chemokine Receptor CX3CR1 .

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HIV

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  1. Rapid Progression to AIDS in HIV+ Individuals with a Structural Variant of the Chemokine Receptor CX3CR1 Sophie Faure, 1 Laurence Meyer, 2 Dominique Costagliola, 3 Céline Vaneensberghe, 1 Emmanuelle Genin, 4 Brigitte Autran, 1 French ALT and IMMUNOCO Study Groups, Jean-François Delfraissy, 5 SEROCO Study Group, David H. McDermott, 6 Philip M. Murphy, 6 Patrice Debré, 1 Ioannis Théodorou, 1* Christophe Combadière 1, 6, 7

  2. HIV • Virus responsible for AIDS • Enters cells in vitro via CD4 • Mutation in coreceptors and chemokine ligands suggest delay in progression

  3. Chemokines • Chemical mediators • Stimulate movement and migration of white blood cells (helpful in fighting off infection)

  4. Focus: CX3CR1 • HIV coreceptor • Leukocyte chemotactic and adhesion receptor for the chemokine fractalkine • Limited interaction with tested HIV envelopes

  5. Fractalkine • Produced by monocytes and dendritic cells • Results in the recruitment of T cells • Contains special adhesion properties • Reinforces cell contact • Efficiently blocks the HIV coreceptor activity of CX3CR1

  6. Investigation • Whether CX3CR1 plays a role in regulating HIV progression

  7. Screening of CX3CR1 Coding Sequence • Screened for mutations by way of a single-stranded conformation polymorphism (SSCP) technique

  8. 4 nonsynonymous A-G subst’n: Thr57 changed to Ala (T57A) G-A subst’n: Val122 changed to Ile (V122I) G-A subst’n: Val240 changed to Ile (V249I) C-T subst’n: Thr280 changed to Met (T280M) 1 nonsynonymous Codon 255: G-A subst’n 5 Single Nucleotide Polymorphisms Identified

  9. Results • 25.7% V249I and 13.5% T280M found among the uninfected population

  10. Study of V249I & T280M • Analyzed via restriction fragment length polymorphism-based method • Study of 565 people among 3 cohorts • IMMUNOCO - intermediate progression • ALT – asymptomatic long term progression • SEROCO – known date of seroconversion

  11. V249 I G/G - homozygous w.t. A/A – homozygous mutation A/A – homozygous mutation A/A – homozygous mutation G/A - heterozygous G/A - heterozygous T280M C/C – homozygous w.t. C/C – homozygous w.t. T/T – homozygous mutation C/T - heterozygous C/C – homozygous w.t. C/T - heterozygous 6 Genotypes observed

  12. ALT IMMUNOCO SEROCO UNINFECTED 3 Haplotypes Observed

  13. Effect of CX3CR1 Variants on HIV Progression

  14. Findings • CX3CR1 is polymorphic in the Caucasian population • I249 M280 associated with accelerated HIV disease • Because CX3CR1 is a coreceptor for HIV, it is a possible target for therapeutic intervention

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