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Mark Connors, M.D. HIV-Specific Immunity Section

Breadth of Neutralizing Antibodies in HIV+ Serum: Clustering Analysis and Association with Clinical Variables. Mark Connors, M.D. HIV-Specific Immunity Section National Institute of Allergy and Infectious Diseases. Introduction.

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Mark Connors, M.D. HIV-Specific Immunity Section

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  1. Breadth of Neutralizing Antibodies in HIV+ Serum: Clustering Analysis and Association with Clinical Variables Mark Connors, M.D. HIV-Specific Immunity Section National Institute of Allergy and Infectious Diseases

  2. Introduction • Induction of broadly cross-reactive neutralizing antibodies (NAb) is a major goal for HIV vaccines • Current vaccine candidates elicit weak, narrowly-directed NAb, however… • Some HIV-infected patients make very broadly cross-reactive NAb

  3. Purpose of Study • Characterize neutralization breadth in a large diverse cohort >100 patients • Previous study: neutralization of 5 isolates, qualitative • This study: neutralization of 20 isolates, quantitative • Find clinical or demographic correlates of breadth • Find patterns of serum reactivity to virus isolates

  4. Methods • Serum; clinical, demographic data from patients at NIH • 25 LTNP/EC, VL <50, stable CD4 • Migueles et al 2002 • 78 viremic patients • Neutralization assay: • TZM-bl assay • 20-virus panel • Primary isolate envs of A, B, C clades • Range of neutralization sensitivities, Tier 2 • Clinical correlations • Clustering analysis

  5. Viremic patients have variable NAb ID50

  6. Breadth is not rare in viremic patients ID50 • Half of sera neutralize at least 11/20 isolates • 20% of sera neutralize at least 15/20 isolates

  7. LTNP/EC LTNP/EC • Rarely have broad NAb • Reflect low end of variation found in viremic patients Viremic

  8. Breadth correlates with viral load • Modest positive correlation with VL • No consistent correlation with: • CD4 count • Years since dx • HLA Class II alleles • ARV experience • Risk Group • Age • Gender • Race/ethnicity Viremic LTNP/EC Log Viral Load Log Geomean ID50 P<0.001, r=0.67

  9. Heatmap of neutralization data Sera <1.0 1.0-1.4 1.4-1.8 1.8-2.2 2.2-2.6 2.6-3.0 3.0-3.4 3.4-3.8 3.8-4.2 Isolates Log ID50

  10. Statistical analysis allows precise cluster assignments Sera <1.0 1.0-1.4 1.4-1.8 1.8-2.2 2.2-2.6 2.6-3.0 3.0-3.4 3.4-3.8 3.8-4.2 Isolates Log ID50

  11. Serum clusters reflect reactivity with isolates LTNP/EC Sera <1.0 1.0-1.4 1.4-1.8 1.8-2.2 2.2-2.6 2.6-3.0 3.0-3.4 3.4-3.8 3.8-4.2 Isolates Log ID50

  12. Isolate clusters based on serum reactivity do not match clades • Cluster ≠ clade • Related sequences are near each other but not always in same cluster

  13. Sera and MAbs define different isolate clusters • Isolate clustering based on sera or monoclonals did not match • Isolate clustering based on sera did not correlate with reactivity to any one monoclonal • Consistent with polyclonal nature of serum IC50 (ug/ml)

  14. Conclusions • Sera with broad NAb are not uncommon in viremic patients • Breadth is associated with exposure to antigen • Clustering analysis reveals relationships between isolates based on patterns of serum neutralization reactivity • Clusters distinct from clade • Clusters distinct from sensitivity to MAb

  15. National Institute of Allergy and Infectious Diseases HIV-Specific Immunity Section Nicole Doria-Rose Rachel Klein Stephen Migueles Adjoa Smalls-Mantey Biostatistics Research Branch Martha Nason Vaccine Research Center John Mascola Sijy O’Dell Krisha Svehla Mark Louder Richard Wyatt Clinical Research Section Nancy Cogliano-Schutta Gregg Roby Cathy Rehm Sara Stallings Los Alamos National Laboratory Bette Korber Marcus Daniels Alan Lapedes Tanmoy Bhattacharya Patients Acknowledgements

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