Germline-targeting chimpanzee SIV Envelopes induce V2-apex broadly neutralizing-like B cell precursors in a rhesus macaque infection model

  1. Rami Musharrafieh
  2. Yana Safonova
  3. Ge Song
  4. Ryan S. Roark
  5. Fang-Hua Lee
  6. Shiyu Zhang
  7. Jonathan Hurtado
  8. Peter Yong
  9. Shuyi Wang
  10. Ronnie M. Russell
  11. Wenge Ding
  12. Yingying Li
  13. Juliette Rando
  14. Alexander I. Murphy
  15. Emily Lindemuth
  16. Chengyan Zhao
  17. Andrew Jesse Connell
  18. Wen-Hsin Lee
  19. Nitesh Mishra
  20. Gabriel Avillion
  21. Wanting He
  22. Sean Callaghan
  23. Katharina Dueker
  24. Anh L. Vo
  25. Xuduo Li
  26. Tazio Capozzola
  27. Collin Joyce
  28. Fangzhu Zhao
  29. Fabio Anzanello
  30. Weimin Liu
  31. Frederic Bibollet-Ruche
  32. Alejandra Ramos
  33. Hui Li
  34. Mark G. Lewis
  35. Gabriel Ozorowski
  36. Elise Landais
  37. Brian T. Foley
  38. Kshitij Wagh
  39. Devin Sok
  40. Bryan Briney
  41. Andrew B. Ward
  42. Beatrice H. Hahn
  43. Dennis R. Burton
  44. George M. Shaw
  45. Raiees Andrabi
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Abstract

Eliciting broadly neutralizing antibodies-(bnAbs) remains a major goal of HIV-1 vaccine research. Previously, we showed that a soluble chimpanzee SIV Envelope-(Env) trimer, MT145K, bound several human V2-apex bnAb-precursors and stimulated an appropriate response in V2-apex bnAb precursor-expressing knock-in mice. Here, we tested the immunogenicity of three MT145 variants (MT145, MT145K, MT145K.dV5) expressed as chimeric simian-chimpanzee-immunodeficiency-viruses-(SCIVs) in rhesus macaques-(RMs). All three viruses established productive infections with high setpoint vRNA titers. RMs infected with the germline-targeting SCIV_MT145K and SCIV_MT145K.dV5 exhibited larger and more clonally expanded B cell lineages featuring long anionic heavy chain complementary-determining-regions-(HCDR3s) compared with wildtype SCIV_MT145. Moreover, antigen-specific B cell analysis revealed enrichment for long-CDHR3-bearing antibodies in SCIV_MT145K.dV5 infected animals with paratope features resembling prototypic V2-apex bnAbs and their precursors. Although none of the animals developed bnAbs, these results show that germline-targeting SCIVs can activate and preferentially expand B cells expressing V2-apex bnAb-like precursors, the first step in bnAb elicitation.

Graphical Abstract

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