4.8 Article

Asymmetric recognition of the HIV-1 trimer by broadly neutralizing antibody PG9

Publisher

NATL ACAD SCIENCES
DOI: 10.1073/pnas.1217537110

Keywords

-

Funding

  1. National Institutes of Health (NIH) [HIVRAD P01 AI82362, R01 AI36082]
  2. International AIDS Vaccine Initiative Neutralizing Antibody Center
  3. Scripps Center for HIV/AIDS Vaccine Immunology and Immunogen Discovery Grant [UM1 AI100663]
  4. University of California, San Diego Center for AIDS Research
  5. NIH [P30 AI036214]
  6. NIH National Institute of Allergy and Infectious Diseases
  7. NIH National Cancer Institute
  8. NIH National Institute of Mental Health
  9. NIH National Institute on Drug Abuse
  10. NIH National Institute of Child Health and Human Development
  11. NIH National Heart, Lung, and Blood Institute
  12. NIH National Institute on Aging
  13. Vidi grant from the Netherlands Organization for Scientific Research
  14. Starting Investigator Grant from the European Research Council
  15. AIDS Fonds Grant [2011032]
  16. Canadian Institutes of Health Research
  17. NIH through the National Center for Research Resources P41 Program [RR017573]
  18. DOE Office of Biological and Environmental Research
  19. NIH National Center for Research Resources, Biomedical Technology Program [P41RR001209]
  20. National Institute of General Medical Sciences

Ask authors/readers for more resources

PG9 is the founder member of an expanding family of glycan-dependent human antibodies that preferentially bind the HIV (HIV-1) envelope (Env) glycoprotein (gp) trimer and broadly neutralize the virus. Here, we show that a soluble SOSIP.664 gp140 trimer constructed from the Clade A BG505 sequence binds PG9 with high affinity (similar to 11 nM), enabling structural and biophysical characterizations of the PG9:Env trimer complex. The BG505 SOSIP.664 gp140 trimer is remarkably stable as assessed by electron microscopy (EM) and differential scanning calorimetry. EM, small angle X-ray scattering, size exclusion chromatography with inline multiangle light scattering and isothermal titration calorimetry all indicate that only a single PG9 fragment antigen-binding (Fab) binds to the Env trimer. An similar to 18 angstrom EM reconstruction demonstrates that PG9 recognizes the trimer asymmetrically at its apex via contact with two of the three gp120 protomers, possibly contributing to its reported preference for a quaternary epitope. Molecular modeling and isothermal titration calorimetry binding experiments with an engineered PG9 mutant suggest that, in addition to the N156 and N160 glycan interactions observed in crystal structures of PG9 with a scaffolded V1/V2 domain, PG9 makes secondary interactions with an N160 glycan from an adjacent gp120 protomer in the antibody-trimer complex. Together, these structural and biophysical findings should facilitate the design of HIV-1 immunogens that possess all elements of the quaternary PG9 epitope required to induce broadly neutralizing antibodies against this region.

Authors

I am an author on this paper
Click your name to claim this paper and add it to your profile.

Reviews

Primary Rating

4.8
Not enough ratings

Secondary Ratings

Novelty
-
Significance
-
Scientific rigor
-
Rate this paper

Recommended

No Data Available
No Data Available