Skip to main content
NCBI home page
Journal of Virology logoLink to Journal of Virology
. 1996 Dec;70(12):9046–9050. doi: 10.1128/jvi.70.12.9046-9050.1996

In vitro antigen challenge of human antibody libraries for vaccine evaluation: the human immunodeficiency virus type 1 envelope.

P W Parren 1, P Fisicaro 1, A F Labrijn 1, J M Binley 1, W P Yang 1, H J Ditzel 1, C F Barbas 3rd 1, D R Burton 1
PMCID: PMC191009  PMID: 8971041

Abstract

Human antibody responses, or versions thereof, can be cloned as phage display libraries. In vaccine evaluation, the possibility therefore exists of challenging the human response in vitro, rather than in vivo, in order to assist in establishing the most promising vaccine leads. The characteristics of the antibodies retrieved directly indicate the strengths and weaknesses of the vaccine at the molecular level. We applied this approach to compare recombinant and native human immunodeficiency virus type 1 envelope preparations. We conclude that recombinant gp160, gp140, and, to a lesser extent, gp120 present epitopes around the CD4 binding site in a conformation different from that of the native multimer and contrary to expected vaccine requirements. Antibodies to the potently neutralizing b12 epitope were selected preferentially from an immune library by purified human immunodeficiency virus type 1 virions. This suggests that b12 is a major epitope on the virions, in contrast to recombinant envelope preparations, in which related, weakly neutralizing epitopes predominate. Although the majority of virions in the preparation used are expected to be noninfective, it appears that they predominantly express a native envelope configuration and would be able to elicit potent neutralizing antibodies.

Full Text

The Full Text of this article is available as a PDF (209.8 KB).

Selected References

These references are in PubMed. This may not be the complete list of references from this article.

  1. Barbas C. F., 3rd, Collet T. A., Amberg W., Roben P., Binley J. M., Hoekstra D., Cababa D., Jones T. M., Williamson R. A., Pilkington G. R. Molecular profile of an antibody response to HIV-1 as probed by combinatorial libraries. J Mol Biol. 1993 Apr 5;230(3):812–823. doi: 10.1006/jmbi.1993.1203. [DOI] [PubMed] [Google Scholar]
  2. Barbas C. F., 3rd, Hu D., Dunlop N., Sawyer L., Cababa D., Hendry R. M., Nara P. L., Burton D. R. In vitro evolution of a neutralizing human antibody to human immunodeficiency virus type 1 to enhance affinity and broaden strain cross-reactivity. Proc Natl Acad Sci U S A. 1994 Apr 26;91(9):3809–3813. doi: 10.1073/pnas.91.9.3809. [DOI] [PMC free article] [PubMed] [Google Scholar]
  3. Berman P. W., Eastman D. J., Wilkes D. M., Nakamura G. R., Gregory T. J., Schwartz D., Gorse G., Belshe R., Clements M. L., Byrn R. A. Comparison of the immune response to recombinant gp120 in humans and chimpanzees. AIDS. 1994 May;8(5):591–601. doi: 10.1097/00002030-199405000-00004. [DOI] [PubMed] [Google Scholar]
  4. Berman P. W., Gregory T. J., Riddle L., Nakamura G. R., Champe M. A., Porter J. P., Wurm F. M., Hershberg R. D., Cobb E. K., Eichberg J. W. Protection of chimpanzees from infection by HIV-1 after vaccination with recombinant glycoprotein gp120 but not gp160. Nature. 1990 Jun 14;345(6276):622–625. doi: 10.1038/345622a0. [DOI] [PubMed] [Google Scholar]
  5. Berman P. W., Riddle L., Nakamura G., Haffar O. K., Nunes W. M., Skehel P., Byrn R., Groopman J., Matthews T., Gregory T. Expression and immunogenicity of the extracellular domain of the human immunodeficiency virus type 1 envelope glycoprotein, gp160. J Virol. 1989 Aug;63(8):3489–3498. doi: 10.1128/jvi.63.8.3489-3498.1989. [DOI] [PMC free article] [PubMed] [Google Scholar]
  6. Broder C. C., Earl P. L., Long D., Abedon S. T., Moss B., Doms R. W. Antigenic implications of human immunodeficiency virus type 1 envelope quaternary structure: oligomer-specific and -sensitive monoclonal antibodies. Proc Natl Acad Sci U S A. 1994 Nov 22;91(24):11699–11703. doi: 10.1073/pnas.91.24.11699. [DOI] [PMC free article] [PubMed] [Google Scholar]
  7. Burioni R., Williamson R. A., Sanna P. P., Bloom F. E., Burton D. R. Recombinant human Fab to glycoprotein D neutralizes infectivity and prevents cell-to-cell transmission of herpes simplex viruses 1 and 2 in vitro. Proc Natl Acad Sci U S A. 1994 Jan 4;91(1):355–359. doi: 10.1073/pnas.91.1.355. [DOI] [PMC free article] [PubMed] [Google Scholar]
  8. Burton D. R., Barbas C. F., 3rd Human antibodies from combinatorial libraries. Adv Immunol. 1994;57:191–280. doi: 10.1016/s0065-2776(08)60674-4. [DOI] [PubMed] [Google Scholar]
  9. Burton D. R., Barbas C. F., 3rd, Persson M. A., Koenig S., Chanock R. M., Lerner R. A. A large array of human monoclonal antibodies to type 1 human immunodeficiency virus from combinatorial libraries of asymptomatic seropositive individuals. Proc Natl Acad Sci U S A. 1991 Nov 15;88(22):10134–10137. doi: 10.1073/pnas.88.22.10134. [DOI] [PMC free article] [PubMed] [Google Scholar]
  10. Burton D. R., Pyati J., Koduri R., Sharp S. J., Thornton G. B., Parren P. W., Sawyer L. S., Hendry R. M., Dunlop N., Nara P. L. Efficient neutralization of primary isolates of HIV-1 by a recombinant human monoclonal antibody. Science. 1994 Nov 11;266(5187):1024–1027. doi: 10.1126/science.7973652. [DOI] [PubMed] [Google Scholar]
  11. Cohen J. Jitters jeopardize AIDS vaccine trials. Science. 1993 Nov 12;262(5136):980–981. doi: 10.1126/science.8235635. [DOI] [PubMed] [Google Scholar]
  12. Crowe J. E., Jr, Murphy B. R., Chanock R. M., Williamson R. A., Barbas C. F., 3rd, Burton D. R. Recombinant human respiratory syncytial virus (RSV) monoclonal antibody Fab is effective therapeutically when introduced directly into the lungs of RSV-infected mice. Proc Natl Acad Sci U S A. 1994 Feb 15;91(4):1386–1390. doi: 10.1073/pnas.91.4.1386. [DOI] [PMC free article] [PubMed] [Google Scholar]
  13. Earl P. L., Broder C. C., Long D., Lee S. A., Peterson J., Chakrabarti S., Doms R. W., Moss B. Native oligomeric human immunodeficiency virus type 1 envelope glycoprotein elicits diverse monoclonal antibody reactivities. J Virol. 1994 May;68(5):3015–3026. doi: 10.1128/jvi.68.5.3015-3026.1994. [DOI] [PMC free article] [PubMed] [Google Scholar]
  14. Graham B. S. Serological responses to candidate AIDS vaccines. AIDS Res Hum Retroviruses. 1994;10 (Suppl 2):S145–S148. [PubMed] [Google Scholar]
  15. Hanson C. V. Measuring vaccine-induced HIV neutralization: report of a workshop. AIDS Res Hum Retroviruses. 1994 Jun;10(6):645–648. doi: 10.1089/aid.1994.10.645. [DOI] [PubMed] [Google Scholar]
  16. Helseth E., Kowalski M., Gabuzda D., Olshevsky U., Haseltine W., Sodroski J. Rapid complementation assays measuring replicative potential of human immunodeficiency virus type 1 envelope glycoprotein mutants. J Virol. 1990 May;64(5):2416–2420. doi: 10.1128/jvi.64.5.2416-2420.1990. [DOI] [PMC free article] [PubMed] [Google Scholar]
  17. Kalyanaraman V. S., Pal R., Gallo R. C., Sarngadharan M. G. A unique human immunodeficiency virus culture secreting soluble gp160. AIDS Res Hum Retroviruses. 1988 Oct;4(5):319–329. doi: 10.1089/aid.1988.4.319. [DOI] [PubMed] [Google Scholar]
  18. Kalyanaraman V. S., Rodriguez V., Veronese F., Rahman R., Lusso P., DeVico A. L., Copeland T., Oroszlan S., Gallo R. C., Sarngadharan M. G. Characterization of the secreted, native gp120 and gp160 of the human immunodeficiency virus type 1. AIDS Res Hum Retroviruses. 1990 Mar;6(3):371–380. doi: 10.1089/aid.1990.6.371. [DOI] [PubMed] [Google Scholar]
  19. Layne S. P., Merges M. J., Dembo M., Spouge J. L., Conley S. R., Moore J. P., Raina J. L., Renz H., Gelderblom H. R., Nara P. L. Factors underlying spontaneous inactivation and susceptibility to neutralization of human immunodeficiency virus. Virology. 1992 Aug;189(2):695–714. doi: 10.1016/0042-6822(92)90593-e. [DOI] [PubMed] [Google Scholar]
  20. Mascola J. R., Snyder S. W., Weislow O. S., Belay S. M., Belshe R. B., Schwartz D. H., Clements M. L., Dolin R., Graham B. S., Gorse G. J. Immunization with envelope subunit vaccine products elicits neutralizing antibodies against laboratory-adapted but not primary isolates of human immunodeficiency virus type 1. The National Institute of Allergy and Infectious Diseases AIDS Vaccine Evaluation Group. J Infect Dis. 1996 Feb;173(2):340–348. doi: 10.1093/infdis/173.2.340. [DOI] [PubMed] [Google Scholar]
  21. Matthews T. J. Dilemma of neutralization resistance of HIV-1 field isolates and vaccine development. AIDS Res Hum Retroviruses. 1994 Jun;10(6):631–632. doi: 10.1089/aid.1994.10.631. [DOI] [PubMed] [Google Scholar]
  22. Parren P. W., Burton D. R. Antibodies against HIV-1 from phage display libraries: mapping of an immune response and progress towards antiviral immunotherapy. Chem Immunol. 1997;65:18–56. doi: 10.1159/000319346. [DOI] [PubMed] [Google Scholar]
  23. Parren P. W., Ditzel H. J., Gulizia R. J., Binley J. M., Barbas C. F., 3rd, Burton D. R., Mosier D. E. Protection against HIV-1 infection in hu-PBL-SCID mice by passive immunization with a neutralizing human monoclonal antibody against the gp120 CD4-binding site. AIDS. 1995 Jun;9(6):F1–F6. doi: 10.1097/00002030-199506000-00001. [DOI] [PubMed] [Google Scholar]
  24. Pasquali J. L., Kieny M. P., Kolbe H., Christmann D., Knapp A. M. Immunogenicity and epitope mapping of a recombinant soluble gp160 of the human immunodeficiency virus type 1 envelope glycoprotein. AIDS Res Hum Retroviruses. 1990 Sep;6(9):1107–1113. doi: 10.1089/aid.1990.6.1107. [DOI] [PubMed] [Google Scholar]
  25. Roben P., Moore J. P., Thali M., Sodroski J., Barbas C. F., 3rd, Burton D. R. Recognition properties of a panel of human recombinant Fab fragments to the CD4 binding site of gp120 that show differing abilities to neutralize human immunodeficiency virus type 1. J Virol. 1994 Aug;68(8):4821–4828. doi: 10.1128/jvi.68.8.4821-4828.1994. [DOI] [PMC free article] [PubMed] [Google Scholar]
  26. VanCott T. C., Veit S. C., Kalyanaraman V., Earl P., Birx D. L. Characterization of a soluble, oligomeric HIV-1 gp160 protein as a potential immunogen. J Immunol Methods. 1995 Jun 14;183(1):103–117. doi: 10.1016/0022-1759(95)00038-c. [DOI] [PubMed] [Google Scholar]
  27. Williamson R. A., Burioni R., Sanna P. P., Partridge L. J., Barbas C. F., 3rd, Burton D. R. Human monoclonal antibodies against a plethora of viral pathogens from single combinatorial libraries. Proc Natl Acad Sci U S A. 1993 May 1;90(9):4141–4145. doi: 10.1073/pnas.90.9.4141. [DOI] [PMC free article] [PubMed] [Google Scholar]

Articles from Journal of Virology are provided here courtesy of American Society for Microbiology (ASM)

RESOURCES