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. 1990 Sep;64(9):4123–4129. doi: 10.1128/jvi.64.9.4123-4129.1990

Analysis of a highly immunodominant epitope in the human immunodeficiency virus type 1 transmembrane glycoprotein, gp41, defined by a human monoclonal antibody.

T H Bugge 1, B O Lindhardt 1, L L Hansen 1, P Kusk 1, E Hulgaard 1, K Holmbäck 1, P J Klasse 1, J Zeuthen 1, K Ulrich 1
PMCID: PMC247875  PMID: 1696634

Abstract

A human monoclonal antibody, 41-7 [immunoglobulin G1(kappa)], directed against the transmembrane glycoprotein gp41 of the human immunodeficiency virus type 1 (HIV-1) has been produced by direct fusion of lymph node cells from an HIV-1-infected individual with a human B-lymphoblastoid cell line. The minimal essential epitope for 41-7 was mapped to a conserved seven-amino acid sequence, N-CSGKLIC-C, located within the N-terminal part of gp41. Antibodies blocking the binding of 41-7 could be detected in the serum of all HIV-1-infected individuals tested, irrespective of the stage of the infection. The epitope is located externally to the plasma membrane, and it is accessible to antibody in the native conformation of the glycoprotein. Despite this, no neutralizing activity of 41-7 could be demonstrated in vitro. These data indicate, directly and indirectly, that this immunodominant epitope on gp41, although exposed on the viral surface, elicits antibodies lacking antiviral activity and, hence, should be avoided in future vaccine candidates.

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Selected References

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  1. Abrams P. G., Knost J. A., Clarke G., Wilburn S., Oldham R. K., Foon K. A. Determination of the optimal human cell lines for development of human hybridomas. J Immunol. 1983 Sep;131(3):1201–1204. [PubMed] [Google Scholar]
  2. Andreassen H., Bohr H., Bohr J., Brunak S., Bugge T., Cotterill R. M., Jacobsen C., Kusk P., Lautrup B., Petersen S. B. Analysis of the secondary structure of the human immunodeficiency virus (HIV) proteins p17, gp120, and gp41 by computer modeling based on neural network methods. J Acquir Immune Defic Syndr. 1990;3(6):615–622. [PubMed] [Google Scholar]
  3. Arendrup M., Ulrich K., Nielsen J. O., Lindhardt B. O., Kusk P., Mathiesen L. R., Pedersen C., Krogsgaard K. HIV neutralizing antibodies: development and association with HIV related disease. Scand J Infect Dis. 1989;21(1):19–26. doi: 10.3109/00365548909035676. [DOI] [PubMed] [Google Scholar]
  4. Banapour B., Rosenthal K., Rabin L., Sharma V., Young L., Fernandez J., Engleman E., McGrath M., Reyes G., Lifson J. Characterization and epitope mapping of a human monoclonal antibody reactive with the envelope glycoprotein of human immunodeficiency virus. J Immunol. 1987 Dec 15;139(12):4027–4033. [PubMed] [Google Scholar]
  5. Berman P. W., Groopman J. E., Gregory T., Clapham P. R., Weiss R. A., Ferriani R., Riddle L., Shimasaki C., Lucas C., Lasky L. A. Human immunodeficiency virus type 1 challenge of chimpanzees immunized with recombinant envelope glycoprotein gp120. Proc Natl Acad Sci U S A. 1988 Jul;85(14):5200–5204. doi: 10.1073/pnas.85.14.5200. [DOI] [PMC free article] [PubMed] [Google Scholar]
  6. Bernard H. U., Remaut E., Hershfield M. V., Das H. K., Helinski D. R., Yanofsky C., Franklin N. Construction of plasmid cloning vehicles that promote gene expression from the bacteriophage lambda pL promoter. Gene. 1979 Jan;5(1):59–76. doi: 10.1016/0378-1119(79)90092-1. [DOI] [PubMed] [Google Scholar]
  7. Bressan G. M., Stanley K. K. pUEX, a bacterial expression vector related to pEX with universal host specificity. Nucleic Acids Res. 1987 Dec 10;15(23):10056–10056. doi: 10.1093/nar/15.23.10056. [DOI] [PMC free article] [PubMed] [Google Scholar]
  8. Cheng-Mayer C., Homsy J., Evans L. A., Levy J. A. Identification of human immunodeficiency virus subtypes with distinct patterns of sensitivity to serum neutralization. Proc Natl Acad Sci U S A. 1988 Apr;85(8):2815–2819. doi: 10.1073/pnas.85.8.2815. [DOI] [PMC free article] [PubMed] [Google Scholar]
  9. Chiodi F., Bredberg-Råden U., Biberfeld G., Böttiger B., Albert J., Asjö B., Fenyö E. M., Norrby E. Radioimmunoprecipitation and Western blotting with sera of human immunodeficiency virus infected patients: a comparative study. AIDS Res Hum Retroviruses. 1987 Summer;3(2):165–176. doi: 10.1089/aid.1987.3.165. [DOI] [PubMed] [Google Scholar]
  10. Desgranges C., Boyer V., Souche S., Sprecher S., Burney A., Gallo R. C., Bernard J., Reveil B., Zagury D. Monoclonal antibodies to HIV in a non-infected, immunised volunteer. Lancet. 1988 Apr 23;1(8591):935–936. doi: 10.1016/s0140-6736(88)91737-0. [DOI] [PubMed] [Google Scholar]
  11. Doorbar J., Campbell D., Grand R. J., Gallimore P. H. Identification of the human papilloma virus-1a E4 gene products. EMBO J. 1986 Feb;5(2):355–362. doi: 10.1002/j.1460-2075.1986.tb04219.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  12. Evans L. A., Homsy J. M., Morrow W. J., Gaston I., Sooy C. D., Levy J. A. Human monoclonal antibody directed against gag gene products of the human immunodeficiency virus. J Immunol. 1988 Feb 1;140(3):941–943. [PubMed] [Google Scholar]
  13. Glassy M. C., Handley H. H., Hagiwara H., Royston I. UC 729-6, a human lymphoblastoid B-cell line useful for generating antibody-secreting human-human hybridomas. Proc Natl Acad Sci U S A. 1983 Oct;80(20):6327–6331. doi: 10.1073/pnas.80.20.6327. [DOI] [PMC free article] [PubMed] [Google Scholar]
  14. Gnann J. W., Jr, Nelson J. A., Oldstone M. B. Fine mapping of an immunodominant domain in the transmembrane glycoprotein of human immunodeficiency virus. J Virol. 1987 Aug;61(8):2639–2641. doi: 10.1128/jvi.61.8.2639-2641.1987. [DOI] [PMC free article] [PubMed] [Google Scholar]
  15. Gorny M. K., Gianakakos V., Sharpe S., Zolla-Pazner S. Generation of human monoclonal antibodies to human immunodeficiency virus. Proc Natl Acad Sci U S A. 1989 Mar;86(5):1624–1628. doi: 10.1073/pnas.86.5.1624. [DOI] [PMC free article] [PubMed] [Google Scholar]
  16. Goudsmit J., Boucher C. A., Meloen R. H., Epstein L. G., Smit L., van der Hoek L., Bakker M. Human antibody response to a strain-specific HIV-1 gp120 epitope associated with cell fusion inhibition. AIDS. 1988 Jun;2(3):157–164. [PubMed] [Google Scholar]
  17. Goudsmit J., Debouck C., Meloen R. H., Smit L., Bakker M., Asher D. M., Wolff A. V., Gibbs C. J., Jr, Gajdusek D. C. Human immunodeficiency virus type 1 neutralization epitope with conserved architecture elicits early type-specific antibodies in experimentally infected chimpanzees. Proc Natl Acad Sci U S A. 1988 Jun;85(12):4478–4482. doi: 10.1073/pnas.85.12.4478. [DOI] [PMC free article] [PubMed] [Google Scholar]
  18. Groopman J. E., Benz P. M., Ferriani R., Mayer K., Allan J. D., Weymouth L. A. Characterization of serum neutralization response to the human immunodeficiency virus (HIV). AIDS Res Hum Retroviruses. 1987 Spring;3(1):71–85. doi: 10.1089/aid.1987.3.71. [DOI] [PubMed] [Google Scholar]
  19. Grunow R., Jahn S., Porstmann T., Kiessig S. S., Steinkellner H., Steindl F., Mattanovich D., Gürtler L., Deinhardt F., Katinger H. The high efficiency, human B cell immortalizing heteromyeloma CB-F7. Production of human monoclonal antibodies to human immunodeficiency virus. J Immunol Methods. 1988 Feb 10;106(2):257–265. doi: 10.1016/0022-1759(88)90206-2. [DOI] [PubMed] [Google Scholar]
  20. Guesdon J. L., Ternynck T., Avrameas S. The use of avidin-biotin interaction in immunoenzymatic techniques. J Histochem Cytochem. 1979 Aug;27(8):1131–1139. doi: 10.1177/27.8.90074. [DOI] [PubMed] [Google Scholar]
  21. Haffar O. K., Dowbenko D. J., Berman P. W. Topogenic analysis of the human immunodeficiency virus type 1 envelope glycoprotein, gp160, in microsomal membranes. J Cell Biol. 1988 Nov;107(5):1677–1687. doi: 10.1083/jcb.107.5.1677. [DOI] [PMC free article] [PubMed] [Google Scholar]
  22. Hoffman A. D., Banapour B., Levy J. A. Characterization of the AIDS-associated retrovirus reverse transcriptase and optimal conditions for its detection in virions. Virology. 1985 Dec;147(2):326–335. doi: 10.1016/0042-6822(85)90135-7. [DOI] [PubMed] [Google Scholar]
  23. Hofmann B., Lindhardt B. O., Gerstoft J., Petersen C. S., Platz P., Ryder L. P., Odum N., Dickmeiss E., Nielsen P. B., Ullman S. Lymphocyte transformation response to pokeweed mitogen as a predictive marker for development of AIDS and AIDS related symptoms in homosexual men with HIV antibodies. Br Med J (Clin Res Ed) 1987 Aug 1;295(6593):293–296. doi: 10.1136/bmj.295.6593.293. [DOI] [PMC free article] [PubMed] [Google Scholar]
  24. Hu S. L., Fultz P. N., McClure H. M., Eichberg J. W., Thomas E. K., Zarling J., Singhal M. C., Kosowski S. G., Swenson R. B., Anderson D. C. Effect of immunization with a vaccinia-HIV env recombinant on HIV infection of chimpanzees. Nature. 1987 Aug 20;328(6132):721–723. doi: 10.1038/328721a0. [DOI] [PubMed] [Google Scholar]
  25. Javaherian K., Langlois A. J., McDanal C., Ross K. L., Eckler L. I., Jellis C. L., Profy A. T., Rusche J. R., Bolognesi D. P., Putney S. D. Principal neutralizing domain of the human immunodeficiency virus type 1 envelope protein. Proc Natl Acad Sci U S A. 1989 Sep;86(17):6768–6772. doi: 10.1073/pnas.86.17.6768. [DOI] [PMC free article] [PubMed] [Google Scholar]
  26. Kjeldsen T. B., Rasmussen B. B., Rose C., Zeuthen J. Human-human hybridomas and human monoclonal antibodies obtained by fusion of lymph node lymphocytes from breast cancer patients. Cancer Res. 1988 Jun 1;48(11):3208–3214. [PubMed] [Google Scholar]
  27. Klasse P. J., Pipkorn R., Blomberg J. Presence of antibodies to a putatively immunosuppressive part of human immunodeficiency virus (HIV) envelope glycoprotein gp41 is strongly associated with health among HIV-positive subjects. Proc Natl Acad Sci U S A. 1988 Jul;85(14):5225–5229. doi: 10.1073/pnas.85.14.5225. [DOI] [PMC free article] [PubMed] [Google Scholar]
  28. Koch C., Skjødt K., Laursen I. A simple immunoblotting method after separation of proteins in agarose gel. J Immunol Methods. 1985 Nov 28;84(1-2):271–278. doi: 10.1016/0022-1759(85)90434-x. [DOI] [PubMed] [Google Scholar]
  29. Kusk P., Ulrich K., Zeuthen J., Pallesen G. Immunological characterization and detection of the major core protein p24 of the human immunodeficiency virus (HIV) using monoclonal antibodies. J Acquir Immune Defic Syndr. 1988;1(4):326–332. [PubMed] [Google Scholar]
  30. Lindhardt B. O., Ulrich K., Kusk P., Hofmann B. Serological response in patients with chronic asymptomatic human immunodeficiency virus infection. Eur J Clin Microbiol Infect Dis. 1988 Jun;7(3):394–399. doi: 10.1007/BF01962344. [DOI] [PubMed] [Google Scholar]
  31. Matthews T. J., Langlois A. J., Robey W. G., Chang N. T., Gallo R. C., Fischinger P. J., Bolognesi D. P. Restricted neutralization of divergent human T-lymphotropic virus type III isolates by antibodies to the major envelope glycoprotein. Proc Natl Acad Sci U S A. 1986 Dec;83(24):9709–9713. doi: 10.1073/pnas.83.24.9709. [DOI] [PMC free article] [PubMed] [Google Scholar]
  32. McDougal J. S., Cort S. P., Kennedy M. S., Cabridilla C. D., Feorino P. M., Francis D. P., Hicks D., Kalyanaraman V. S., Martin L. S. Immunoassay for the detection and quantitation of infectious human retrovirus, lymphadenopathy-associated virus (LAV). J Immunol Methods. 1985 Jan 21;76(1):171–183. doi: 10.1016/0022-1759(85)90489-2. [DOI] [PubMed] [Google Scholar]
  33. Modrow S., Hahn B. H., Shaw G. M., Gallo R. C., Wong-Staal F., Wolf H. Computer-assisted analysis of envelope protein sequences of seven human immunodeficiency virus isolates: prediction of antigenic epitopes in conserved and variable regions. J Virol. 1987 Feb;61(2):570–578. doi: 10.1128/jvi.61.2.570-578.1987. [DOI] [PMC free article] [PubMed] [Google Scholar]
  34. Norrby E., Biberfeld G., Chiodi F., von Gegerfeldt A., Nauclér A., Parks E., Lerner R. Discrimination between antibodies to HIV and to related retroviruses using site-directed serology. Nature. 1987 Sep 17;329(6136):248–250. doi: 10.1038/329248a0. [DOI] [PubMed] [Google Scholar]
  35. Närvänen A., Korkolainen M., Kontio S., Suni J., Turtianen S., Partanen P., Soos J., Vaheri A., Huhtala M. L. Highly immunoreactive antigenic site in a hydrophobic domain of HIV-1 gp41 which remains undetectable with conventional immunochemical methods. AIDS. 1988 Apr;2(2):119–123. doi: 10.1097/00002030-198804000-00008. [DOI] [PubMed] [Google Scholar]
  36. Orskov Lindhardt B., Ulrich K., Ryder L., Dickmeiss E., Sørensen H., Jørgensen J., Jersild C., Grunnet N. HTLV-III antibody testing in three Danish blood banks. Vox Sang. 1986;51 (Suppl 1):9–14. doi: 10.1111/j.1423-0410.1986.tb01987.x. [DOI] [PubMed] [Google Scholar]
  37. Palker T. J., Clark M. E., Langlois A. J., Matthews T. J., Weinhold K. J., Randall R. R., Bolognesi D. P., Haynes B. F. Type-specific neutralization of the human immunodeficiency virus with antibodies to env-encoded synthetic peptides. Proc Natl Acad Sci U S A. 1988 Mar;85(6):1932–1936. doi: 10.1073/pnas.85.6.1932. [DOI] [PMC free article] [PubMed] [Google Scholar]
  38. Palker T. J., Matthews T. J., Clark M. E., Cianciolo G. J., Randall R. R., Langlois A. J., White G. C., Safai B., Snyderman R., Bolognesi D. P. A conserved region at the COOH terminus of human immunodeficiency virus gp120 envelope protein contains an immunodominant epitope. Proc Natl Acad Sci U S A. 1987 Apr;84(8):2479–2483. doi: 10.1073/pnas.84.8.2479. [DOI] [PMC free article] [PubMed] [Google Scholar]
  39. Popovic M., Sarngadharan M. G., Read E., Gallo R. C. Detection, isolation, and continuous production of cytopathic retroviruses (HTLV-III) from patients with AIDS and pre-AIDS. Science. 1984 May 4;224(4648):497–500. doi: 10.1126/science.6200935. [DOI] [PubMed] [Google Scholar]
  40. Ratner L., Haseltine W., Patarca R., Livak K. J., Starcich B., Josephs S. F., Doran E. R., Rafalski J. A., Whitehorn E. A., Baumeister K. Complete nucleotide sequence of the AIDS virus, HTLV-III. Nature. 1985 Jan 24;313(6000):277–284. doi: 10.1038/313277a0. [DOI] [PubMed] [Google Scholar]
  41. Reitz M. S., Jr, Wilson C., Naugle C., Gallo R. C., Robert-Guroff M. Generation of a neutralization-resistant variant of HIV-1 is due to selection for a point mutation in the envelope gene. Cell. 1988 Jul 1;54(1):57–63. doi: 10.1016/0092-8674(88)90179-1. [DOI] [PubMed] [Google Scholar]
  42. Rusche J. R., Javaherian K., McDanal C., Petro J., Lynn D. L., Grimaila R., Langlois A., Gallo R. C., Arthur L. O., Fischinger P. J. Antibodies that inhibit fusion of human immunodeficiency virus-infected cells bind a 24-amino acid sequence of the viral envelope, gp120. Proc Natl Acad Sci U S A. 1988 May;85(9):3198–3202. doi: 10.1073/pnas.85.9.3198. [DOI] [PMC free article] [PubMed] [Google Scholar]
  43. Saiki R. K., Gelfand D. H., Stoffel S., Scharf S. J., Higuchi R., Horn G. T., Mullis K. B., Erlich H. A. Primer-directed enzymatic amplification of DNA with a thermostable DNA polymerase. Science. 1988 Jan 29;239(4839):487–491. doi: 10.1126/science.2448875. [DOI] [PubMed] [Google Scholar]
  44. Skinner M. A., Langlois A. J., McDanal C. B., McDougal J. S., Bolognesi D. P., Matthews T. J. Neutralizing antibodies to an immunodominant envelope sequence do not prevent gp120 binding to CD4. J Virol. 1988 Nov;62(11):4195–4200. doi: 10.1128/jvi.62.11.4195-4200.1988. [DOI] [PMC free article] [PubMed] [Google Scholar]
  45. Stanley K. K., Luzio J. P. Construction of a new family of high efficiency bacterial expression vectors: identification of cDNA clones coding for human liver proteins. EMBO J. 1984 Jun;3(6):1429–1434. doi: 10.1002/j.1460-2075.1984.tb01988.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  46. Till M. A., Zolla-Pazner S., Gorny M. K., Patton J. S., Uhr J. W., Vitetta E. S. Human immunodeficiency virus-infected T cells and monocytes are killed by monoclonal human anti-gp41 antibodies coupled to ricin A chain. Proc Natl Acad Sci U S A. 1989 Mar;86(6):1987–1991. doi: 10.1073/pnas.86.6.1987. [DOI] [PMC free article] [PubMed] [Google Scholar]
  47. Wang J. J., Steel S., Wisniewolski R., Wang C. Y. Detection of antibodies to human T-lymphotropic virus type III by using a synthetic peptide of 21 amino acid residues corresponding to a highly antigenic segment of gp41 envelope protein. Proc Natl Acad Sci U S A. 1986 Aug;83(16):6159–6163. doi: 10.1073/pnas.83.16.6159. [DOI] [PMC free article] [PubMed] [Google Scholar]
  48. Weiss R. A., Clapham P. R., Cheingsong-Popov R., Dalgleish A. G., Carne C. A., Weller I. V., Tedder R. S. Neutralization of human T-lymphotropic virus type III by sera of AIDS and AIDS-risk patients. Nature. 1985 Jul 4;316(6023):69–72. doi: 10.1038/316069a0. [DOI] [PubMed] [Google Scholar]
  49. Weiss R. A., Clapham P. R., Weber J. N., Dalgleish A. G., Lasky L. A., Berman P. W. Variable and conserved neutralization antigens of human immunodeficiency virus. Nature. 1986 Dec 11;324(6097):572–575. doi: 10.1038/324572a0. [DOI] [PubMed] [Google Scholar]
  50. Wendler I., Bienzle U., Hunsmann G. Neutralizing antibodies and the course of HIV-induced disease. AIDS Res Hum Retroviruses. 1987 Summer;3(2):157–163. doi: 10.1089/aid.1987.3.157. [DOI] [PubMed] [Google Scholar]

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