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. 1997 Feb;71(2):925–933. doi: 10.1128/jvi.71.2.925-933.1997

A novel antibody-dependent cellular cytotoxicity epitope in gp120 is identified by two monoclonal antibodies isolated from a long-term survivor of human immunodeficiency virus type 1 infection.

O Alsmadi 1, R Herz 1, E Murphy 1, A Pinter 1, S A Tilley 1
PMCID: PMC191140  PMID: 8995609

Abstract

Two monoclonal antibodies (MAbs), 42F and 43F, were isolated some 14 months apart from a single long-term survivor of human immunodeficiency virus type 1 (HIV-1) infection. These MAbs were found to be indistinguishable in terms of their isotypes, specificities, affinities, and biological activities. Both 42F and 43F directed substantial antibody-dependent cellular cytotoxicity (ADCC) against cells infected with four divergent lab-adapted strains of HIV-1, but no neutralizing activity against these strains was detectable. The ability of MAbs 42F and 43F, as well as that of MAbs against two other gp120 epitopes, to direct ADCC against uninfected CD4+ cells to which recombinant gp120SF2 had been adsorbed (i.e., "innocent bystanders") was demonstrated to be less efficient by at least an order of magnitude than their ability to direct ADCC against HIV-1-infected cells. Flow cytometry analyses showed that 42F and 43F also bind to native primary isolate Envs from clades B and E expressed on cell surfaces. By direct binding and competition assays, it was demonstrated that the 42F/43F epitope lies in a domain of gp120 outside the previously described CD4-binding site and V3 loop ADCC epitope clusters. Immunoblot analysis revealed that the 42F/43F epitope is not dependent on disulfide bonds or N-linked glycans in gp120. Epitope mapping of 42F and 43F by binding to linear peptides demonstrated specificity of these MAbs for a sequence of 10 amino acids in the C5 domain comprising residues 491 to 500 (Los Alamos National Laboratory numbering for the HXB2 strain). Thus, 42F and 43F define a new ADCC epitope in gp120. Because of the relative conservation of this epitope and the fact that it appears to have been significantly immunogenic in the individual from which these MAbs were derived, it may prove to be a useful component of HIV vaccines. Furthermore, these MAbs may be used as tools to probe the potential importance of ADCC as an antiviral activity in HIV-1 infection.

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Selected References

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  1. Belo M., Yagello M., Girard M., Greenlee R., Deslandres A., Barré-Sinoussi F., Gluckman J. C. Antibody-dependent cellular cytotoxicity against HIV-1 in sera of immunized chimpanzees. AIDS. 1991 Feb;5(2):169–176. doi: 10.1097/00002030-199102000-00006. [DOI] [PubMed] [Google Scholar]
  2. 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]
  3. Cao Y., Qin L., Zhang L., Safrit J., Ho D. D. Virologic and immunologic characterization of long-term survivors of human immunodeficiency virus type 1 infection. N Engl J Med. 1995 Jan 26;332(4):201–208. doi: 10.1056/NEJM199501263320401. [DOI] [PubMed] [Google Scholar]
  4. Clerici M., Shearer G. M. The Th1-Th2 hypothesis of HIV infection: new insights. Immunol Today. 1994 Dec;15(12):575–581. doi: 10.1016/0167-5699(94)90220-8. [DOI] [PubMed] [Google Scholar]
  5. Connor R. I., Dinces N. B., Howell A. L., Romet-Lemonne J. L., Pasquali J. L., Fanger M. W. Fc receptors for IgG (Fc gamma Rs) on human monocytes and macrophages are not infectivity receptors for human immunodeficiency virus type 1 (HIV-1): studies using bispecific antibodies to target HIV-1 to various myeloid cell surface molecules, including the Fc gamma R. Proc Natl Acad Sci U S A. 1991 Nov 1;88(21):9593–9597. doi: 10.1073/pnas.88.21.9593. [DOI] [PMC free article] [PubMed] [Google Scholar]
  6. Earl P. L., Hügin A. W., Moss B. Removal of cryptic poxvirus transcription termination signals from the human immunodeficiency virus type 1 envelope gene enhances expression and immunogenicity of a recombinant vaccinia virus. J Virol. 1990 May;64(5):2448–2451. doi: 10.1128/jvi.64.5.2448-2451.1990. [DOI] [PMC free article] [PubMed] [Google Scholar]
  7. Ferrari G., Ottinger J., Place C., Nigida S. M., Jr, Arthur L. O., Weinhold K. J. The impact of HIV-1 infection on phenotypic and functional parameters of cellular immunity in chimpanzees. AIDS Res Hum Retroviruses. 1993 Jul;9(7):647–656. doi: 10.1089/aid.1993.9.647. [DOI] [PubMed] [Google Scholar]
  8. Folks T., Benn S., Rabson A., Theodore T., Hoggan M. D., Martin M., Lightfoote M., Sell K. Characterization of a continuous T-cell line susceptible to the cytopathic effects of the acquired immunodeficiency syndrome (AIDS)-associated retrovirus. Proc Natl Acad Sci U S A. 1985 Jul;82(13):4539–4543. doi: 10.1073/pnas.82.13.4539. [DOI] [PMC free article] [PubMed] [Google Scholar]
  9. Gorny M. K., Xu J. Y., Karwowska S., Buchbinder A., Zolla-Pazner S. Repertoire of neutralizing human monoclonal antibodies specific for the V3 domain of HIV-1 gp120. J Immunol. 1993 Jan 15;150(2):635–643. [PubMed] [Google Scholar]
  10. Homsy J., Meyer M., Tateno M., Clarkson S., Levy J. A. The Fc and not CD4 receptor mediates antibody enhancement of HIV infection in human cells. Science. 1989 Jun 16;244(4910):1357–1360. doi: 10.1126/science.2786647. [DOI] [PubMed] [Google Scholar]
  11. Howell A. L., Guyre P. M., You K., Fanger M. W. Targeting HIV-1 to Fc gamma R on human phagocytes via bispecific antibodies reduces infectivity of HIV-1 to T cells. J Leukoc Biol. 1994 Mar;55(3):385–391. doi: 10.1002/jlb.55.3.385. [DOI] [PubMed] [Google Scholar]
  12. Howell D. N., Andreotti P. E., Dawson J. R., Cresswell P. Natural killing target antigens as inducers of interferon: studies with an immunoselected, natural killing-resistant human T lymphoblastoid cell line. J Immunol. 1985 Feb;134(2):971–976. [PubMed] [Google Scholar]
  13. Karwowska S., Gorny M. K., Buchbinder A., Gianakakos V., Williams C., Fuerst T., Zolla-Pazner S. Production of human monoclonal antibodies specific for conformational and linear non-V3 epitopes of gp120. AIDS Res Hum Retroviruses. 1992 Jun;8(6):1099–1106. doi: 10.1089/aid.1992.8.1099. [DOI] [PubMed] [Google Scholar]
  14. Kostrikis L. G., Cao Y., Ngai H., Moore J. P., Ho D. D. Quantitative analysis of serum neutralization of human immunodeficiency virus type 1 from subtypes A, B, C, D, E, F, and I: lack of direct correlation between neutralization serotypes and genetic subtypes and evidence for prevalent serum-dependent infectivity enhancement. J Virol. 1996 Jan;70(1):445–458. doi: 10.1128/jvi.70.1.445-458.1996. [DOI] [PMC free article] [PubMed] [Google Scholar]
  15. Koup R. A., Safrit J. T., Cao Y., Andrews C. A., McLeod G., Borkowsky W., Farthing C., Ho D. D. Temporal association of cellular immune responses with the initial control of viremia in primary human immunodeficiency virus type 1 syndrome. J Virol. 1994 Jul;68(7):4650–4655. doi: 10.1128/jvi.68.7.4650-4655.1994. [DOI] [PMC free article] [PubMed] [Google Scholar]
  16. Laal S., Burda S., Gorny M. K., Karwowska S., Buchbinder A., Zolla-Pazner S. Synergistic neutralization of human immunodeficiency virus type 1 by combinations of human monoclonal antibodies. J Virol. 1994 Jun;68(6):4001–4008. doi: 10.1128/jvi.68.6.4001-4008.1994. [DOI] [PMC free article] [PubMed] [Google Scholar]
  17. Lee C. N., Robinson J., Cheng Y. L., Essex M., Lee T. H. Influence of deletions in N or C terminus of HIV-1 glycoprotein 120 on binding of infectivity-enhancing antibody. AIDS Res Hum Retroviruses. 1994 Sep;10(9):1065–1069. doi: 10.1089/aid.1994.10.1065. [DOI] [PubMed] [Google Scholar]
  18. Ljunggren K., Moschese V., Broliden P. A., Giaquinto C., Quinti I., Fenyö E. M., Wahren B., Rossi P., Jondal M. Antibodies mediating cellular cytotoxicity and neutralization correlate with a better clinical stage in children born to human immunodeficiency virus-infected mothers. J Infect Dis. 1990 Feb;161(2):198–202. doi: 10.1093/infdis/161.2.198. [DOI] [PubMed] [Google Scholar]
  19. Lyerly H. K., Matthews T. J., Langlois A. J., Bolognesi D. P., Weinhold K. J. Human T-cell lymphotropic virus IIIB glycoprotein (gp120) bound to CD4 determinants on normal lymphocytes and expressed by infected cells serves as target for immune attack. Proc Natl Acad Sci U S A. 1987 Jul;84(13):4601–4605. doi: 10.1073/pnas.84.13.4601. [DOI] [PMC free article] [PubMed] [Google Scholar]
  20. Mabondzo A., Aussage P., Bartholeyns J., Le Naour R., Raoul H., Romet-Lemonne J. L., Dormont D. Bispecific antibody targeting of human immunodeficiency virus type 1 (HIV-1) glycoprotein 41 to human macrophages through the Fc IgG receptor I mediates neutralizing effects in HIV-1 infection. J Infect Dis. 1992 Jul;166(1):93–99. doi: 10.1093/infdis/166.1.93. [DOI] [PubMed] [Google Scholar]
  21. Mabondzo A., Boussin F., Raoul H., Le Naour R., Gras G., Vaslin B., Bartholeyns J., Romet-Lemonne J. L., Dormont D. Antibody-dependent cellular cytotoxicity and neutralization of human immunodeficiency virus type 1 by high affinity cross-linking of gp41 to human macrophage Fc IgG receptor using bispecific antibody. J Gen Virol. 1994 Jun;75(Pt 6):1451–1456. doi: 10.1099/0022-1317-75-6-1451. [DOI] [PubMed] [Google Scholar]
  22. Mascola J. R., Mathieson B. J., Zack P. M., Walker M. C., Halstead S. B., Burke D. S. Summary report: workshop on the potential risks of antibody-dependent enhancement in human HIV vaccine trials. AIDS Res Hum Retroviruses. 1993 Dec;9(12):1175–1184. doi: 10.1089/aid.1993.9.1175. [DOI] [PubMed] [Google Scholar]
  23. Matsushita S., Robert-Guroff M., Rusche J., Koito A., Hattori T., Hoshino H., Javaherian K., Takatsuki K., Putney S. Characterization of a human immunodeficiency virus neutralizing monoclonal antibody and mapping of the neutralizing epitope. J Virol. 1988 Jun;62(6):2107–2114. doi: 10.1128/jvi.62.6.2107-2114.1988. [DOI] [PMC free article] [PubMed] [Google Scholar]
  24. McCutchan F. E., Hegerich P. A., Brennan T. P., Phanuphak P., Singharaj P., Jugsudee A., Berman P. W., Gray A. M., Fowler A. K., Burke D. S. Genetic variants of HIV-1 in Thailand. AIDS Res Hum Retroviruses. 1992 Nov;8(11):1887–1895. doi: 10.1089/aid.1992.8.1887. [DOI] [PubMed] [Google Scholar]
  25. Montefiori D. C., Pantaleo G., Fink L. M., Zhou J. T., Zhou J. Y., Bilska M., Miralles G. D., Fauci A. S. Neutralizing and infection-enhancing antibody responses to human immunodeficiency virus type 1 in long-term nonprogressors. J Infect Dis. 1996 Jan;173(1):60–67. doi: 10.1093/infdis/173.1.60. [DOI] [PubMed] [Google Scholar]
  26. Ojo-Amaize E. A., Nishanian P., Keith D. E., Jr, Houghton R. L., Heitjan D. F., Fahey J. L., Giorgi J. V. Antibodies to human immunodeficiency virus in human sera induce cell-mediated lysis of human immunodeficiency virus-infected cells. J Immunol. 1987 Oct 1;139(7):2458–2463. [PubMed] [Google Scholar]
  27. 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]
  28. Pinter A., Honnen W. J., Racho M. E., Tilley S. A. A potent, neutralizing human monoclonal antibody against a unique epitope overlapping the CD4-binding site of HIV-1 gp120 that is broadly conserved across North American and African virus isolates. AIDS Res Hum Retroviruses. 1993 Oct;9(10):985–996. doi: 10.1089/aid.1993.9.985. [DOI] [PubMed] [Google Scholar]
  29. Pinter A., Honnen W. J., Tilley S. A. Conformational changes affecting the V3 and CD4-binding domains of human immunodeficiency virus type 1 gp120 associated with env processing and with binding of ligands to these sites. J Virol. 1993 Sep;67(9):5692–5697. doi: 10.1128/jvi.67.9.5692-5697.1993. [DOI] [PMC free article] [PubMed] [Google Scholar]
  30. Posner M. R., Elboim H. S., Cannon T., Cavacini L., Hideshima T. Functional activity of an HIV-1 neutralizing IgG human monoclonal antibody: ADCC and complement-mediated lysis. AIDS Res Hum Retroviruses. 1992 May;8(5):553–558. doi: 10.1089/aid.1992.8.553. [DOI] [PubMed] [Google Scholar]
  31. Robinson J. E., Holton D., Pacheco-Morell S., Liu J., McMurdo H. Identification of conserved and variant epitopes of human immunodeficiency virus type 1 (HIV-1) gp120 by human monoclonal antibodies produced by EBV-transformed cell lines. AIDS Res Hum Retroviruses. 1990 May;6(5):567–579. doi: 10.1089/aid.1990.6.567. [DOI] [PubMed] [Google Scholar]
  32. Robinson W. E., Jr, Kawamura T., Gorny M. K., Lake D., Xu J. Y., Matsumoto Y., Sugano T., Masuho Y., Mitchell W. M., Hersh E. Human monoclonal antibodies to the human immunodeficiency virus type 1 (HIV-1) transmembrane glycoprotein gp41 enhance HIV-1 infection in vitro. Proc Natl Acad Sci U S A. 1990 Apr;87(8):3185–3189. doi: 10.1073/pnas.87.8.3185. [DOI] [PMC free article] [PubMed] [Google Scholar]
  33. Sawyer L. A., Katzenstein D. A., Hendry R. M., Boone E. J., Vujcic L. K., Williams C. C., Zeger S. L., Saah A. J., Rinaldo C. R., Jr, Phair J. P. Possible beneficial effects of neutralizing antibodies and antibody-dependent, cell-mediated cytotoxicity in human immunodeficiency virus infection. AIDS Res Hum Retroviruses. 1990 Mar;6(3):341–356. doi: 10.1089/aid.1990.6.341. [DOI] [PubMed] [Google Scholar]
  34. Shang F., Huang H., Revesz K., Chen H. C., Herz R., Pinter A. Characterization of monoclonal antibodies against the human immunodeficiency virus matrix protein, p17gag: identification of epitopes exposed at the surfaces of infected cells. J Virol. 1991 Sep;65(9):4798–4804. doi: 10.1128/jvi.65.9.4798-4804.1991. [DOI] [PMC free article] [PubMed] [Google Scholar]
  35. Sullivan N., Sun Y., Li J., Hofmann W., Sodroski J. Replicative function and neutralization sensitivity of envelope glycoproteins from primary and T-cell line-passaged human immunodeficiency virus type 1 isolates. J Virol. 1995 Jul;69(7):4413–4422. doi: 10.1128/jvi.69.7.4413-4422.1995. [DOI] [PMC free article] [PubMed] [Google Scholar]
  36. Takeda A., Robinson J. E., Ho D. D., Debouck C., Haigwood N. L., Ennis F. A. Distinction of human immunodeficiency virus type 1 neutralization and infection enhancement by human monoclonal antibodies to glycoprotein 120. J Clin Invest. 1992 Jun;89(6):1952–1957. doi: 10.1172/JCI115802. [DOI] [PMC free article] [PubMed] [Google Scholar]
  37. Takeda A., Sweet R. W., Ennis F. A. Two receptors are required for antibody-dependent enhancement of human immunodeficiency virus type 1 infection: CD4 and Fc gamma R. J Virol. 1990 Nov;64(11):5605–5610. doi: 10.1128/jvi.64.11.5605-5610.1990. [DOI] [PMC free article] [PubMed] [Google Scholar]
  38. Tilley S. A., Honnen W. J., Racho M. E., Chou T. C., Pinter A. Synergistic neutralization of HIV-1 by human monoclonal antibodies against the V3 loop and the CD4-binding site of gp120. AIDS Res Hum Retroviruses. 1992 Apr;8(4):461–467. doi: 10.1089/aid.1992.8.461. [DOI] [PubMed] [Google Scholar]
  39. Tilley S. A., Honnen W. J., Racho M. E., Hilgartner M., Pinter A. A human monoclonal antibody against the CD4-binding site of HIV1 gp120 exhibits potent, broadly neutralizing activity. Res Virol. 1991 Jul-Aug;142(4):247–259. doi: 10.1016/0923-2516(91)90010-z. [DOI] [PubMed] [Google Scholar]
  40. Warrier S. V., Pinter A., Honnen W. J., Girard M., Muchmore E., Tilley S. A. A novel, glycan-dependent epitope in the V2 domain of human immunodeficiency virus type 1 gp120 is recognized by a highly potent, neutralizing chimpanzee monoclonal antibody. J Virol. 1994 Jul;68(7):4636–4642. doi: 10.1128/jvi.68.7.4636-4642.1994. [DOI] [PMC free article] [PubMed] [Google Scholar]
  41. Weinhold K. J., Lyerly H. K., Matthews T. J., Tyler D. S., Ahearne P. M., Stine K. C., Langlois A. J., Durack D. T., Bolognesi D. P. Cellular anti-GP120 cytolytic reactivities in HIV-1 seropositive individuals. Lancet. 1988 Apr 23;1(8591):902–905. doi: 10.1016/s0140-6736(88)91713-8. [DOI] [PubMed] [Google Scholar]

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