Abstract
Macaques immunized with uninfected human cells have been shown to be protected from challenge with simian immunodeficiency virus (SIV) propagated in human cells. To identify the potential antigens involved in this protection, macaques were immunized with uninfected human cells, sucrose density gradient-purified culture fluid from uninfected human cells (mock virus), beta-2 microglobulin (beta 2M), immunoaffinity-purified HLA class I and class II proteins from these human cells, and adjuvant. Although all macaques immunized with beta 2M and HLA class I developed high antibody titers to beta 2M, these animals were not protected from a subsequent challenge with infectious SIV grown in human cells. In contrast, the macaques immunized with class II protein (HLA-DR) and mock virus developed antibodies to class II protein and were protected from the intravenous infectious virus challenge. The class II protein- and mock virus-immunized animals which were protected from challenge were given boosters of the appropriate antigen and challenged with the same SIV propagated in macaque cells. All animals became infected, indicating that the protection seen with human class II protein did not extend to protection from infection with SIV containing macaque class II proteins. Since the virus released from SIV-infected macaque cells would contain macaque class II proteins, our results suggest that the initial SIV infected was completely prevented. In addition, the lack of protection from challenge with SIV propagated in macaque cells provided strong evidence that the protection was due to an immune response to the cellular proteins and not to epitopes cross-reactive between class II proteins and the viral proteins, since the identical virus proteins were present in both challenge stocks. These results are the first demonstration that immunization with a purified cellular protein can protect from virus infection.
Full Text
The Full Text of this article is available as a PDF (402.5 KB).
Selected References
These references are in PubMed. This may not be the complete list of references from this article.
- Arthur L. O., Bess J. W., Jr, Sowder R. C., 2nd, Benveniste R. E., Mann D. L., Chermann J. C., Henderson L. E. Cellular proteins bound to immunodeficiency viruses: implications for pathogenesis and vaccines. Science. 1992 Dec 18;258(5090):1935–1938. doi: 10.1126/science.1470916. [DOI] [PubMed] [Google Scholar]
- Arthur L. O., Bess J. W., Jr, Waters D. J., Pyle S. W., Kelliher J. C., Nara P. L., Krohn K., Robey W. G., Langlois A. J., Gallo R. C. Challenge of chimpanzees (Pan troglodytes) immunized with human immunodeficiency virus envelope glycoprotein gp120. J Virol. 1989 Dec;63(12):5046–5053. doi: 10.1128/jvi.63.12.5046-5053.1989. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Azocar J., Essex M. Incorporation of HLA antigens into the envelope of RNA tumor viruses grown in human cells. Cancer Res. 1979 Sep;39(9):3388–3391. [PubMed] [Google Scholar]
- Benveniste R. E., Hill R. W., Eron L. J., Csaikl U. M., Knott W. B., Henderson L. E., Sowder R. C., Nagashima K., Gonda M. A. Characterization of clones of HIV-1 infected HuT 78 cells defective in gag gene processing and of SIV clones producing large amounts of envelope glycoprotein. J Med Primatol. 1990;19(3-4):351–366. [PubMed] [Google Scholar]
- Benveniste R. E., Kuller L., Roodman S. T., Hu S. L., Morton W. R. Long-term protection of macaques against high-dose type D retrovirus challenge after immunization with recombinant vaccinia virus expressing envelope glycoproteins. J Med Primatol. 1993 Feb-May;22(2-3):74–79. [PubMed] [Google Scholar]
- Benveniste R. E., Morton W. R., Clark E. A., Tsai C. C., Ochs H. D., Ward J. M., Kuller L., Knott W. B., Hill R. W., Gale M. J. Inoculation of baboons and macaques with simian immunodeficiency virus/Mne, a primate lentivirus closely related to human immunodeficiency virus type 2. J Virol. 1988 Jun;62(6):2091–2101. doi: 10.1128/jvi.62.6.2091-2101.1988. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Benveniste R. E., Roodman S. T., Hill R. W., Knott W. B., Ribas J. L., Lewis M. G., Eddy G. A. Infectivity of titered doses of simian immunodeficiency virus clone E11S inoculated intravenously into rhesus macaques (Macaca mulatta). J Med Primatol. 1994 Feb-May;23(2-3):83–88. doi: 10.1111/j.1600-0684.1994.tb00106.x. [DOI] [PubMed] [Google Scholar]
- Bess J. W., Jr, Powell P. J., Issaq H. J., Schumack L. J., Grimes M. K., Henderson L. E., Arthur L. O. Tightly bound zinc in human immunodeficiency virus type 1, human T-cell leukemia virus type I, and other retroviruses. J Virol. 1992 Feb;66(2):840–847. doi: 10.1128/jvi.66.2.840-847.1992. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Biberfield G., Putkonen P., Thorstensson R., Norrby E. Prevention of HIV-2 and SIVSM infection in cynomolgus monkeys by active or passive immunization. AIDS Res Hum Retroviruses. 1992 Aug;8(8):1511–1513. doi: 10.1089/aid.1992.8.1511. [DOI] [PubMed] [Google Scholar]
- Brown J. H., Jardetzky T. S., Gorga J. C., Stern L. J., Urban R. G., Strominger J. L., Wiley D. C. Three-dimensional structure of the human class II histocompatibility antigen HLA-DR1. Nature. 1993 Jul 1;364(6432):33–39. doi: 10.1038/364033a0. [DOI] [PubMed] [Google Scholar]
- Bubbers J. E., Lilly F. Selective incorporation of H-2 antigenic determinants into Friend virus particles. Nature. 1977 Mar 31;266(5601):458–459. doi: 10.1038/266458a0. [DOI] [PubMed] [Google Scholar]
- Calafat J., Janssen H., Démant P., Hilgers J., Závada J. Specific selection of host cell glycoproteins during assembly of murine leukaemia virus and vesicular stomatitis virus: presence of Thy-1 glycoprotein and absence of H-2, Pgp-1 and T-200 glycoproteins on the envelopes of these virus particles. J Gen Virol. 1983 Jun;64(Pt 6):1241–1253. doi: 10.1099/0022-1317-64-6-1241. [DOI] [PubMed] [Google Scholar]
- Capobianchi M. R., Fais S., Castilletti C., Gentile M., Ameglio F., Dianzani F. A simple and reliable method to detect cell membrane proteins on infectious human immunodeficiency virus type 1 particles. J Infect Dis. 1994 Apr;169(4):886–889. doi: 10.1093/infdis/169.4.886. [DOI] [PubMed] [Google Scholar]
- Carlson J. R., McGraw T. P., Keddie E., Yee J. L., Rosenthal A., Langlois A. J., Dickover R., Donovan R., Luciw P. A., Jennings M. B. Vaccine protection of rhesus macaques against simian immunodeficiency virus infection. AIDS Res Hum Retroviruses. 1990 Nov;6(11):1239–1246. doi: 10.1089/aid.1990.6.1239. [DOI] [PubMed] [Google Scholar]
- Carrington M., Miller T., White M., Gerrard B., Stewart C., Dean M., Mann D. Typing of HLA-DQA1 and DQB1 using DNA single-strand conformation polymorphism. Hum Immunol. 1992 Mar;33(3):208–212. doi: 10.1016/0198-8859(92)90073-v. [DOI] [PubMed] [Google Scholar]
- Cranage M. P., Baskerville A., Ashworth L. A., Dennis M., Cook N., Sharpe S., Farrar G., Rose J., Kitchin P. A., Greenaway P. J. Intrarectal challenge of macaques vaccinated with formalin-inactivated simian immunodeficiency virus. Lancet. 1992 Feb 1;339(8788):273–274. doi: 10.1016/0140-6736(92)91335-6. [DOI] [PubMed] [Google Scholar]
- Cranage M. P., Polyanskaya N., McBride B., Cook N., Ashworth L. A., Dennis M., Baskerville A., Greenaway P. J., Corcoran T., Kitchin P. Studies on the specificity of the vaccine effect elicited by inactivated simian immunodeficiency virus. AIDS Res Hum Retroviruses. 1993 Jan;9(1):13–22. doi: 10.1089/aid.1993.9.13. [DOI] [PubMed] [Google Scholar]
- Cranage M., Stott J., Mills K., Ashworth T., Taffs F., Farrar G., Chan L., Dennis M., Putkonen P., Biberfeld G. Vaccine studies with the 32H reisolate of SIVmac251: an overview. AIDS Res Hum Retroviruses. 1992 Aug;8(8):1479–1481. doi: 10.1089/aid.1992.8.1479. [DOI] [PubMed] [Google Scholar]
- Daniel M. D., Kirchhoff F., Czajak S. C., Sehgal P. K., Desrosiers R. C. Protective effects of a live attenuated SIV vaccine with a deletion in the nef gene. Science. 1992 Dec 18;258(5090):1938–1941. doi: 10.1126/science.1470917. [DOI] [PubMed] [Google Scholar]
- Desrosiers R. C., Wyand M. S., Kodama T., Ringler D. J., Arthur L. O., Sehgal P. K., Letvin N. L., King N. W., Daniel M. D. Vaccine protection against simian immunodeficiency virus infection. Proc Natl Acad Sci U S A. 1989 Aug;86(16):6353–6357. doi: 10.1073/pnas.86.16.6353. [DOI] [PMC free article] [PubMed] [Google Scholar]
- GREENWOOD F. C., HUNTER W. M., GLOVER J. S. THE PREPARATION OF I-131-LABELLED HUMAN GROWTH HORMONE OF HIGH SPECIFIC RADIOACTIVITY. Biochem J. 1963 Oct;89:114–123. doi: 10.1042/bj0890114. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Gelderblom H., Reupke H., Winkel T., Kunze R., Pauli G. MHC-antigens: constituents of the envelopes of human and simian immunodeficiency viruses. Z Naturforsch C. 1987 Nov-Dec;42(11-12):1328–1334. doi: 10.1515/znc-1987-11-1230. [DOI] [PubMed] [Google Scholar]
- Golding H., Robey F. A., Gates F. T., 3rd, Linder W., Beining P. R., Hoffman T., Golding B. Identification of homologous regions in human immunodeficiency virus I gp41 and human MHC class II beta 1 domain. I. Monoclonal antibodies against the gp41-derived peptide and patients' sera react with native HLA class II antigens, suggesting a role for autoimmunity in the pathogenesis of acquired immune deficiency syndrome. J Exp Med. 1988 Mar 1;167(3):914–923. doi: 10.1084/jem.167.3.914. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Golding H., Shearer G. M., Hillman K., Lucas P., Manischewitz J., Zajac R. A., Clerici M., Gress R. E., Boswell R. N., Golding B. Common epitope in human immunodeficiency virus (HIV) I-GP41 and HLA class II elicits immunosuppressive autoantibodies capable of contributing to immune dysfunction in HIV I-infected individuals. J Clin Invest. 1989 Apr;83(4):1430–1435. doi: 10.1172/JCI114034. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Gorga J. C., Brown J. H., Jardetzky T., Wiley D. C., Strominger J. L. Crystallization of HLA-DR antigens. Res Immunol. 1991 Jun-Aug;142(5-6):401–407. doi: 10.1016/0923-2494(91)90038-k. [DOI] [PubMed] [Google Scholar]
- Gorga J. C., Horejsí V., Johnson D. R., Raghupathy R., Strominger J. L. Purification and characterization of class II histocompatibility antigens from a homozygous human B cell line. J Biol Chem. 1987 Nov 25;262(33):16087–16094. [PubMed] [Google Scholar]
- Hartung S., Norley S. G., Ennen J., Cichutek K., Plesker R., Kurth R. Vaccine protection against SIVmac infection by high- but not low-dose whole inactivated virus immunogen. J Acquir Immune Defic Syndr. 1992;5(5):461–468. [PubMed] [Google Scholar]
- Heeney J. L., de Vries P., Dubbes R., Koornstra W., Niphuis H., ten Haaft P., Boes J., Dings M. E., Morein B., Osterhaus A. D. Comparison of protection from homologous cell-free vs cell-associated SIV challenge afforded by inactivated whole SIV vaccines. J Med Primatol. 1992 Feb-May;21(2-3):126–130. [PubMed] [Google Scholar]
- Henderson L. E., Sowder R., Copeland T. D., Oroszlan S., Arthur L. O., Robey W. G., Fischinger P. J. Direct identification of class II histocompatibility DR proteins in preparations of human T-cell lymphotropic virus type III. J Virol. 1987 Feb;61(2):629–632. doi: 10.1128/jvi.61.2.629-632.1987. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Hoxie J. A., Fitzharris T. P., Youngbar P. R., Matthews D. M., Rackowski J. L., Radka S. F. Nonrandom association of cellular antigens with HTLV-III virions. Hum Immunol. 1987 Jan;18(1):39–52. doi: 10.1016/0198-8859(87)90111-x. [DOI] [PubMed] [Google Scholar]
- Hu S. L., Abrams K., Barber G. N., Moran P., Zarling J. M., Langlois A. J., Kuller L., Morton W. R., Benveniste R. E. Protection of macaques against SIV infection by subunit vaccines of SIV envelope glycoprotein gp160. Science. 1992 Jan 24;255(5043):456–459. doi: 10.1126/science.1531159. [DOI] [PubMed] [Google Scholar]
- Johnson P. R., Montefiori D. C., Goldstein S., Hamm T. E., Zhou J., Kitov S., Haigwood N. L., Misher L., London W. T., Gerin J. L. Inactivated whole SIV vaccine in macaques: evaluation of protective efficacy against challenge with cell-free virus or infected cells. AIDS Res Hum Retroviruses. 1992 Aug;8(8):1501–1505. doi: 10.1089/aid.1992.8.1501. [DOI] [PubMed] [Google Scholar]
- Johnson P. R., Montefiori D. C., Goldstein S., Hamm T. E., Zhou J., Kitov S., Haigwood N. L., Misher L., London W. T., Gerin J. L. Inactivated whole-virus vaccine derived from a proviral DNA clone of simian immunodeficiency virus induces high levels of neutralizing antibodies and confers protection against heterologous challenge. Proc Natl Acad Sci U S A. 1992 Mar 15;89(6):2175–2179. doi: 10.1073/pnas.89.6.2175. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Kiprov D. D., Sheppard H. W., Hanson C. V. Alloimmunization to prevent AIDS? Science. 1994 Feb 11;263(5148):737–738. doi: 10.1126/science.8303282. [DOI] [PubMed] [Google Scholar]
- Lando Z., Sarin P., Megson M., Greene W. C., Waldman T. A., Gallo R. C., Broder S. Association of human T-cell leukaemia/lymphoma virus with the Tac antigen marker for the human T-cell growth factor receptor. Nature. 1983 Oct 20;305(5936):733–736. doi: 10.1038/305733a0. [DOI] [PubMed] [Google Scholar]
- Le Grand R., Vogt G., Vaslin B., Roques P., Théodoro F., Aubertin A. M., Dormont D. Specific and non-specific immunity and protection of macaques against SIV infection. Vaccine. 1992;10(12):873–879. doi: 10.1016/0264-410x(92)90052-l. [DOI] [PubMed] [Google Scholar]
- Marthas M. L., Miller C. J., Sutjipto S., Higgins J., Torten J., Lohman B. L., Unger R. E., Ramos R. A., Kiyono H., McGhee J. R. Efficacy of live-attenuated and whole-inactivated simian immunodeficiency virus vaccines against vaginal challenge with virulent SIV. J Med Primatol. 1992 Feb-May;21(2-3):99–107. [PubMed] [Google Scholar]
- Marx P. A., Compans R. W., Gettie A., Staas J. K., Gilley R. M., Mulligan M. J., Yamshchikov G. V., Chen D., Eldridge J. H. Protection against vaginal SIV transmission with microencapsulated vaccine. Science. 1993 May 28;260(5112):1323–1327. doi: 10.1126/science.8493576. [DOI] [PubMed] [Google Scholar]
- Meerloo T., Parmentier H. K., Osterhaus A. D., Goudsmit J., Schuurman H. J. Modulation of cell surface molecules during HIV-1 infection of H9 cells. An immunoelectron microscopic study. AIDS. 1992 Oct;6(10):1105–1116. doi: 10.1097/00002030-199210000-00007. [DOI] [PubMed] [Google Scholar]
- Meerloo T., Sheikh M. A., Bloem A. C., de Ronde A., Schutten M., van Els C. A., Roholl P. J., Joling P., Goudsmit J., Schuurman H. J. Host cell membrane proteins on human immunodeficiency virus type 1 after in vitro infection of H9 cells and blood mononuclear cells. An immuno-electron microscopic study. J Gen Virol. 1993 Jan;74(Pt 1):129–135. doi: 10.1099/0022-1317-74-1-129. [DOI] [PubMed] [Google Scholar]
- Mills K. H., Page M., Chan W. L., Kitchin P., Stott E. J., Taffs F., Jones W., Rose J., Ling C., Silvera P. Protection against SIV infection in macaques by immunization with inactivated virus from the BK28 molecular clone, but not with BK28-derived recombinant env and gag proteins. J Med Primatol. 1992 Feb-May;21(2-3):50–58. [PubMed] [Google Scholar]
- Murphey-Corb M., Martin L. N., Davison-Fairburn B., Montelaro R. C., Miller M., West M., Ohkawa S., Baskin G. B., Zhang J. Y., Putney S. D. A formalin-inactivated whole SIV vaccine confers protection in macaques. Science. 1989 Dec 8;246(4935):1293–1297. doi: 10.1126/science.2555923. [DOI] [PubMed] [Google Scholar]
- Murphey-Corb M., Ohkawa S., Davison-Fairburn B., Martin L. N., Baskin G. B., Langlois A. J., McIntee M., Narayan O., Gardner M. B. A formalin-fixed whole SIV vaccine induces protective responses that are cross-protective and durable. AIDS Res Hum Retroviruses. 1992 Aug;8(8):1475–1478. doi: 10.1089/aid.1992.8.1475. [DOI] [PubMed] [Google Scholar]
- Orentas R. J., Hildreth J. E. Association of host cell surface adhesion receptors and other membrane proteins with HIV and SIV. AIDS Res Hum Retroviruses. 1993 Nov;9(11):1157–1165. doi: 10.1089/aid.1993.9.1157. [DOI] [PubMed] [Google Scholar]
- Putkonen P., Nilsson C., Hild K., Benthin R., Cranage M., Aubertin A. M., Biberfeld G. Whole inactivated SIV vaccine grown on human cells fails to protect against homologous SIV grown on simian cells. J Med Primatol. 1993 Feb-May;22(2-3):100–103. [PubMed] [Google Scholar]
- Putkonen P., Thorstensson R., Cranage M., Nilsson C., Ghavamzadeh L., Albert J., Greenaway P., Biberfeld G. A formalin inactivated whole SIVmac vaccine in Ribi adjuvant protects against homologous and heterologous SIV challenge. J Med Primatol. 1992 Feb-May;21(2-3):108–112. [PubMed] [Google Scholar]
- Schols D., Pauwels R., Desmyter J., De Clercq E. Presence of class II histocompatibility DR proteins on the envelope of human immunodeficiency virus demonstrated by FACS analysis. Virology. 1992 Jul;189(1):374–376. doi: 10.1016/0042-6822(92)90719-6. [DOI] [PubMed] [Google Scholar]
- Shafferman A., Jahrling P. B., Benveniste R. E., Lewis M. G., Phipps T. J., Eden-McCutchan F., Sadoff J., Eddy G. A., Burke D. S. Protection of macaques with a simian immunodeficiency virus envelope peptide vaccine based on conserved human immunodeficiency virus type 1 sequences. Proc Natl Acad Sci U S A. 1991 Aug 15;88(16):7126–7130. doi: 10.1073/pnas.88.16.7126. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Shearer G. M., Clerici M., Dalgleish A. Alloimmunization as an AIDS vaccine? Science. 1993 Oct 8;262(5131):161–162. doi: 10.1126/science.8211133. [DOI] [PubMed] [Google Scholar]
- Stahl-Hennig C., Voss G., Dittmer U., Coulibaly C., Petry H., Makoschey B., Cranage M. P., Aubertin A. M., Lüke W., Hunsmann G. Protection of monkeys by a split vaccine against SIVmac depends upon biological properties of the challenge virus. AIDS. 1993 Jun;7(6):787–795. doi: 10.1097/00002030-199306000-00005. [DOI] [PubMed] [Google Scholar]
- Stahl-Hennig C., Voss G., Nick S., Petry H., Fuchs D., Wachter H., Coulibaly C., Lüke W., Hunsmann G. Immunization with tween-ether-treated SIV adsorbed onto aluminum hydroxide protects monkeys against experimental SIV infection. Virology. 1992 Feb;186(2):588–596. doi: 10.1016/0042-6822(92)90025-k. [DOI] [PubMed] [Google Scholar]
- Stott E. J. Anti-cell antibody in macaques. Nature. 1991 Oct 3;353(6343):393–393. doi: 10.1038/353393a0. [DOI] [PubMed] [Google Scholar]
- Sutjipto S., Pedersen N. C., Miller C. J., Gardner M. B., Hanson C. V., Gettie A., Jennings M., Higgins J., Marx P. A. Inactivated simian immunodeficiency virus vaccine failed to protect rhesus macaques from intravenous or genital mucosal infection but delayed disease in intravenously exposed animals. J Virol. 1990 May;64(5):2290–2297. doi: 10.1128/jvi.64.5.2290-2297.1990. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Voss G., Stahl-Hennig C., Petry H., Coulibaly C., Nick S., Fuchs D., Wachter H., Lüke W., Hunsmann G. Immunization of rhesus monkeys with high- and low-dose Tween-ether-disrupted SIVMAC. AIDS Res Hum Retroviruses. 1992 Aug;8(8):1397–1400. doi: 10.1089/aid.1992.8.1397. [DOI] [PubMed] [Google Scholar]
- Warren J. T., Dolatshahi M. First updated and revised survey of worldwide HIV and SIV vaccine challenge studies in nonhuman primates: progress in first and second order studies. J Med Primatol. 1993 Feb-May;22(2-3):203–235. [PubMed] [Google Scholar]
- Young J. A., Bates P., Willert K., Varmus H. E. Efficient incorporation of human CD4 protein into avian leukosis virus particles. Science. 1990 Dec 7;250(4986):1421–1423. doi: 10.1126/science.2175047. [DOI] [PubMed] [Google Scholar]
