Skip to main content
Journal of Virology logoLink to Journal of Virology
. 1995 Nov;69(11):6678–6686. doi: 10.1128/jvi.69.11.6678-6686.1995

Mucosal model of immunization against human immunodeficiency virus type 1 with a chimeric influenza virus.

T Muster 1, B Ferko 1, A Klima 1, M Purtscher 1, A Trkola 1, P Schulz 1, A Grassauer 1, O G Engelhardt 1, A García-Sástre 1, P Palese 1, et al.
PMCID: PMC189577  PMID: 7474077

Abstract

Previously, we constructed a chimeric influenza virus that expresses the highly conserved amino acid sequence ELDKWA of gp41 of human immunodeficiency virus type 1 (HIV-1). Antisera elicited in mice by infection with this chimeric virus showed neutralizing activity against distantly related HIV-1 isolates (T. Muster, R. Guinea, A. Trkola, M. Purtscher, A. Klima, F. Steindl, P. Palese, and H. Katinger, J. Virol. 68:4031-4034, 1994). In the present study, we demonstrated that intranasal immunizations with this chimeric virus are also able to induce a humoral immune response at the mucosal level. The immunized mice had ELDKWA-specific immunoglobulins A in respiratory, intestinal, and vaginal secretions. Sustained levels of these secretory immunoglobulins A were detectable for more than 1 year after immunization. The results show that influenza virus can be used to efficiently induce secretory antibodies against antigens from foreign pathogens. Since long-lasting mucosal immunity in the genital and intestinal tracts might be essential for protective immunity against HIV-1, influenza virus appears to be a promising vector for HIV-1-derived immunogens.

Full Text

The Full Text of this article is available as a PDF (1.2 MB).

Selected References

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

  1. Adachi A., Koenig S., Gendelman H. E., Daugherty D., Gattoni-Celli S., Fauci A. S., Martin M. A. Productive, persistent infection of human colorectal cell lines with human immunodeficiency virus. J Virol. 1987 Jan;61(1):209–213. doi: 10.1128/jvi.61.1.209-213.1987. [DOI] [PMC free article] [PubMed] [Google Scholar]
  2. Beagley K. W., Eldridge J. H., Lee F., Kiyono H., Everson M. P., Koopman W. J., Hirano T., Kishimoto T., McGhee J. R. Interleukins and IgA synthesis. Human and murine interleukin 6 induce high rate IgA secretion in IgA-committed B cells. J Exp Med. 1989 Jun 1;169(6):2133–2148. doi: 10.1084/jem.169.6.2133. [DOI] [PMC free article] [PubMed] [Google Scholar]
  3. Brandtzaeg P. Overview of the mucosal immune system. Curr Top Microbiol Immunol. 1989;146:13–25. doi: 10.1007/978-3-642-74529-4_2. [DOI] [PubMed] [Google Scholar]
  4. Buchacher A., Predl R., Strutzenberger K., Steinfellner W., Trkola A., Purtscher M., Gruber G., Tauer C., Steindl F., Jungbauer A. Generation of human monoclonal antibodies against HIV-1 proteins; electrofusion and Epstein-Barr virus transformation for peripheral blood lymphocyte immortalization. AIDS Res Hum Retroviruses. 1994 Apr;10(4):359–369. doi: 10.1089/aid.1994.10.359. [DOI] [PubMed] [Google Scholar]
  5. Castrucci M. R., Hou S., Doherty P. C., Kawaoka Y. Protection against lethal lymphocytic choriomeningitis virus (LCMV) infection by immunization of mice with an influenza virus containing an LCMV epitope recognized by cytotoxic T lymphocytes. J Virol. 1994 Jun;68(6):3486–3490. doi: 10.1128/jvi.68.6.3486-3490.1994. [DOI] [PMC free article] [PubMed] [Google Scholar]
  6. Clements M. L., Betts R. F., Tierney E. L., Murphy B. R. Serum and nasal wash antibodies associated with resistance to experimental challenge with influenza A wild-type virus. J Clin Microbiol. 1986 Jul;24(1):157–160. doi: 10.1128/jcm.24.1.157-160.1986. [DOI] [PMC free article] [PubMed] [Google Scholar]
  7. Clements M. L., Murphy B. R. Development and persistence of local and systemic antibody responses in adults given live attenuated or inactivated influenza A virus vaccine. J Clin Microbiol. 1986 Jan;23(1):66–72. doi: 10.1128/jcm.23.1.66-72.1986. [DOI] [PMC free article] [PubMed] [Google Scholar]
  8. Conley A. J., Kessler J. A., 2nd, Boots L. J., Tung J. S., Arnold B. A., Keller P. M., Shaw A. R., Emini E. A. Neutralization of divergent human immunodeficiency virus type 1 variants and primary isolates by IAM-41-2F5, an anti-gp41 human monoclonal antibody. Proc Natl Acad Sci U S A. 1994 Apr 12;91(8):3348–3352. doi: 10.1073/pnas.91.8.3348. [DOI] [PMC free article] [PubMed] [Google Scholar]
  9. Czerkinsky C. C., Nilsson L. A., Nygren H., Ouchterlony O., Tarkowski A. A solid-phase enzyme-linked immunospot (ELISPOT) assay for enumeration of specific antibody-secreting cells. J Immunol Methods. 1983 Dec 16;65(1-2):109–121. doi: 10.1016/0022-1759(83)90308-3. [DOI] [PubMed] [Google Scholar]
  10. Enami M., Luytjes W., Krystal M., Palese P. Introduction of site-specific mutations into the genome of influenza virus. Proc Natl Acad Sci U S A. 1990 May;87(10):3802–3805. doi: 10.1073/pnas.87.10.3802. [DOI] [PMC free article] [PubMed] [Google Scholar]
  11. Enami M., Palese P. High-efficiency formation of influenza virus transfectants. J Virol. 1991 May;65(5):2711–2713. doi: 10.1128/jvi.65.5.2711-2713.1991. [DOI] [PMC free article] [PubMed] [Google Scholar]
  12. Fantini J., Yahi N., Chermann J. C. Human immunodeficiency virus can infect the apical and basolateral surfaces of human colonic epithelial cells. Proc Natl Acad Sci U S A. 1991 Oct 15;88(20):9297–9301. doi: 10.1073/pnas.88.20.9297. [DOI] [PMC free article] [PubMed] [Google Scholar]
  13. Feng N., Burns J. W., Bracy L., Greenberg H. B. Comparison of mucosal and systemic humoral immune responses and subsequent protection in mice orally inoculated with a homologous or a heterologous rotavirus. J Virol. 1994 Dec;68(12):7766–7773. doi: 10.1128/jvi.68.12.7766-7773.1994. [DOI] [PMC free article] [PubMed] [Google Scholar]
  14. Fujihashi K., Taguchi T., Aicher W. K., McGhee J. R., Bluestone J. A., Eldridge J. H., Kiyono H. Immunoregulatory functions for murine intraepithelial lymphocytes: gamma/delta T cell receptor-positive (TCR+) T cells abrogate oral tolerance, while alpha/beta TCR+ T cells provide B cell help. J Exp Med. 1992 Mar 1;175(3):695–707. doi: 10.1084/jem.175.3.695. [DOI] [PMC free article] [PubMed] [Google Scholar]
  15. Furuta Y., Eriksson K., Svennerholm B., Fredman P., Horal P., Jeansson S., Vahlne A., Holmgren J., Czerkinsky C. Infection of vaginal and colonic epithelial cells by the human immunodeficiency virus type 1 is neutralized by antibodies raised against conserved epitopes in the envelope glycoprotein gp120. Proc Natl Acad Sci U S A. 1994 Dec 20;91(26):12559–12563. doi: 10.1073/pnas.91.26.12559. [DOI] [PMC free article] [PubMed] [Google Scholar]
  16. García-Sastre A., Muster T., Barclay W. S., Percy N., Palese P. Use of a mammalian internal ribosomal entry site element for expression of a foreign protein by a transfectant influenza virus. J Virol. 1994 Oct;68(10):6254–6261. doi: 10.1128/jvi.68.10.6254-6261.1994. [DOI] [PMC free article] [PubMed] [Google Scholar]
  17. Johnson P. R., Feldman S., Thompson J. M., Mahoney J. D., Wright P. F. Immunity to influenza A virus infection in young children: a comparison of natural infection, live cold-adapted vaccine, and inactivated vaccine. J Infect Dis. 1986 Jul;154(1):121–127. doi: 10.1093/infdis/154.1.121. [DOI] [PubMed] [Google Scholar]
  18. KERR W. R., ROBERTSON M. Active and passive sensitization of the uterus of the cow in vivo against Trichomonas foetus antigen and the evidence for the local production of antibody in that site. J Hyg (Lond) 1953 Sep;51(3):405–415. doi: 10.1017/s0022172400015825. [DOI] [PMC free article] [PubMed] [Google Scholar]
  19. Li S., Polonis V., Isobe H., Zaghouani H., Guinea R., Moran T., Bona C., Palese P. Chimeric influenza virus induces neutralizing antibodies and cytotoxic T cells against human immunodeficiency virus type 1. J Virol. 1993 Nov;67(11):6659–6666. doi: 10.1128/jvi.67.11.6659-6666.1993. [DOI] [PMC free article] [PubMed] [Google Scholar]
  20. Li S., Rodrigues M., Rodriguez D., Rodriguez J. R., Esteban M., Palese P., Nussenzweig R. S., Zavala F. Priming with recombinant influenza virus followed by administration of recombinant vaccinia virus induces CD8+ T-cell-mediated protective immunity against malaria. Proc Natl Acad Sci U S A. 1993 Jun 1;90(11):5214–5218. doi: 10.1073/pnas.90.11.5214. [DOI] [PMC free article] [PubMed] [Google Scholar]
  21. Liew F. Y., Russell S. M., Appleyard G., Brand C. M., Beale J. Cross-protection in mice infected with influenza A virus by the respiratory route is correlated with local IgA antibody rather than serum antibody or cytotoxic T cell reactivity. Eur J Immunol. 1984 Apr;14(4):350–356. doi: 10.1002/eji.1830140414. [DOI] [PubMed] [Google Scholar]
  22. 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]
  23. Mathijs J. M., Hing M., Grierson J., Dwyer D. E., Goldschmidt C., Cooper D. A., Cunningham A. L. HIV infection of rectal mucosa. Lancet. 1988 May 14;1(8594):1111–1111. doi: 10.1016/s0140-6736(88)91932-0. [DOI] [PubMed] [Google Scholar]
  24. Mazanec M. B., Coudret C. L., Fletcher D. R. Intracellular neutralization of influenza virus by immunoglobulin A anti-hemagglutinin monoclonal antibodies. J Virol. 1995 Feb;69(2):1339–1343. doi: 10.1128/jvi.69.2.1339-1343.1995. [DOI] [PMC free article] [PubMed] [Google Scholar]
  25. Mazanec M. B., Kaetzel C. S., Lamm M. E., Fletcher D., Nedrud J. G. Intracellular neutralization of virus by immunoglobulin A antibodies. Proc Natl Acad Sci U S A. 1992 Aug 1;89(15):6901–6905. doi: 10.1073/pnas.89.15.6901. [DOI] [PMC free article] [PubMed] [Google Scholar]
  26. McDermott M. R., Smiley J. R., Leslie P., Brais J., Rudzroga H. E., Bienenstock J. Immunity in the female genital tract after intravaginal vaccination of mice with an attenuated strain of herpes simplex virus type 2. J Virol. 1984 Sep;51(3):747–753. doi: 10.1128/jvi.51.3.747-753.1984. [DOI] [PMC free article] [PubMed] [Google Scholar]
  27. McGhee J. R., Kiyono H. New perspectives in vaccine development: mucosal immunity to infections. Infect Agents Dis. 1993 Apr;2(2):55–73. [PubMed] [Google Scholar]
  28. Mega J., Bruce M. G., Beagley K. W., McGhee J. R., Taguchi T., Pitts A. M., McGhee M. L., Bucy R. P., Eldridge J. H., Mestecky J. Regulation of mucosal responses by CD4+ T lymphocytes: effects of anti-L3T4 treatment on the gastrointestinal immune system. Int Immunol. 1991 Aug;3(8):793–805. doi: 10.1093/intimm/3.8.793. [DOI] [PubMed] [Google Scholar]
  29. Meitin C. A., Bender B. S., Small P. A., Jr Enteric immunization of mice against influenza with recombinant vaccinia. Proc Natl Acad Sci U S A. 1994 Nov 8;91(23):11187–11191. doi: 10.1073/pnas.91.23.11187. [DOI] [PMC free article] [PubMed] [Google Scholar]
  30. Mestecky J., Kutteh W. H., Jackson S. Mucosal immunity in the female genital tract: relevance to vaccination efforts against the human immunodeficiency virus. AIDS Res Hum Retroviruses. 1994;10 (Suppl 2):S11–S20. [PubMed] [Google Scholar]
  31. Milligan G. N., Bernstein D. I. Generation of humoral immune responses against herpes simplex virus type 2 in the murine female genital tract. Virology. 1995 Jan 10;206(1):234–241. doi: 10.1016/s0042-6822(95)80038-7. [DOI] [PubMed] [Google Scholar]
  32. Muster T., Guinea R., Trkola A., Purtscher M., Klima A., Steindl F., Palese P., Katinger H. Cross-neutralizing activity against divergent human immunodeficiency virus type 1 isolates induced by the gp41 sequence ELDKWAS. J Virol. 1994 Jun;68(6):4031–4034. doi: 10.1128/jvi.68.6.4031-4034.1994. [DOI] [PMC free article] [PubMed] [Google Scholar]
  33. Muster T., Steindl F., Purtscher M., Trkola A., Klima A., Himmler G., Rüker F., Katinger H. A conserved neutralizing epitope on gp41 of human immunodeficiency virus type 1. J Virol. 1993 Nov;67(11):6642–6647. doi: 10.1128/jvi.67.11.6642-6647.1993. [DOI] [PMC free article] [PubMed] [Google Scholar]
  34. Muster T., Subbarao E. K., Enami M., Murphy B. R., Palese P. An influenza A virus containing influenza B virus 5' and 3' noncoding regions on the neuraminidase gene is attenuated in mice. Proc Natl Acad Sci U S A. 1991 Jun 15;88(12):5177–5181. doi: 10.1073/pnas.88.12.5177. [DOI] [PMC free article] [PubMed] [Google Scholar]
  35. Ogra P. L., Ogra S. S. Local antibody response to poliovaccine in the human female genital tract. J Immunol. 1973 May;110(5):1307–1311. [PubMed] [Google Scholar]
  36. Percy N., Barclay W. S., García-Sastre A., Palese P. Expression of a foreign protein by influenza A virus. J Virol. 1994 Jul;68(7):4486–4492. doi: 10.1128/jvi.68.7.4486-4492.1994. [DOI] [PMC free article] [PubMed] [Google Scholar]
  37. Purtscher M., Trkola A., Gruber G., Buchacher A., Predl R., Steindl F., Tauer C., Berger R., Barrett N., Jungbauer A. A broadly neutralizing human monoclonal antibody against gp41 of human immunodeficiency virus type 1. AIDS Res Hum Retroviruses. 1994 Dec;10(12):1651–1658. doi: 10.1089/aid.1994.10.1651. [DOI] [PubMed] [Google Scholar]
  38. Renegar K. B., Small P. A., Jr Immunoglobulin A mediation of murine nasal anti-influenza virus immunity. J Virol. 1991 Apr;65(4):2146–2148. doi: 10.1128/jvi.65.4.2146-2148.1991. [DOI] [PMC free article] [PubMed] [Google Scholar]
  39. Rodrigues M., Li S., Murata K., Rodriguez D., Rodriguez J. R., Bacik I., Bennink J. R., Yewdell J. W., Garcia-Sastre A., Nussenzweig R. S. Influenza and vaccinia viruses expressing malaria CD8+ T and B cell epitopes. Comparison of their immunogenicity and capacity to induce protective immunity. J Immunol. 1994 Nov 15;153(10):4636–4648. [PubMed] [Google Scholar]
  40. Schulman J. L., Palese P. Virulence factors of influenza A viruses: WSN virus neuraminidase required for plaque production in MDBK cells. J Virol. 1977 Oct;24(1):170–176. doi: 10.1128/jvi.24.1.170-176.1977. [DOI] [PMC free article] [PubMed] [Google Scholar]
  41. Staats H. F., Jackson R. J., Marinaro M., Takahashi I., Kiyono H., McGhee J. R. Mucosal immunity to infection with implications for vaccine development. Curr Opin Immunol. 1994 Aug;6(4):572–583. doi: 10.1016/0952-7915(94)90144-9. [DOI] [PubMed] [Google Scholar]
  42. Taguchi T., McGhee J. R., Coffman R. L., Beagley K. W., Eldridge J. H., Takatsu K., Kiyono H. Analysis of Th1 and Th2 cells in murine gut-associated tissues. Frequencies of CD4+ and CD8+ T cells that secrete IFN-gamma and IL-5. J Immunol. 1990 Jul 1;145(1):68–77. [PubMed] [Google Scholar]
  43. Trkola A., Pomales A. B., Yuan H., Korber B., Maddon P. J., Allaway G. P., Katinger H., Barbas C. F., 3rd, Burton D. R., Ho D. D. Cross-clade neutralization of primary isolates of human immunodeficiency virus type 1 by human monoclonal antibodies and tetrameric CD4-IgG. J Virol. 1995 Nov;69(11):6609–6617. doi: 10.1128/jvi.69.11.6609-6617.1995. [DOI] [PMC free article] [PubMed] [Google Scholar]
  44. Wu H. Y., Russell M. W. Induction of mucosal immunity by intranasal application of a streptococcal surface protein antigen with the cholera toxin B subunit. Infect Immun. 1993 Jan;61(1):314–322. doi: 10.1128/iai.61.1.314-322.1993. [DOI] [PMC free article] [PubMed] [Google Scholar]
  45. deVos T., Dick T. A. A rapid method to determine the isotype and specificity of coproantibodies in mice infected with Trichinella or fed cholera toxin. J Immunol Methods. 1991 Aug 9;141(2):285–288. doi: 10.1016/0022-1759(91)90155-9. [DOI] [PubMed] [Google Scholar]

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

RESOURCES