Abstract
Human immunodeficiency virus (HIV) can be transmitted through infected seminal fluid or vaginal or rectal secretions during heterosexual or homosexual intercourse. To prevent mucosal transmission and spread to the regional lymph nodes, an effective vaccine may need to stimulate immune responses at the genitourinary mucosa. In this study, we have developed a mucosal model of genital immunization in male rhesus macaques, by topical urethral immunization with recombinant simian immunodeficiency virus p27gag, expressed as a hybrid Ty virus-like particle (Ty-VLP) and covalently linked to cholera toxin B subunit. This treatment was augmented by oral immunization with the same vaccine but with added killed cholera vibrios. Polymeric secretory immunoglobulin A (sIgA) and IgG antibodies to p27 were induced in urethral secretions, urine, and seminal fluid. This raises the possibility that the antibodies may function as a primary mucosal defense barrier against SIV (HIV) infection. The regional lymph nodes which constitute the genital-associated lymphoid tissue contained p27-specific CD4+ proliferative and helper T cells for antibody synthesis by B cells, which may function as a secondary immune barrier to infection. Blood and splenic lymphocytes also showed p27-sensitized CD4+ T cells and B cells in addition to serum IgG and IgA p27-specific antibodies; this constitutes a third level of immunity against dissemination of the virus. A comparison of genito-oral with recto-oral and intramuscular routes of immunization suggests that only genito-oral immunization elicits specific sIgA and IgG antibodies in the urine, urethra, and seminal fluid. Both genito-oral and recto-oral immunizations induced T-cell and B-cell immune responses in regional lymph nodes, with preferential IgA antibody synthesis. The mucosal route of immunization may prevent not only virus transmission through the genital mucosa but also dissemination and latency of the virus in the draining lymph nodes.
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Selected References
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- Adams S. E., Dawson K. M., Gull K., Kingsman S. M., Kingsman A. J. The expression of hybrid HIV:Ty virus-like particles in yeast. Nature. 1987 Sep 3;329(6134):68–70. doi: 10.1038/329068a0. [DOI] [PubMed] [Google Scholar]
- Belec L., Georges A. J., Steenman G., Martin P. M. Antibodies to human immunodeficiency virus in the semen of heterosexual men. J Infect Dis. 1989 Feb;159(2):324–327. doi: 10.1093/infdis/159.2.324. [DOI] [PubMed] [Google Scholar]
- Cebra J. J., Komisar J. L., Schweitzer P. A. CH isotype 'switching' during normal B-lymphocyte development. Annu Rev Immunol. 1984;2:493–548. doi: 10.1146/annurev.iy.02.040184.002425. [DOI] [PubMed] [Google Scholar]
- Curran J. W., Morgan W. M., Hardy A. M., Jaffe H. W., Darrow W. W., Dowdle W. R. The epidemiology of AIDS: current status and future prospects. Science. 1985 Sep 27;229(4720):1352–1357. doi: 10.1126/science.2994217. [DOI] [PubMed] [Google Scholar]
- Czerkinsky C., Prince S. J., Michalek S. M., Jackson S., Russell M. W., Moldoveanu Z., McGhee J. R., Mestecky J. IgA antibody-producing cells in peripheral blood after antigen ingestion: evidence for a common mucosal immune system in humans. Proc Natl Acad Sci U S A. 1987 Apr;84(8):2449–2453. doi: 10.1073/pnas.84.8.2449. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Czerkinsky C., Russell M. W., Lycke N., Lindblad M., Holmgren J. Oral administration of a streptococcal antigen coupled to cholera toxin B subunit evokes strong antibody responses in salivary glands and extramucosal tissues. Infect Immun. 1989 Apr;57(4):1072–1077. doi: 10.1128/iai.57.4.1072-1077.1989. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Embretson J., Zupancic M., Beneke J., Till M., Wolinsky S., Ribas J. L., Burke A., Haase A. T. Analysis of human immunodeficiency virus-infected tissues by amplification and in situ hybridization reveals latent and permissive infections at single-cell resolution. Proc Natl Acad Sci U S A. 1993 Jan 1;90(1):357–361. doi: 10.1073/pnas.90.1.357. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Embretson J., Zupancic M., Ribas J. L., Burke A., Racz P., Tenner-Racz K., Haase A. T. Massive covert infection of helper T lymphocytes and macrophages by HIV during the incubation period of AIDS. Nature. 1993 Mar 25;362(6418):359–362. doi: 10.1038/362359a0. [DOI] [PubMed] [Google Scholar]
- Fellowes R., Lehner T. An investigation of the T cell requirements of in vitro antibody forming B cells detected by the ELISPOT assay and a comparison with antibody synthesis. J Immunol Methods. 1990 Sep 14;132(2):165–172. doi: 10.1016/0022-1759(90)90026-r. [DOI] [PubMed] [Google Scholar]
- Homsy J., Thomson-Honnebier G. A., Cheng-Mayer C., Levy J. A. Detection of human immunodeficiency virus (HIV) in serum and body fluids by sequential competition ELISA. J Virol Methods. 1988 Jan;19(1):43–56. doi: 10.1016/0166-0934(88)90006-7. [DOI] [PubMed] [Google Scholar]
- Hussain L. A., Kelly C. G., Fellowes R., Hecht E. M., Wilson J., Chapman M., Lehner T. Expression and gene transcript of Fc receptors for IgG, HLA class II antigens and Langerhans cells in human cervico-vaginal epithelium. Clin Exp Immunol. 1992 Dec;90(3):530–538. doi: 10.1111/j.1365-2249.1992.tb05878.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Hussain L. A., Kelly C. G., Hecht E. M., Fellowes R., Jourdan M., Lehner T. The expression of Fc receptors for immunoglobulin G in human rectal epithelium. AIDS. 1991 Sep;5(9):1089–1094. doi: 10.1097/00002030-199109000-00004. [DOI] [PubMed] [Google Scholar]
- Kawanishi H., Saltzman L. E., Strober W. Characteristics and regulatory function of murine con A-induced, cloned T cells obtained from Peyer's patches and spleen: mechanisms regulating isotype-specific immunoglobulin production by Peyer's patch B cells. J Immunol. 1982 Aug;129(2):475–483. [PubMed] [Google Scholar]
- Kawanishi H., Saltzman L. E., Strober W. Mechanisms regulating IgA class-specific immunoglobulin production in murine gut-associated lymphoid tissues. I. T cells derived from Peyer's patches that switch sIgM B cells to sIgA B cells in vitro. J Exp Med. 1983 Feb 1;157(2):433–450. doi: 10.1084/jem.157.2.433. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Lehner T., Bergmeier L. A., Panagiotidi C., Tao L., Brookes R., Klavinskis L. S., Walker P., Walker J., Ward R. G., Hussain L. Induction of mucosal and systemic immunity to a recombinant simian immunodeficiency viral protein. Science. 1992 Nov 20;258(5086):1365–1369. doi: 10.1126/science.1360702. [DOI] [PubMed] [Google Scholar]
- Lehner T., Brookes R., Panagiotidi C., Tao L., Klavinskis L. S., Walker J., Walker P., Ward R., Hussain L., Gearing J. H. T- and B-cell functions and epitope expression in nonhuman primates immunized with simian immunodeficiency virus antigen by the rectal route. Proc Natl Acad Sci U S A. 1993 Sep 15;90(18):8638–8642. doi: 10.1073/pnas.90.18.8638. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Maghazachi A. A., Phillips-Quagliata J. M. Keyhole limpet hemocyanin-propagated Peyer's patch T cell clones that help IgA responses. J Immunol. 1988 May 15;140(10):3380–3388. [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]
- Mayer K. H., Ayotte D., Groopman J. E., Stoddard A. M., Sarngadharan M., Gallo R. Association of human T lymphotropic virus type III antibodies with sexual and other behaviors in a cohort of homosexual men from Boston with and without generalized lymphadenopathy. Am J Med. 1986 Mar;80(3):357–363. doi: 10.1016/0002-9343(86)90706-0. [DOI] [PubMed] [Google Scholar]
- 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]
- Miller C. J., Alexander N. J., Sutjipto S., Lackner A. A., Gettie A., Hendrickx A. G., Lowenstine L. J., Jennings M., Marx P. A. Genital mucosal transmission of simian immunodeficiency virus: animal model for heterosexual transmission of human immunodeficiency virus. J Virol. 1989 Oct;63(10):4277–4284. doi: 10.1128/jvi.63.10.4277-4284.1989. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Mills H. R., Berry N., Burns N. R., Jones I. M. Simple and efficient production of the core antigens of HIV-1, HIV-2 and simian immunodeficiency virus using pGEX expression vectors in Escherichia coli. AIDS. 1992 Apr;6(4):437–439. [PubMed] [Google Scholar]
- 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]
- Pantaleo G., Graziosi C., Demarest J. F., Butini L., Montroni M., Fox C. H., Orenstein J. M., Kotler D. P., Fauci A. S. HIV infection is active and progressive in lymphoid tissue during the clinically latent stage of disease. Nature. 1993 Mar 25;362(6418):355–358. doi: 10.1038/362355a0. [DOI] [PubMed] [Google Scholar]
- Richman L. K., Graeff A. S., Yarchoan R., Strober W. Simultaneous induction of antigen-specific IgA helper T cells and IgG suppressor T cells in the murine Peyer's patch after protein feeding. J Immunol. 1981 Jun;126(6):2079–2083. [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]
- Temin H. M., Bolognesi D. P. AIDS. Where has HIV been hiding? Nature. 1993 Mar 25;362(6418):292–293. doi: 10.1038/362292a0. [DOI] [PubMed] [Google Scholar]
- Waldman R. H., Stone J., Bergmann K. C., Khakoo R., Lazzell V., Jacknowitz A., Waldman E. R., Howard S. Secretory antibody following oral influenza immunization. Am J Med Sci. 1986 Dec;292(6):367–371. doi: 10.1097/00000441-198612000-00006. [DOI] [PubMed] [Google Scholar]
- Winkelstein W., Jr, Wiley J. A., Padian N., Levy J. Potential for transmission of AIDS-associated retrovirus from bisexual men in San Francisco to their female sexual contacts. JAMA. 1986 Feb 21;255(7):901–901. [PubMed] [Google Scholar]
- Wolff H., Mayer K., Seage G., Politch J., Horsburgh C. R., Anderson D. A comparison of HIV-1 antibody classes, titers, and specificities in paired semen and blood samples from HIV-1 seropositive men. J Acquir Immune Defic Syndr. 1992;5(1):65–69. [PubMed] [Google Scholar]