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. 1995 Jul;96(1):456–464. doi: 10.1172/JCI118056

Secretory leukocyte protease inhibitor: a human saliva protein exhibiting anti-human immunodeficiency virus 1 activity in vitro.

T B McNeely 1, M Dealy 1, D J Dripps 1, J M Orenstein 1, S P Eisenberg 1, S M Wahl 1
PMCID: PMC185219  PMID: 7615818

Abstract

Infection of adherent primary monocytes with HIV-1Ba-L is significantly suppressed in the presence of human saliva. By reverse transcriptase (RT) levels, saliva, although present for only 1 h during monocyte viral exposure, inhibited HIV-1 infectivity for 3 wk after infection, whereas human plasma and synovial fluid failed to inhibit HIV-1 infectivity. Antiviral activity was identified in the saliva soluble fraction, and to determine the factor(s) responsible, individual saliva proteins were examined. Of those proteins examined, only secretory leukocyte protease inhibitor (SLPI) was found to possess anti-HIV-1 activity at physiological concentrations. SLPI anti-HIV-1 activity was dose dependent, with maximal inhibition at 1-10 micrograms/ml (> 90% inhibition of RT activity). SLPI also partially inhibited HIV-1IIIB infection in proliferating human T cells. SLPI appears to target a host cell-associated molecule, since no interaction with viral proteins could be demonstrated. However, SLPI anti-HIV-1 activity was not due to direct interaction with or downregulation of the CD4 antigen. Partial depletion of SLPI in whole saliva resulted in decreased anti-HIV-1 activity of saliva. These data indicate that SLPI has antiretroviral activity and may contribute to the important antiviral activity of saliva associated with the infrequent oral transmission of HIV-1.

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Selected References

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  1. Allen J. B., McCartney-Francis N., Smith P. D., Simon G., Gartner S., Wahl L. M., Popovic M., Wahl S. M. Expression of interleukin 2 receptors by monocytes from patients with acquired immunodeficiency syndrome and induction of monocyte interleukin 2 receptors by human immunodeficiency virus in vitro. J Clin Invest. 1990 Jan;85(1):192–199. doi: 10.1172/JCI114412. [DOI] [PMC free article] [PubMed] [Google Scholar]
  2. Allen J. B., Wong H. L., Guyre P. M., Simon G. L., Wahl S. M. Association of circulating receptor Fc gamma RIII-positive monocytes in AIDS patients with elevated levels of transforming growth factor-beta. J Clin Invest. 1991 May;87(5):1773–1779. doi: 10.1172/JCI115196. [DOI] [PMC free article] [PubMed] [Google Scholar]
  3. Archibald D. W., Cole G. A. In vitro inhibition of HIV-1 infectivity by human salivas. AIDS Res Hum Retroviruses. 1990 Dec;6(12):1425–1432. doi: 10.1089/aid.1990.6.1425. [DOI] [PubMed] [Google Scholar]
  4. Ashorn P. A., Berger E. A., Moss B. Human immunodeficiency virus envelope glycoprotein/CD4-mediated fusion of nonprimate cells with human cells. J Virol. 1990 May;64(5):2149–2156. doi: 10.1128/jvi.64.5.2149-2156.1990. [DOI] [PMC free article] [PubMed] [Google Scholar]
  5. Avril L. E., Di Martino-Ferrer M., Pignede G., Séman M., Gauthier F. Identification of the U-937 membrane-associated proteinase interacting with the V3 loop of HIV-1 gp120 as cathepsin G. FEBS Lett. 1994 May 23;345(1):81–86. doi: 10.1016/0014-5793(94)00410-2. [DOI] [PubMed] [Google Scholar]
  6. Baron S., Niesel D., Singh I. P., McKerlie L., Poast J., Chopra A., Antonelli G., Dianzani F., Coppenhaver D. H. Recently described innate broad spectrum virus inhibitors. Microb Pathog. 1989 Oct;7(4):237–247. doi: 10.1016/0882-4010(89)90042-9. [DOI] [PMC free article] [PubMed] [Google Scholar]
  7. Bergey E. J., Cho M. I., Hammarskjöld M. L., Rekosh D., Levine M. J., Blumberg B. M., Epstein L. G. Aggregation of human immunodeficiency virus type 1 by human salivary secretions. Crit Rev Oral Biol Med. 1993;4(3-4):467–474. doi: 10.1177/10454411930040033001. [DOI] [PubMed] [Google Scholar]
  8. Brigham-Burke M., Edwards J. R., O'Shannessy D. J. Detection of receptor-ligand interactions using surface plasmon resonance: model studies employing the HIV-1 gp120/CD4 interaction. Anal Biochem. 1992 Aug 15;205(1):125–131. doi: 10.1016/0003-2697(92)90588-x. [DOI] [PubMed] [Google Scholar]
  9. Broder C. C., Nussbaum O., Gutheil W. G., Bachovchin W. W., Berger E. A. CD26 antigen and HIV fusion? Science. 1994 May 20;264(5162):1156–1165. doi: 10.1126/science.7909959. [DOI] [PubMed] [Google Scholar]
  10. Callebaut C., Krust B., Jacotot E., Hovanessian A. G. T cell activation antigen, CD26, as a cofactor for entry of HIV in CD4+ cells. Science. 1993 Dec 24;262(5142):2045–2050. doi: 10.1126/science.7903479. [DOI] [PubMed] [Google Scholar]
  11. Campbell E. J., Silverman E. K., Campbell M. A. Elastase and cathepsin G of human monocytes. Quantification of cellular content, release in response to stimuli, and heterogeneity in elastase-mediated proteolytic activity. J Immunol. 1989 Nov 1;143(9):2961–2968. [PubMed] [Google Scholar]
  12. Clapham P. R., Blanc D., Weiss R. A. Specific cell surface requirements for the infection of CD4-positive cells by human immunodeficiency virus types 1 and 2 and by Simian immunodeficiency virus. Virology. 1991 Apr;181(2):703–715. doi: 10.1016/0042-6822(91)90904-P. [DOI] [PMC free article] [PubMed] [Google Scholar]
  13. Clements G. J., Price-Jones M. J., Stephens P. E., Sutton C., Schulz T. F., Clapham P. R., McKeating J. A., McClure M. O., Thomson S., Marsh M. The V3 loops of the HIV-1 and HIV-2 surface glycoproteins contain proteolytic cleavage sites: a possible function in viral fusion? AIDS Res Hum Retroviruses. 1991 Jan;7(1):3–16. doi: 10.1089/aid.1991.7.3. [DOI] [PubMed] [Google Scholar]
  14. Coppenhaver D. H., Baron J. L., McKerlie M. L., Sabados J., Baron S. Size and stability of a naturally occurring virus inhibitor. Antimicrob Agents Chemother. 1984 May;25(5):646–649. doi: 10.1128/aac.25.5.646. [DOI] [PMC free article] [PubMed] [Google Scholar]
  15. Coppenhaver D. H., Sriyuktasuth-Woo P., Baron S., Barr C. E., Qureshi M. N. Correlation of nonspecific antiviral activity with the ability to isolate infectious HIV-1 from saliva. N Engl J Med. 1994 May 5;330(18):1314–1315. doi: 10.1056/NEJM199405053301815. [DOI] [PubMed] [Google Scholar]
  16. Eisenberg S. P., Hale K. K., Heimdal P., Thompson R. C. Location of the protease-inhibitory region of secretory leukocyte protease inhibitor. J Biol Chem. 1990 May 15;265(14):7976–7981. [PubMed] [Google Scholar]
  17. Finberg R. W., Wahl S. M., Allen J. B., Soman G., Strom T. B., Murphy J. R., Nichols J. C. Selective elimination of HIV-1-infected cells with an interleukin-2 receptor-specific cytotoxin. Science. 1991 Jun 21;252(5013):1703–1705. doi: 10.1126/science.1904628. [DOI] [PubMed] [Google Scholar]
  18. Fox P. C., Wolff A., Yeh C. K., Atkinson J. C., Baum B. J. Saliva inhibits HIV-1 infectivity. J Am Dent Assoc. 1988 May;116(6):635–637. doi: 10.14219/jada.archive.1988.0002. [DOI] [PubMed] [Google Scholar]
  19. Fox P. C., Wolff A., Yeh C. K., Atkinson J. C., Baum B. J. Salivary inhibition of HIV-1 infectivity: functional properties and distribution in men, women, and children. J Am Dent Assoc. 1989 Jun;118(6):709–711. doi: 10.14219/jada.archive.1989.0165. [DOI] [PubMed] [Google Scholar]
  20. Friedland G. H., Saltzman B. R., Rogers M. F., Kahl P. A., Lesser M. L., Mayers M. M., Klein R. S. Lack of transmission of HTLV-III/LAV infection to household contacts of patients with AIDS or AIDS-related complex with oral candidiasis. N Engl J Med. 1986 Feb 6;314(6):344–349. doi: 10.1056/NEJM198602063140604. [DOI] [PubMed] [Google Scholar]
  21. Fultz P. N. Components of saliva inactivate human immunodeficiency virus. Lancet. 1986 Nov 22;2(8517):1215–1215. doi: 10.1016/s0140-6736(86)92218-x. [DOI] [PubMed] [Google Scholar]
  22. Gartner S., Markovits P., Markovitz D. M., Kaplan M. H., Gallo R. C., Popovic M. The role of mononuclear phagocytes in HTLV-III/LAV infection. Science. 1986 Jul 11;233(4760):215–219. doi: 10.1126/science.3014648. [DOI] [PubMed] [Google Scholar]
  23. Gerberding J. L., Bryant-LeBlanc C. E., Nelson K., Moss A. R., Osmond D., Chambers H. F., Carlson J. R., Drew W. L., Levy J. A., Sande M. A. Risk of transmitting the human immunodeficiency virus, cytomegalovirus, and hepatitis B virus to health care workers exposed to patients with AIDS and AIDS-related conditions. J Infect Dis. 1987 Jul;156(1):1–8. doi: 10.1093/infdis/156.1.1. [DOI] [PubMed] [Google Scholar]
  24. Gillissen A., Birrer P., McElvaney N. G., Buhl R., Vogelmeier C., Hoyt R. F., Jr, Hubbard R. C., Crystal R. G. Recombinant secretory leukoprotease inhibitor augments glutathione levels in lung epithelial lining fluid. J Appl Physiol (1985) 1993 Aug;75(2):825–832. doi: 10.1152/jappl.1993.75.2.825. [DOI] [PubMed] [Google Scholar]
  25. Hattori T., Koito A., Takatsuki K., Kido H., Katunuma N. Involvement of tryptase-related cellular protease(s) in human immunodeficiency virus type 1 infection. FEBS Lett. 1989 May 8;248(1-2):48–52. doi: 10.1016/0014-5793(89)80429-6. [DOI] [PubMed] [Google Scholar]
  26. Kalebic T., Kinter A., Poli G., Anderson M. E., Meister A., Fauci A. S. Suppression of human immunodeficiency virus expression in chronically infected monocytic cells by glutathione, glutathione ester, and N-acetylcysteine. Proc Natl Acad Sci U S A. 1991 Feb 1;88(3):986–990. doi: 10.1073/pnas.88.3.986. [DOI] [PMC free article] [PubMed] [Google Scholar]
  27. Klein R. S., Phelan J. A., Freeman K., Schable C., Friedland G. H., Trieger N., Steigbigel N. H. Low occupational risk of human immunodeficiency virus infection among dental professionals. N Engl J Med. 1988 Jan 14;318(2):86–90. doi: 10.1056/NEJM198801143180205. [DOI] [PubMed] [Google Scholar]
  28. Kramps J. A., Franken C., Dijkman J. H. ELISA for quantitative measurement of low-molecular-weight bronchial protease inhibitor in human sputum. Am Rev Respir Dis. 1984 Jun;129(6):959–963. doi: 10.1164/arrd.1984.129.6.959. [DOI] [PubMed] [Google Scholar]
  29. Lamkin M. S., Oppenheim F. G. Structural features of salivary function. Crit Rev Oral Biol Med. 1993;4(3-4):251–259. doi: 10.1177/10454411930040030101. [DOI] [PubMed] [Google Scholar]
  30. Lazzarin A., Saracco A., Musicco M., Nicolosi A. Man-to-woman sexual transmission of the human immunodeficiency virus. Risk factors related to sexual behavior, man's infectiousness, and woman's susceptibility. Italian Study Group on HIV Heterosexual Transmission. Arch Intern Med. 1991 Dec;151(12):2411–2416. [PubMed] [Google Scholar]
  31. Lucey E. C., Stone P. J., Ciccolella D. E., Breuer R., Christensen T. G., Thompson R. C., Snider G. L. Recombinant human secretory leukocyte-protease inhibitor: in vitro properties, and amelioration of human neutrophil elastase-induced emphysema and secretory cell metaplasia in the hamster. J Lab Clin Med. 1990 Feb;115(2):224–232. [PubMed] [Google Scholar]
  32. Malamud D., Davis C., Berthold P., Roth E., Friedman H. Human submandibular saliva aggregates HIV. AIDS Res Hum Retroviruses. 1993 Jul;9(7):633–637. doi: 10.1089/aid.1993.9.633. [DOI] [PubMed] [Google Scholar]
  33. Malamud D., Friedman H. M. HIV in the oral cavity: virus, viral inhibitory activity, and antiviral antibodies: a review. Crit Rev Oral Biol Med. 1993;4(3-4):461–466. doi: 10.1177/10454411930040032901. [DOI] [PubMed] [Google Scholar]
  34. Malmqvist M. Biospecific interaction analysis using biosensor technology. Nature. 1993 Jan 14;361(6408):186–187. doi: 10.1038/361186a0. [DOI] [PubMed] [Google Scholar]
  35. Meltzer M. S., Skillman D. R., Gomatos P. J., Kalter D. C., Gendelman H. E. Role of mononuclear phagocytes in the pathogenesis of human immunodeficiency virus infection. Annu Rev Immunol. 1990;8:169–194. doi: 10.1146/annurev.iy.08.040190.001125. [DOI] [PubMed] [Google Scholar]
  36. 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]
  37. Mitsuya H., Looney D. J., Kuno S., Ueno R., Wong-Staal F., Broder S. Dextran sulfate suppression of viruses in the HIV family: inhibition of virion binding to CD4+ cells. Science. 1988 Apr 29;240(4852):646–649. doi: 10.1126/science.2452480. [DOI] [PubMed] [Google Scholar]
  38. Moore B. E., Flaitz C. M., Coppenhaver D. H., Nichols M., Kalmaz G. D., Bessman J. D., Cloyd M. W., Lynch D. P., Prabhakar B. S., Baron S. HIV recovery from saliva before and after dental treatment: inhibitors may have critical role in viral inactivation. J Am Dent Assoc. 1993 Oct;124(10):67–74. doi: 10.14219/jada.archive.1993.0197. [DOI] [PubMed] [Google Scholar]
  39. Moore J. P., Nara P. L. The role of the V3 loop of gp120 in HIV infection. AIDS. 1991;5 (Suppl 2):S21–S33. doi: 10.1097/00002030-199101001-00004. [DOI] [PubMed] [Google Scholar]
  40. Robinovitch M. R., Iversen J. M., Resnick L. Anti-infectivity activity of human salivary secretions toward human immunodeficiency virus. Crit Rev Oral Biol Med. 1993;4(3-4):455–459. doi: 10.1177/10454411930040032801. [DOI] [PubMed] [Google Scholar]
  41. Roederer M., Staal F. J., Raju P. A., Ela S. W., Herzenberg L. A., Herzenberg L. A. Cytokine-stimulated human immunodeficiency virus replication is inhibited by N-acetyl-L-cysteine. Proc Natl Acad Sci U S A. 1990 Jun;87(12):4884–4888. doi: 10.1073/pnas.87.12.4884. [DOI] [PMC free article] [PubMed] [Google Scholar]
  42. Ryser H. J., Levy E. M., Mandel R., DiSciullo G. J. Inhibition of human immunodeficiency virus infection by agents that interfere with thiol-disulfide interchange upon virus-receptor interaction. Proc Natl Acad Sci U S A. 1994 May 10;91(10):4559–4563. doi: 10.1073/pnas.91.10.4559. [DOI] [PMC free article] [PubMed] [Google Scholar]
  43. Stetler G., Brewer M. T., Thompson R. C. Isolation and sequence of a human gene encoding a potent inhibitor of leukocyte proteases. Nucleic Acids Res. 1986 Oct 24;14(20):7883–7896. doi: 10.1093/nar/14.20.7883. [DOI] [PMC free article] [PubMed] [Google Scholar]
  44. Stromatt S. C. Secretory leukocyte protease inhibitor in cystic fibrosis. Agents Actions Suppl. 1993;42:103–110. doi: 10.1007/978-3-0348-7397-0_9. [DOI] [PubMed] [Google Scholar]
  45. 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]
  46. Szebeni J., Wahl S. M., Popovic M., Wahl L. M., Gartner S., Fine R. L., Skaleric U., Friedmann R. M., Weinstein J. N. Dipyridamole potentiates the inhibition by 3'-azido-3'-deoxythymidine and other dideoxynucleosides of human immunodeficiency virus replication in monocyte-macrophages. Proc Natl Acad Sci U S A. 1989 May;86(10):3842–3846. doi: 10.1073/pnas.86.10.3842. [DOI] [PMC free article] [PubMed] [Google Scholar]
  47. Thompson R. C., Ohlsson K. Isolation, properties, and complete amino acid sequence of human secretory leukocyte protease inhibitor, a potent inhibitor of leukocyte elastase. Proc Natl Acad Sci U S A. 1986 Sep;83(18):6692–6696. doi: 10.1073/pnas.83.18.6692. [DOI] [PMC free article] [PubMed] [Google Scholar]
  48. Ueno R., Kuno S. Dextran sulphate, a potent anti-HIV agent in vitro having synergism with zidovudine. Lancet. 1987 Jun 13;1(8546):1379–1379. doi: 10.1016/s0140-6736(87)90681-7. [DOI] [PubMed] [Google Scholar]
  49. VanCott T. C., Loomis L. D., Redfield R. R., Birx D. L. Real-time biospecific interaction analysis of antibody reactivity to peptides from the envelope glycoprotein, gp160, of HIV-1. J Immunol Methods. 1992 Feb 5;146(2):163–176. doi: 10.1016/0022-1759(92)90225-i. [DOI] [PubMed] [Google Scholar]
  50. Wahl L. M., Katona I. M., Wilder R. L., Winter C. C., Haraoui B., Scher I., Wahl S. M. Isolation of human mononuclear cell subsets by counterflow centrifugal elutriation (CCE). I. Characterization of B-lymphocyte-, T-lymphocyte-, and monocyte-enriched fractions by flow cytometric analysis. Cell Immunol. 1984 May;85(2):373–383. doi: 10.1016/0008-8749(84)90251-x. [DOI] [PubMed] [Google Scholar]
  51. Wahl S. M., Allen J. B., Gartner S., Orenstein J. M., Popovic M., Chenoweth D. E., Arthur L. O., Farrar W. L., Wahl L. M. HIV-1 and its envelope glycoprotein down-regulate chemotactic ligand receptors and chemotactic function of peripheral blood monocytes. J Immunol. 1989 May 15;142(10):3553–3559. [PubMed] [Google Scholar]
  52. Wahl S. M., Allen J. B., Wong H. L., Dougherty S. F., Ellingsworth L. R. Antagonistic and agonistic effects of transforming growth factor-beta and IL-1 in rheumatoid synovium. J Immunol. 1990 Oct 15;145(8):2514–2519. [PubMed] [Google Scholar]
  53. Yeh C. K., Handelman B., Fox P. C., Baum B. J. Further studies of salivary inhibition of HIV-1 infectivity. J Acquir Immune Defic Syndr. 1992;5(9):898–903. [PubMed] [Google Scholar]
  54. Yeung S. C., Kazazi F., Randle C. G., Howard R. C., Rizvi N., Downie J. C., Donovan B. J., Cooper D. A., Sekine H., Dwyer D. E. Patients infected with human immunodeficiency virus type 1 have low levels of virus in saliva even in the presence of periodontal disease. J Infect Dis. 1993 Apr;167(4):803–809. doi: 10.1093/infdis/167.4.803. [DOI] [PubMed] [Google Scholar]

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