This review summarizes the data on the anti-human immunodeficiency virus (HIV) activity associated with saliva and the possible routes of oral transmission of HIV. Saliva can be passed from an HIV-infected individual to an uninfected person via sexual or non-sexual activities. The relative risk of HIV transmission through saliva is a subject of continuing concern for dental practitioners. HIV-infected individuals frequently have oral lesions that can cause bleeding and release of the virus into the oral cavity. In addition, viral p24 and HIV-1 RNA were detected in tonsils and adenoids even in asymptomatic seropositive individuals. Nevertheless, the potential HIV-infectivity of saliva is low, although both infectious HIV-1 and HIV DNA have been detected in saliva. This observation has led to the suggestion that saliva may contain factors that inhibit HIV-1 infectivity. At least two anti-HIV activities have been partially characterized: (i) physical entrapment of HIV by high-molecular-weight molecules (e.g., mucins), and (ii) inhibition of viral infection by soluble proteins. Several studies have indicated that, of the salivary proteins evaluated, recombinant secretory leukocyte protease inhibitor (rSLPI) could inhibit HIV-1 infection in macrophages at physiological concentrations. The anti-HIV activity of the serine protease inhibitor rSLPI is most likely due to its interaction with a cell-surface molecule(s) other than the primary HIV-1 receptor, CD4, and may involve (i) inhibition of cell-surface serine protease(s), and/or (ii) interaction with other human-specific co-factors essential for viral entry.
Adachi A., Koenig S., Gendelman HE, Daugherty D., Gattoni-Celli S., Fauci AS, et al. (1987). Productive, persistent infection of human colorectal cell lines with human immunodeficiency virus. J Virol61:209-213.
2.
Archibald DW, Cole GA ( 1990). In vitro inhibition of HIV-1 infectivity by human salivas . AIDS Res Hum Retroviruses6:1425-1432.
3.
Avril LE, di Martino-Ferrer M., Brillard-Bourdet M., Gauthier F. (1995). Inhibition of U-937 membrane-associated cathepsin G by gpl20 (IIIB) and V3 loop-derived peptides from several strains of HIV-1 . FEBS Lett367:251-256.
4.
Ayehunie S., Groves RW, Bruzzese AM, Ruprecht RM, Kupper TS, Langhoff E. (1995). Acutely infected Langerhans cells are more efficient than T cells in disseminating HIV type 1 to activated T cells following a short cell-cell contact. AIDS Res Hum Retroviruses11:877-884.
5.
Baba TW, Trichel AM, An L., Liska V., Martin LN, Murphey-Corb M., et al. (1996). Infection and AIDS in adult macaques after nontraumatic oral exposure to cell-free SIV. Science272:1486-1489.
6.
Barr CE, Miller LK, Lopez MR, Croxson TS, Schwartz SA, Denman H., et al. (1992). Recovery of infectious HIV-1 from whole saliva. J Am Dent Assoc123:37-48.
7.
Bergey EJ, Cho MI, Hammarskjold ML, Rekosh D., Levine MJ, Blumberg BM, et al. (1993). Aggregation of human immunodeficiency virus type 1 by human salivary secretions. Crit Rev Oral Biol Med4:467-474.
8.
Bergey EJ, Cho MI, Blumberg BM, Hammarskjold ML, Rekosh D., Epstein LG, et al. (1994). Interaction of HIV-1 and human salivary mucins. J Acquir Immune Defic Syndr7:995-1002.
9.
Berson JF, Long D., Doranz BJ, Rucker J., Jirik FR, Doms RW ( 1996). A seven-transmembrane domain receptor involved in fusion and entry of T-cell-tropic human immunodeficiency virus type 1 strains. J Virol70:6288-6295.
10.
Birrer P. (1995). Proteases and antiproteases in cystic fibrosis: pathogenetic considerations and therapeutic strategies. Respiration62(Suppl 1):25-28.
11.
Bu M., Turpin JA, Schaeffer CA, Graham L., Buckheit RW, Rice WG ( 1995). Secretory leukocyte protease inhibitor (SLPI) does not effectively inhibit HIV-1 replication. In: Proceedings of the 35th Interscience Conference on Antimicrobial Agents and Chemotherapy , Sept. 17-20, 1995, San Francisco. San Francisco, CA: American Society for Microbiology .
12.
Callebaut C., Krust B., Jacotot E., Hovanessian AG (1993). T-cell activation antigen, CD26, as a cofactor for entry of HIV in CD4+ cells. Science262:2045-2050.
13.
Clements GJ, Price-Jones MJ, Stephens PE, Sutton C., Schultz TF, Clapham PR, et al. (1991). 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 Retroviruses7:3-16.
14.
Cocchi F., DeVico AL, Garzino-Demo A., Arya SK, Gallo RC, Lusso P. (1995). Identification of RANTES, MIP-la, and MIP-1β as the major HIV-suppressive factors produced by CD8+ T cells. Science270:1811-1815.
15.
Delorme P., Dezutter-Dambuyant C., Ebersold A., Desgranges C., Thivolet J., Schmitt D. (1993). In vitro infection of epidermal Langerhans cells with human immunodeficiency virus type 1 (HTLV-III B isolate). Res Virol144:53-58.
16.
Deng H., Liu R., Ellmeier W., Choe S., Unutmaz D., Burkhart M., et al. (1996). Identification of a major co-receptor for primary isolates of HIV-1. Nature381:661-666.
17.
Dragic T., Litwin V., Allaway GP, Martin SR, Huang Y., Nagashima KA, et al. (1996). HIV-1 entry into CD4+ cells is mediated by the chemokine receptor CC-CKR-5. Nature381:667-673.
18.
Dukes CS, Yu Y., Rivadeneira ED, Sauls DL, Liao HX, Haynes BF, et al. (1995). Cellular CD44S as a determinant of human immunodeficiency virus type 1 infection and cellular tropism. J Virol69:4000-4005.
19.
Faller B., Mely Y., Gerard D., Bieth JG (1992). Heparin-induced conformational change and activation of mucus proteinase inhibitor. Biochemistry31:8285-8290.
20.
Faust RA, Henry K., Dailey P., Melroe H., Sullivan C., Erice A., et al. (1996). Outpatient biopsies of the palatine tonsil: access to lymphoid tissue for assessment of human immunodeficiency virus RNA titers. Otolaryngol Head Neck Surg114:593-598.
21.
Feng Y., Broder CC, Kennedy FE, Berger EA (1996). HIV-1 entry cofactor: functional cDNA cloning of a seven-transmembrane, G protein-coupled receptor. Science272:872-877.
22.
Fox PC (1993). Anti-HIV-1 activity in human saliva. In: Oral manifestations of HIV infection. Greenspan JS, Greenspan D, editors. Chicago: Quintessence, pp. 130-137.
23.
Fox PC, Wolff A., Yeh CK, Atkinson JC, Baum BJ ( 1988). Saliva inhibits HIV-1 infectivity. J Am Dent Assoc116:635-637.
24.
Fox PC, Wolff A., Yeh CK, Atkinson JC, Baum BJ ( 1989). Salivary inhibition of HIV-1 infectivity: functional properties and distribution in men, women, and children. J Am Dent Assoc118:709-711.
25.
Frankel SS, Wenig BM, Burke AF, Mannan P., Thompson LD, Abbondanzo SL, et al. (1996). Replication of HIV-1 in dendritic cell-derived syncytia at the mucosal surface of the adenoid. Science272:115-117.
26.
Franken C., Meijer Cjlm, Dijkman JH (1989). Tissue distribution of antileukoprotease and lysozyme in humans. J Histochem Cytochem37:493-498.
27.
Friedland GH, Saltzman BR, Rogers MF, Kahl PA, Lesser ML, Mayers MM, et al. (1986). Lack of transmission of HTLV-III/LAV to household contacts of patients with AIDS or AIDS-related complex with oral candidiasis. N Engl J Med314:344-349.
28.
Fultz PN (1986). Components of saliva inactivate human immunodeficiency virus. Lancet2:1215.
29.
Groopman JE, Salahuddin SZ, Sarngadharan MG, Markham PD, Gonda M., Sliski A., et al. (1984). HTLV-III in saliva of people with AIDS-related complex and healthy homosexual men at risk for AIDS. Science226:447-449.
30.
Grutter MG, Fendrich G., Huber R., Bode W. ( 1988). The 2.5 A x-ray crystal structure of the acid-stable proteinase inhibitor from human mucous secretions analysed in its complex with bovine a-chymotrypsin. EMBO J7:345-351.
31.
Handley MA, Steigbigel RT, Morrison SA (1996). A role for urokinase-type plasminogen activator in human immunodeficiency virus type 1 infection of macrophages. J Virol70:4451-4456.
32.
Hasunuma T., Tsubota H., Watanabe M., Chen ZW, Lord CI, Burkly LC, et al. (1992). Regions of the CD4 molecule not involved in virus binding or syncytia formation are required for HIV-1 infection of lymphocytes. J Immunol148:1841-1846.
33.
Hattori T., Koito A., Takatsuki K., Kido H., Katunuma N. (1989). Involvement of tryptase-related cellular protease(s) in human immunodeficiency virus type 1 infection. FEBS Lett248:48-52.
34.
Ho DD, Byington RE, Schooley RT, Flynn T., Rota TR, Hirsch MS (1985). Infrequency of isolation of HTLV-III virus from saliva in AIDS (letter). N Engl J Med313:1606.
35.
Ito M., Baba M., Sato A., Pauwels R., De Clercq R., Shigeta S. (1987). Inhibitory effect of dextran sulfate and heparin on the replication of human immunodeficiency virus (HIV) in vitro. Antiviral Res7:361-367.
36.
Jonak ZL, Clark RK, Matour D., Trulli S., Craig E., Henri E., et al. (1993). A human lymphoid recombinant cell line with functional human immunodeficiency virus type 1 envelope. AIDS Res Hum Retroviruses9:23-32.
37.
Kido H., Fukutomi A., Katunuma N. (1990). A novel membrane-bound serine esterase in human T4+ lymphocytes immunologically reactive with antibody inhibiting syncytia induced by HIV-1. Purification and characterization. J Biol Chem265:21979-21985.
38.
Kido H., Fukutomi A., Katunuma N. (1991). Tryptase TL2 in the membrane of human T4+ lymphocytes is a novel binding protein of the V3 domain of HIV-1 envelope glycoprotein gpl20. FEBS Lett286:233-236.
39.
Klein RS, Phelan JA, Freeman K., Schable C., Friedland GH, Trieger N., et al. (1988). Low occupational risk of human immunodeficiency virus infection among dental professionals. N Engl J Med318:86-90.
40.
Konopka K., Pretzer E., Celada F., Düzgüneş N. (1995). A monoclonal antibody to the gpl20-CD4 complex has differential effects on HIV-induced syncytium formation and viral infectivity . J Gen Virol76:669-679.
41.
Kuppers F. (1971). Protease inhibitor in human tears. Biochim Biophys Acta229:845-849.
42.
Lafont V., Dornand J., d'Angeac AD, Monier S., Alcover A., Favero J. (1994). Jacalin, a lectin that inhibits in vitro HIV-1 infection, induces intracellular calcium increase via CD4 in cells lacking the CD3/TcR complex. J Leukocyte Biol56:521-524.
43.
Levy JA ( 1993). Pathogenesis of human immunodeficiency virus infection . Microbiol Rev57:183-289.
44.
Levy JA, Greenspan D (1988). HIV in saliva (letter). Lancet 2:1248. Liuzzi G, Chirianni A, Tullio CP, Conte MC, Barsanti LA, Ceccherini NL, et al. (1994). Presence of HIV-1 proviral sequences in saliva of infected individuals in relation with clinical stage and CD4+ lymphocyte count. Bollettino-Societa Italiana Biologia Sperimentale 70:345-352.
45.
Lucey EC, Stone PJ, Ciccolella DE, Breuer R., Christensen TG, Thompson RC, et al. (1990). 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 Med115:224-232.
46.
Malamud D., Friedman HM (1993). HIV in the oral cavity: virus, viral inhibitory activity, and antiviral antibodies: a review. Crit Rev Oral Biol Med4:461-466.
47.
Malamud D., Davis C., Berthold P., Roth E., Friedman H. (1993). Human submandibular saliva aggregates HIV. AIDS Res Hum Retroviruses9:633-637.
48.
Masuda K., Suga T., Takeuchi A., Kanesaki M., Imaizumi A., Suzuki Y. (1994). Specific cleavage of secretory leukoprotease inhibitor by neutrophil elastase and saliva. Biochem Pharmacol48:651-657.
49.
McNeely TB, Dealy M., Dripps DJ, Orenstein JM, Eisenberg SP, Wahl SM ( 1995). Secretory leukocyte protease inhibitor: a human saliva protein exhibiting anti-human immunodeficiency virus 1 activity in vitro. J Clin Invest96:456-464.
50.
Miller CJ, McGhee JR, Gardner MB (1993). Mucosal immunity, HIV transmission, and AIDS. Lab Invest68:129-145.
51.
Moore BE, Flaitz CM, Coppenhaver DH, Nichols M., Kalmaz GD, Bessman JD, et al. (1993). HIV recovery from saliva before and after dental treatment: inhibitors may have critical role in viral inactivation . J Am Dent Assoc124:67-74.
52.
Moore JP, Jameson BA, Weiss RA, Sattentau QJ (1993). The HIVcell fusion reaction. In: Viral fusion mechanisms. Bentz J, editor. Boca Raton, FL: CRC Press, pp. 233-289.
53.
Nadziejko C., Finkelstein I. (1994). Inhibition of neutrophil elastase by mucus glycoprotein . Am J Respir Cell Mol Biol11:103-107.
54.
Niwa Y., Yano M., Kutaki S., Okumura Y., Kido H. ( 1996). T-cell membrane-associated serine protease, tryptase TL2, binds human immunodeficiency virus type 1 gpl20 and cleaves the third-variable-domain loop of gpl20. Neutralizing antibodies of human immunodeficiency virus type 1 inhibit cleavage of gpl20. Eur J Biochem237:64-70.
55.
Ohlsson M., Tegner H., Akesson U. (1977). Isolation and partial characterization of a low molecular weight acid-stable protease inhibitor from human bronchial secretion . Hoppe-Seyler's Z Physiol Chem358:583-589.
56.
Ohlsson M., Rosengren M., Tegner H., Ohlsson K. (1983). Quantification of granulocyte elastase inhibitors in human mixed saliva and in pure parotid secretion. Hoppe-Seyler's Z Physiol Chem364:1323-1328.
57.
Oravecz T., Rodriquez G., Koffi J., Wang J., Ditto M., Bou-Habib DC, et al. (1995). CD26 expression correlates with entry, replication and cytopathicity of monocytotropic HIV-1 strains in a T-cell line. Nature Med1:919-926.
58.
Padian N. (1987). Heterosexual transmission of acquired immunodeficiency syndrome: international perspectives and national projections. Rev Infect Dis9:947-960.
59.
Paxton WA, Dragic T., Koup RA, Moore JP (1996). Perspective: Research highlights at the Aaron Diamond AIDS Research Center: The β-chemokines, HIV type 1 second receptors, and exposed uninfected persons. AIDS Res Hum Retroviruses12:1203-1207.
60.
Phillips DM, Zacharopoulos V., Tan X., Pearce-Pratt R. (1994). Mechanisms of sexual transmission of HIV: does HIV infect intact epithelia?Trends Microbiol2:454-458.
61.
Qureshi MN, Barr CE, Seshamma T., Reidy J., Pomerantz RJ, Bagasra 0 (1995). Infection of oral mucosal cells by human immunodeficiency virus type 1 in seropositive persons. J Infect Dis171:190-193.
62.
Qureshi MN, Barr CE, Oda D., Reidy J., Bagasra 0, Teplitz C. (1996). A model of HIV infection of buccal epithelial cells (abstract). J Dent Res75:238.
63.
Rappersberger K., Gartner S., Schenk P., Stingl G., Groh V., Tschachler E., et al. (1988). Langerhans' cells are an actual site of HIV-1 replication. Intervirology29:185-194.
64.
Rice WG, Weiss SJ (1990). Regulation of proteolysis at the neutrophil-substrate interface by secretory leukoprotease inhibitor. Science249:178-181.
65.
Rice WG, Schaeffer CA, McDougal JS, Orloff SL (1991). Nature of inhibitors of HIV in human secretory fluids (abstract). Contemporary developments in salivary research, Buffalo, NY.
66.
Robinovitch MR, Iversen JM, Resnick L. (1993). Anti-infectivity activity of human salivary secretions toward human immunodeficiency virus. Crit Rev Oral Biol Med4:455-459.
67.
Rudolphus A., Kramps JA, Dijkman JH (1991). Effect of human antileukoprotease on experimental emphysema. Eur Respir J4:31-39.
68.
Sato AI, Balamuth FB, Ugen KE, Williams WV, Weiner DB (1994). Identification of CD7 glycoprotein as an accessory molecule in HIV-1-mediated syncytium formation and cell free infection. J Immunol152:5142-5152.
69.
Schiessler H., Arnhold M., Ohlsson K., Fritz H. (1976). Inhibitors of acrosin and granulocyte proteinases from human genital tract secretions. Hoppe-Seyler's Z Physiol Chem357:1251-1260.
70.
Schiødt M., Greenspan D., Levy JA, Nelson JA, Chernoff D., Hollander H., et al. (1989). Does HIV cause salivary gland disease? AIDS3:819-822.
71.
Schmitt D., Dezutter-Dambuyant C. (1994). Epidermal and mucosal dendritic cells and HIV-1 infection. Path Res Pract190:955-959.
72.
Schulz TF, Reeves JD, Hoad JG, Tailor C., Stephens P., Clements G., et al. (1993). Effect of mutations in the V3 loop of HIV-1 gpl20 on infectivity and susceptibility to proteolytic cleavage. AIDS Res Hum Retroviruses9:159-166.
73.
Serb P., Yeung S. (1994). HIV infection and the dentist. 1. The presence of HIV in saliva and its implications to dental practice. Aust Dent J39:67-72.
74.
Shugars DC, McNeely TB, Eisenberg SP, Wahl SM ( 1996). Secretory leukocyte protease inhibitor targets an early event in HIV infection (abstract). J Dent Res75:114.
75.
Soto-Ramirez LE, Renjifo B., McLane MF, Marlink R., O'Hara C., Sutthent R., et al. (1996). HIV-1 Langerhans' cell tropism associated with heterosexual transmission of HIV. Science271:1291-1293.
76.
Tabak LA (1995). In defense of the oral cavity: structure, biosynthesis, and function of salivary mucins. Ann Rev Physiol57:547-564.
77.
Tan X., Pearce-Pratt R., Phillips DM (1993). Productive infection of a cervical epithelial cell line with human immunodeficiency virus: implications for sexual transmission . J Virol67:6447-6452.
78.
Thompson RC, Ohlsson K. (1986). Isolation, properties, and complete amino acid sequence of human secretory leukocyte protease inhibitor, a potent inhibitor of leukocyte elastase. Proc Natl Acad Sci USA83:6692-6696.
79.
Turpin JA, Schaeffer CA, Bu M., Graham L., Buckheit RW Jr, Clanton D., et al. (1996). Human immunodeficiency virus type-1 (HIV-1) replication is unaffected by human secretory leukocyte protease inhibitor . Antiviral Res29:269-277.
80.
Van-Seuningen I., Houdret N., Hayem A., Davril M. (1992). Strong ionic interactions between mucins and two basic proteins, mucus proteinase inhibitor and lysozyme, in human bronchial secretions. Int J Biochem24:303-311.
81.
Wallner 0, Fritz H. (1974). Characterization of an acid-stable proteinase inhibitor in human cervical mucus. Hoppe-Seyler's Z Physiol Chem355:709-715.
82.
Wenig BM, Thompson Ldr, Frankel SS, Burke AP, Abbandanzo SL, Sesterhenn I., et al. (1996). Lymphoid changes of the nasopharyngeal and palatine tonsils that are indicative of human immunodeficiency virus infection . Am J Surg Pathol20:572-587.
83.
Yeh CK, Handelman B., Fox PC, Baum BJ ( 1992). Further studies of salivary inhibition of HIV-1 infectivity . J Acquir Immune Defic Syndr5:898-903.
84.
Yeung SC, Kazazi F., Randle CG, Howard RC, Rizvi N., Downie JC, et al. (1993). Patients infected with human immunodeficiency virus type 1 have low levels of virus in saliva even in the presence of periodontal disease. J Infect Dis167:803-809.
85.
Yeung S., Serb P. ( 1994). HIV infection and the dentist. 2. The diagnosis and management of gingivitis and periodontitis. Aust Dent J39:73-76.
