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Development of a Topical Vaginal Microbicide

Lessons Learned from Human Milk
  • Charles E. Isaacs
  • Raju Pullarkat
  • Richard Kascsak
Part of the Advances in Experimental Medicine and Biology book series (AEMB, volume 501)

Abstract

Vaccines are not presently available to prevent adherence and transmission of many common pathogens at mucosal surfaces. As a result, sexually transmitted diseases were one of the most commonly reported infections in the US in 1999. New methods are needed to reduce the spread of mucosal infections. Providing nonspecific protective factors, such as lipids and retinoids found in human milk to mucosal surfaces could reduce mucosal infection caused by viruses, e.g., herpes simplex virus-1 (HSV-1) and bacteria, e.g., Pseudomonas aeruginosa. Human milk lipids enzymatically modified to produce monoglycerides were antimicrobial and inactivated enveloped viruses, as well as gram-positive and gram-negative bacteria. Enveloped viruses were inactivated in seconds following contact with antimicrobial lipids, and P. aeruginosa infectivity was reduced by 99.9% after 2 hours. Transmission of pathogens at mucosal surfaces can also be prevented using retinoids that inhibit viral replication. In a human embryonic intestinal cell line the retinoic acid (RA) derivatives alltrans-RA and 9-cis-RA (10µg/mL) decreased the production of HSV-1 and Echo-6 viruses by 1-2log,o over a 48-hour period. In addition, all-trans-RA inhibited HSV-1 replication in Vero cells as effectively as interferon beta, reducing viral production by 2.5 logio. These studies indicate that lipids and retinoids could be part of a topical microbicide to prevent mucosal infections.

Keywords

Retinoic Acid Human Milk Mucosal Surface Bacterial Vaginosis Envelop Virus 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.

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References

  1. Aral SO, Holmes KK. Epidemiology of sexual behavior and sexually transmitted diseases. In: Holmes KK, Mardh I, Sparling PF, Wiesner PJ, Cates W Jr, Lemon SM, Stamm WE, editors. Sexually Transmitted Diseases. 2“d ed. New York: McGraw-Hill; 1990. pp. 19–36.Google Scholar
  2. Arvin AM, Prober CG. Herpes simplex virus infections: The genital tract and the newborn. Pediatr Rev 1992;13:107–112.PubMedCrossRefGoogle Scholar
  3. Baba TW, Koch KJ, Mittler ES, Greene M, Wyand M, Penninck D, Ruprecht RM. Mucosal infection of neonatal rhesus monkeys with cell-free SIV. AIDS Res Hum Retroviruses 1994;10:351–357.PubMedCrossRefGoogle Scholar
  4. Bartels JH, Christophers E, Schroder J-M. A peptide antibiotic from human skin. Nature 1997;387:861.PubMedCrossRefGoogle Scholar
  5. Bibel DJ, Miller SJ, Brown BE, Bandey BB, Elias PM, Shinefield HR, Aly R. Antimicrobial activity of stratum corneum lipids from normal and essential fatty acid-deficient mice. J Invest Dermatol 1989; 92:632–638.PubMedCrossRefGoogle Scholar
  6. Bird KD. The use of spermicide containing nonoxynol-9 in the prevention of HIV infection. AIDS 1991;5:791–796.PubMedCrossRefGoogle Scholar
  7. Brown ZA, Selke SS, Zeh J, Kopelman J, Maslow A, Ashley RL, Watts H, Berry S, Herd M, Corey L. The acquisition of herpes simplex virus during pregnancy. N Engl J Med 1997;337:509–515.PubMedCrossRefGoogle Scholar
  8. Connor EM, Sperling RS, Gelber R, Kiselev P, Scott G, O’Sullivan MJ, VanDyke R, Bey M, Shearer W, Jacobson RL, Jimenez E, O’Neill E, Bazin B, Delfraissy JF, Culnane M, Coombs R, Elkins M, Moye J, Stratton P, Bailey J. Reduction of maternal-infant transmission of human immunodeficiency virus type 1 with zidovudine treatment. N Engl J Med 1994;331:1173–1180.PubMedCrossRefGoogle Scholar
  9. Coonrod JD. The role of extracellular bactericidal factors in pulmonary host defense. Semin Respir Infect 1986;1:118–129.PubMedGoogle Scholar
  10. Coonrod JD, Yoneda K. Detection and partial characterization of antibacterial factor(s) in alveolar lining material of rats. J Clin Invest 1983;71:129–141.PubMedCrossRefGoogle Scholar
  11. Das AK, Holmes RD, Wilson GN, Hajra AK. Dietary ether lipid incorporation into tissue plasmalogens of humans and rodents. Lipids 1992;27:401–405.PubMedCrossRefGoogle Scholar
  12. Davies J. Bacteria on the rampage. Nature 1996;383:219–220.PubMedCrossRefGoogle Scholar
  13. Fearon DT. Seeking wisdom in innate immunity. Nature 1997;388:323–3.PubMedCrossRefGoogle Scholar
  14. Fox DCA, Meldrum SJ, Watson BW. Continuous measurement by radio-telemetry of vaginal pH during human coitus. J Reprod Fertil 1973;33:69–75.PubMedCrossRefGoogle Scholar
  15. Ghazal P, DeMattei C, Giulietti E, Kliewer SA, Umesono K, Evans RM. Retinoic acid receptors initiate induction of the cytomegalovirus enhancer in embryonal cells. Proc Natl Acad Sci USA 1992;89:7630–7634.PubMedCrossRefGoogle Scholar
  16. Goedert JJ, Drummond JE, Minkoff HL, Stevens R, Blattner WA, Mendez H, Robert-Guroff M, Holman S, Rubinstein A, Willoughby A, Landesman SH. Mother-to-infant transmission of human immunodeficiency virus type 1: Association with prematurity or low anti-gp120. Lancet 1989;2:1351–1354.PubMedCrossRefGoogle Scholar
  17. Goldenberg RL, Andrews WW, Yuan AC, MacKay HT, Michael E. Sexually transmitted diseases and adverse outcomes of pregnancy. Clin Perinatol 1997;24:23–41.PubMedGoogle Scholar
  18. Goldman AS, Pong AJH, Goldblum RM. Host Defenses: Development and maternal contributions. In: Barness LA, editor. Advances in Pediatrics. Chicago: Year Book Medical Publishers; 1985. pp. 71–100.Google Scholar
  19. Goldman AS, Goldblum RM. Immunologic system in human milk: Characteristics and effects. In: Lebenthal E, editor. Textbook of Gastroenterology and Nutrition in Infancy. 2nd ed. New York: Raven Press; 1989. pp. 135–142.Google Scholar
  20. Grazioso CF, Werner AL, Ailing DW, Bishop PR, Buescher ES. Antiinflammatory effects of human milk on chemically induced colitis in rats. Pediatr Res 1997;42:1–5.CrossRefGoogle Scholar
  21. Hernell O, Ward H, Blackberg L, Pereira MEA. Killing of Giardia lamblia by human milk lipases: An effect mediated by lipolysis of milk lipids. J Infect Dis 1986;153:715–720.PubMedCrossRefGoogle Scholar
  22. Hillier SL, Nugent RP, Eschenbach DA, Krohn MA, Gibbs RS, Martin DH, Cotch MF, Edelman R, Pastorek JG, Rao AV, McNellis D, Regan JA, Carey C, Klebanoff MA. Association between bacterial vaginosis and preterm delivery of a low-birth-weight infant. N Engl J Med 1995;333:1737–1742.PubMedCrossRefGoogle Scholar
  23. Hsu S, Lin Y, Chou C. Retinoic acid biphasically regulated the gene expression of hepatitis B virus surface antigen in human hepatoma Hep3B cells. J Biol Chem 1993;268:23093–23097.PubMedGoogle Scholar
  24. Huan B, Siddiqui A. Retinoid X receptor RXR-a binds to and trans-activates the hepatitis B virus enhancer. Proc Natl Acad Sci USA 1992;89:9059–9063.PubMedCrossRefGoogle Scholar
  25. Hussey GD, Klein M. A randomized, controlled trial of vitamin A in children with severe measles. N Engl J Med 1990;323:160–164.PubMedCrossRefGoogle Scholar
  26. Isaacs CE, Thormar H. Human milk lipids inactivate enveloped viruses. In: Atkinson SA, Hanson LA, Chandra RK, editors. Breastfeeding, Nutrition, Infection and Infant Growth in Developed and Emerging Countries. ARTS Biomedical Publishers: St. John’s, Newfoundland, Canada; 1990. pp. 161–174.Google Scholar
  27. Isaacs CE, Thormar H. The role of milk-derived antimicrobial lipids as antiviral and antibacterial agents. Adv Exp Med Biol 1991;310:159–165.PubMedCrossRefGoogle Scholar
  28. Isaacs CE, Kashyap S, Heird WC, Thormar H. Antiviral and antibacterial lipids in human milk and infant formula feeds. Arch Dis Child 1990;65:861–864.PubMedCrossRefGoogle Scholar
  29. Isaacs CE, Litov RE, Thormar H. Antimicrobial activity of lipids added to human milk, infant formula, and bovine milk. J Nutr Biochem 1995;6:362–366.PubMedCrossRefGoogle Scholar
  30. Isaacs CE, Kascsak R, Pullarkat RK, Xu W, Schneidman K. Inhibition of herpes simplex virus replication by retinoic acid. Anti Res 1997;33:117–127.CrossRefGoogle Scholar
  31. Jensen RG. The lipids in human milk. Prog Lipid Res 1996;35:53–92.PubMedCrossRefGoogle Scholar
  32. Jensen RG, Ferris AM, Lammi-Keefe CJ, Henderson RA. Lipids of bovine and human milks: A comparison. J Dairy Sci 1990;73:223–230.PubMedCrossRefGoogle Scholar
  33. Kabara JJ. Fatty acids and derivatives as antimicrobial agents. A review. In: Kabara JJ, editor. The Pharmacological Effect of Lipids. St. Louis: The American Oil Chemists’ Society; 1978. pp. 1–14.Google Scholar
  34. Knapp HR, Melly MA. Bactericidal effects of polyunsaturated fatty acids. J Infect Dis 1986;154:84–94.PubMedCrossRefGoogle Scholar
  35. Kreiss J, Ngugi E, Holmes K, Ndinya-Achola J, Waiyaki P, Roberts PL, Ruminjo I, Sajabi R, Kimata J, Fleming TR, Anzala A, Holton D, Plummer F. Efficacy of nonoxynol-9 contraceptive sponge use in preventing heterosexual acquisition of HIV in Nairobi prostitutes. JAMA 1992;268:477–482.PubMedCrossRefGoogle Scholar
  36. Mangold HK. Ether lipids in the diet of humans and animals. In: Mangold HK, Paltauf F, editors. Ether Lipids. Biochemical and Biomedical Aspects. New York: Academic Press; 1983. pp. 231–238.Google Scholar
  37. Medzhitov R, Janeway CA Jr. Innate immunity: the virtues of a nonclonal system of recognition. Cell 1997;91:295–298.PubMedCrossRefGoogle Scholar
  38. Miller SJ, Aly R, Shinefeld HR, Elias PM. In vitro and in vivo antistaphylococcal activity of human stratum corneum lipids. Arch Dermatol 1988;1:209–214.CrossRefGoogle Scholar
  39. Mostad SB, Overbaugh J, DeVange DM, Welch MJ, Chohan B, Mandaliya K, Byange P, Martin HL Jr, Ndinya-Achola J, Bwayo JJ, Kreiss JK. Hormonal contraception, vitamin A deficiency, and other risk factors for shedding of HIV-1 infected cells from the cervix and vagina. Lancet 1997; 350:922–927.PubMedCrossRefGoogle Scholar
  40. Murphy FA, Kingsbury DW. Virus taxonomy. In: Fields BN, Knipe DM, editors. Fields Virology. 2“d ed. New York: Raven Press; 1990. pp. 9–35.Google Scholar
  41. Napoli JL, Race KR. Biogenesis of retinoic acid from 3-carotene. J Biol Chem 1988;263:17372–17377.PubMedGoogle Scholar
  42. Neuzil KM, Gruber WC, Chytil F, Stahlman MT, Engelhardt B, Graham BS. Serum vitamin A levels in respiratory syncytial virus infection. J Pediatr 1994;1:433–446.Google Scholar
  43. Niruthisard S, Roddi RE, Chutivongse S. The effects of frequent nonoxynol-9 use on the vaginal and cervical mucosa. Sex Transm Dis 1991;18:176–179.PubMedCrossRefGoogle Scholar
  44. Paltauf F. Ether lipids as substrates for lipolytic enzymes. In: Mangold HK, Paltauf F, editors. Ether Lipids. Biochemical and Biomedical Aspects. New Ycrk: Academic Press; 1983. pp. 211–229Google Scholar
  45. Pauwels R, de Clercq E. Development of vaginal microbicides for the prevention of heterosexual transmission of HIV. J Acquir Immunne Defic Syndr Human Retrovirol 1996;11:211–221.CrossRefGoogle Scholar
  46. Rein MF, Muller M. Trichomonas vaginalis and trichomoniasis. In: Holmes KK, Mardh I, Sparling PF, Wiesner PJ, Cates W Jr, Lemon SM, Stamm WE, editors. Sexually Transmitted Diseases. 2“ ed. New York: McGraw-Hill; 1990. pp. 481–492.Google Scholar
  47. Reiner DS, Wang C, Gitlin D. Human milk kills Giardia lamblia by generating toxic lipolytic products. J Infect Dis 1986;154:825–832.PubMedCrossRefGoogle Scholar
  48. Ross AC. Vitamin A status: Relationship to immunity and the antibody response. Proc Soc Exp Biol Med 1992;200:303–320.PubMedGoogle Scholar
  49. Semba RD, Miotti PGF, Chiphangwi JD, Saah AJ, Canner JK, Dallabetta GA. Maternal vitamin A deficiency and mother-to-child transmission of HIV-1. Lancet 1994;343:1593–1597.PubMedCrossRefGoogle Scholar
  50. Shibasaki I, Kato N. Combined effects on antibacterial activity of fatty acids and their esters against gram-negative bacteria. In: Kabara JJ, editor. The Pharmacological Effect of Lipids. St. Louis: The American Oil Chemists’ Society; 1978. pp. 15–24.Google Scholar
  51. Sista ND, Pagano JS, Liao W, Kenney S. Retinoid acid is a negative regulator of the Epstein-Barr virus protein (BZLF1) that mediates disruption of latent infection. Proc Nat] Acad Sci USA 1993; 90:3894–3898.CrossRefGoogle Scholar
  52. Thormar H, Isaacs CE, Brown HR, Barshatzky MR, Pessolano T. Inactivation of enveloped viruses and killing of cells by fatty acids and monoglycerides. Antimicrob Agents Chemother 1987;31:27–31.PubMedCrossRefGoogle Scholar
  53. Voeller B, Anderon DJ. Heterosexual transmission of HIV. JAMA 1992;267:1917–1918.CrossRefGoogle Scholar
  54. Wang XD, Krinsky NI, Benotti PN, Russell RM. Biosynthesis of 9-cis-retinoic acid from 9-cis-(3-carotenein human intestinal mucosa in vitro. Arch Biochem Biophys 1994;313:150–155.PubMedCrossRefGoogle Scholar
  55. Weber N. Metabolism of orally administered rac-1–0[l’-14C]dodecylglycerol and nutritional effects of dietary rac-l-0-dodecylglycerol in mice. J Lipid Res 1985;26:1412–1420.PubMedGoogle Scholar
  56. Whitley RJ. Herpes simplex virus infections of women and their offspring: Implications for a developed society. Proc Natl Acad Sci USA 1994;91:41–47.CrossRefGoogle Scholar
  57. Xanthou M, Bines J, Walker WA. Human milk and intestinal host defense in newborns: An update. Adv Pediatr 1995;42:171–208.PubMedGoogle Scholar
  58. Zhao Z, Ross AC. Retinoic acid repletion restores the number of leukocytes and their subsets and stimulates natural cytotoxicity in vitamin A-deficient rats. J Nutr 1995;125:2064–2073.PubMedGoogle Scholar

Copyright information

© Springer Science+Business Media New York 2001

Authors and Affiliations

  • Charles E. Isaacs
    • 1
  • Raju Pullarkat
    • 2
  • Richard Kascsak
    • 2
  1. 1.Department of Developmental BiochemistryNew York State Institute for Basic Research in Developmental DisabilitiesStaten Island
  2. 2.Department of VirologyNew York State Institute for Basic Research in Developmental DisabilitiesStaten Island

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