Skip to main content
PMC home page
The Journal of Clinical Investigation logoLink to The Journal of Clinical Investigation
. 1997 Jun 15;99(12):2837–2841. doi: 10.1172/JCI119476

Inhibition of murine embryonic growth by human immunodeficiency virus envelope protein and its prevention by vasoactive intestinal peptide and activity-dependent neurotrophic factor.

D A Dibbern Jr 1, G W Glazner 1, I Gozes 1, D E Brenneman 1, J M Hill 1
PMCID: PMC508133  PMID: 9185505

Abstract

Intrauterine growth retardation and neurodevelopmental handicaps are common among infants born to HIV-positive mothers and may be due to the actions of virions and/or maternally derived viral products. The viral envelope protein, gp120, is toxic to neurons, induces neuronal dystrophy, and retards behavioral development in neonatal rats. Vasoactive intestinal peptide, a neuropeptide regulator of early postimplantation embryonic growth, and the neuroprotective protein, activity-dependent neurotrophic factor, prevent gp120-induced neurotoxicity. Whole embryo culture of gestational day 9.5 mouse embryos was used to assess the effect of gp120 on growth. Embryos treated with gp120 exhibited a dose-dependent inhibition of growth. gp120-treated embryos (10(-8) M) grew 1.2 somites in the 6-h incubation period, compared with 3.9 somites by control embryos. Embryos treated with gp120 were significantly smaller in cross-sectional area and had significantly less DNA and protein than controls. Growth inhibition induced by gp120 was prevented by cotreatment with vasoactive intestinal peptide or activity-dependent neurotrophic factor. gp120 may play a role in the growth retardation and developmental delays experienced by infants born to HIV-positive mothers. Vasoactive intestinal peptide and related factors may provide a therapeutic strategy in preventing developmental deficits.

Full Text

The Full Text of this article is available as a PDF (166.1 KB).

Selected References

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

  1. Arock M., Dedenon A., Le Goff L., Michel A., Missenard G., Debré P., Guillosson J. J. Specific ligation of the HIV-1 viral envelope protein gp120 on human CD34+ bone marrow-derived progenitors. Cell Mol Biol (Noisy-le-grand) 1994 May;40(3):319–323. [PubMed] [Google Scholar]
  2. BURTON K. A study of the conditions and mechanism of the diphenylamine reaction for the colorimetric estimation of deoxyribonucleic acid. Biochem J. 1956 Feb;62(2):315–323. doi: 10.1042/bj0620315. [DOI] [PMC free article] [PubMed] [Google Scholar]
  3. Braddick M. R., Kreiss J. K., Embree J. B., Datta P., Ndinya-Achola J. O., Pamba H., Maitha G., Roberts P. L., Quinn T. C., Holmes K. K. Impact of maternal HIV infection on obstetrical and early neonatal outcome. AIDS. 1990 Oct;4(10):1001–1005. doi: 10.1097/00002030-199010000-00009. [DOI] [PubMed] [Google Scholar]
  4. Bradford M. M. A rapid and sensitive method for the quantitation of microgram quantities of protein utilizing the principle of protein-dye binding. Anal Biochem. 1976 May 7;72:248–254. doi: 10.1016/0003-2697(76)90527-3. [DOI] [PubMed] [Google Scholar]
  5. Brenneman D. E., Eiden L. E. Vasoactive intestinal peptide and electrical activity influence neuronal survival. Proc Natl Acad Sci U S A. 1986 Feb;83(4):1159–1162. doi: 10.1073/pnas.83.4.1159. [DOI] [PMC free article] [PubMed] [Google Scholar]
  6. Brenneman D. E., Gozes I. A femtomolar-acting neuroprotective peptide. J Clin Invest. 1996 May 15;97(10):2299–2307. doi: 10.1172/JCI118672. [DOI] [PMC free article] [PubMed] [Google Scholar]
  7. Brenneman D. E., Hill J. M., Glazner G. W., Gozes I., Phillips T. W. Interleukin-1 alpha and vasoactive intestinal peptide: enigmatic regulation of neuronal survival. Int J Dev Neurosci. 1995 Jun-Jul;13(3-4):187–200. doi: 10.1016/0736-5748(95)00014-8. [DOI] [PubMed] [Google Scholar]
  8. Brenneman D. E., Neale E. A., Foster G. A., d'Autremont S. W., Westbrook G. L. Nonneuronal cells mediate neurotrophic action of vasoactive intestinal peptide. J Cell Biol. 1987 Jun;104(6):1603–1610. doi: 10.1083/jcb.104.6.1603. [DOI] [PMC free article] [PubMed] [Google Scholar]
  9. Brenneman D. E., Westbrook G. L., Fitzgerald S. P., Ennist D. L., Elkins K. L., Ruff M. R., Pert C. B. Neuronal cell killing by the envelope protein of HIV and its prevention by vasoactive intestinal peptide. Nature. 1988 Oct 13;335(6191):639–642. doi: 10.1038/335639a0. [DOI] [PubMed] [Google Scholar]
  10. Brown N. A., Fabro S. Quantitation of rat embryonic development in vitro: a morphological scoring system. Teratology. 1981 Aug;24(1):65–78. doi: 10.1002/tera.1420240108. [DOI] [PubMed] [Google Scholar]
  11. Bulterys M., Chao A., Munyemana S., Kurawige J. B., Nawrocki P., Habimana P., Kageruka M., Mukantabana S., Mbarutso E., Dushimimana A. Maternal human immunodeficiency virus 1 infection and intrauterine growth: a prospective cohort study in Butare, Rwanda. Pediatr Infect Dis J. 1994 Feb;13(2):94–100. doi: 10.1097/00006454-199402000-00003. [DOI] [PubMed] [Google Scholar]
  12. Buzy J., Brenneman D. E., Pert C. B., Martin A., Salazar A., Ruff M. R. Potent gp120-like neurotoxic activity in the cerebrospinal fluid of HIV-infected individuals is blocked by peptide T. Brain Res. 1992 Dec 11;598(1-2):10–18. doi: 10.1016/0006-8993(92)90161-2. [DOI] [PubMed] [Google Scholar]
  13. Children born to women with HIV-1 infection: natural history and risk of transmission. European Collaborative Study. Lancet. 1991 Feb 2;337(8736):253–260. [PubMed] [Google Scholar]
  14. Chirmule N., Kalyanaraman V. S., Oyaizu N., Slade H. B., Pahwa S. Inhibition of functional properties of tetanus antigen-specific T-cell clones by envelope glycoprotein GP120 of human immunodeficiency virus. Blood. 1990 Jan 1;75(1):152–159. [PubMed] [Google Scholar]
  15. Cortey A., Jarvik J. G., Lenkinski R. E., Grossman R. I., Frank I., Delivoria-Papadopoulos M. Proton MR spectroscopy of brain abnormalities in neonates born to HIV-positive mothers. AJNR Am J Neuroradiol. 1994 Nov;15(10):1853–1859. [PMC free article] [PubMed] [Google Scholar]
  16. Dawson T. M., Dawson V. L., Snyder S. H. Molecular mechanisms of nitric oxide actions in the brain. Ann N Y Acad Sci. 1994 Nov 17;738:76–85. doi: 10.1111/j.1749-6632.1994.tb21792.x. [DOI] [PubMed] [Google Scholar]
  17. Dawson V. L., Dawson T. M., Uhl G. R., Snyder S. H. Human immunodeficiency virus type 1 coat protein neurotoxicity mediated by nitric oxide in primary cortical cultures. Proc Natl Acad Sci U S A. 1993 Apr 15;90(8):3256–3259. doi: 10.1073/pnas.90.8.3256. [DOI] [PMC free article] [PubMed] [Google Scholar]
  18. Dreyer E. B., Kaiser P. K., Offermann J. T., Lipton S. A. HIV-1 coat protein neurotoxicity prevented by calcium channel antagonists. Science. 1990 Apr 20;248(4953):364–367. doi: 10.1126/science.2326646. [DOI] [PubMed] [Google Scholar]
  19. Festoff B. W., Nelson P. G., Brenneman D. E. Prevention of activity-dependent neuronal death: vasoactive intestinal polypeptide stimulates astrocytes to secrete the thrombin-inhibiting neurotrophic serpin, protease nexin I. J Neurobiol. 1996 Jun;30(2):255–266. doi: 10.1002/(SICI)1097-4695(199606)30:2<255::AID-NEU7>3.0.CO;2-4. [DOI] [PubMed] [Google Scholar]
  20. Franks R. R., Ray P. E., Babbott C. C., Bryant J. L., Notkins A. L., Santoro T. J., Klotman P. E. Maternal-fetal interactions affect growth of human immunodeficiency virus type 1 transgenic mice. Pediatr Res. 1995 Jan;37(1):56–63. doi: 10.1203/00006450-199501000-00012. [DOI] [PubMed] [Google Scholar]
  21. Gabiano C., Tovo P. A., de Martino M., Galli L., Giaquinto C., Loy A., Schoeller M. C., Giovannini M., Ferranti G., Rancilio L. Mother-to-child transmission of human immunodeficiency virus type 1: risk of infection and correlates of transmission. Pediatrics. 1992 Sep;90(3):369–374. [PubMed] [Google Scholar]
  22. Gendelman H. E., Lipton S. A., Tardieu M., Bukrinsky M. I., Nottet H. S. The neuropathogenesis of HIV-1 infection. J Leukoc Biol. 1994 Sep;56(3):389–398. doi: 10.1002/jlb.56.3.389. [DOI] [PubMed] [Google Scholar]
  23. Giulian D., Vaca K., Noonan C. A. Secretion of neurotoxins by mononuclear phagocytes infected with HIV-1. Science. 1990 Dec 14;250(4987):1593–1596. doi: 10.1126/science.2148832. [DOI] [PubMed] [Google Scholar]
  24. Giulian D., Wendt E., Vaca K., Noonan C. A. The envelope glycoprotein of human immunodeficiency virus type 1 stimulates release of neurotoxins from monocytes. Proc Natl Acad Sci U S A. 1993 Apr 1;90(7):2769–2773. doi: 10.1073/pnas.90.7.2769. [DOI] [PMC free article] [PubMed] [Google Scholar]
  25. Glowa J. R., Panlilio L. V., Brenneman D. E., Gozes I., Fridkin M., Hill J. M. Learning impairment following intracerebral administration of the HIV envelope protein gp120 or a VIP antagonist. Brain Res. 1992 Jan 20;570(1-2):49–53. doi: 10.1016/0006-8993(92)90562-n. [DOI] [PubMed] [Google Scholar]
  26. Gressens P., Hill J. M., Gozes I., Fridkin M., Brenneman D. E. Growth factor function of vasoactive intestinal peptide in whole cultured mouse embryos. Nature. 1993 Mar 11;362(6416):155–158. doi: 10.1038/362155a0. [DOI] [PubMed] [Google Scholar]
  27. Gressens P., Hill J. M., Paindaveine B., Gozes I., Fridkin M., Brenneman D. E. Severe microcephaly induced by blockade of vasoactive intestinal peptide function in the primitive neuroepithelium of the mouse. J Clin Invest. 1994 Nov;94(5):2020–2027. doi: 10.1172/JCI117555. [DOI] [PMC free article] [PubMed] [Google Scholar]
  28. Halsey N. A., Boulos R., Holt E., Ruff A., Brutus J. R., Kissinger P., Quinn T. C., Coberly J. S., Adrien M., Boulos C. Transmission of HIV-1 infections from mothers to infants in Haiti. Impact on childhood mortality and malnutrition. The CDS/JHU AIDS Project Team. JAMA. 1990 Oct 24;264(16):2088–2092. [PubMed] [Google Scholar]
  29. Heyes M. P., Brew B. J., Martin A., Price R. W., Salazar A. M., Sidtis J. J., Yergey J. A., Mouradian M. M., Sadler A. E., Keilp J. Quinolinic acid in cerebrospinal fluid and serum in HIV-1 infection: relationship to clinical and neurological status. Ann Neurol. 1991 Feb;29(2):202–209. doi: 10.1002/ana.410290215. [DOI] [PubMed] [Google Scholar]
  30. Hill J. M., Agoston D. V., Gressens P., McCune S. K. Distribution of VIP mRNA and two distinct VIP binding sites in the developing rat brain: relation to ontogenic events. J Comp Neurol. 1994 Apr 8;342(2):186–205. doi: 10.1002/cne.903420204. [DOI] [PubMed] [Google Scholar]
  31. Hill J. M., McCune S. K., Alvero R. J., Glazner G. W., Henins K. A., Stanziale S. F., Keimowitz J. R., Brenneman D. E. Maternal vasoactive intestinal peptide and the regulation of embryonic growth in the rodent. J Clin Invest. 1996 Jan 1;97(1):202–208. doi: 10.1172/JCI118391. [DOI] [PMC free article] [PubMed] [Google Scholar]
  32. Hill J. M., Mervis R. F., Avidor R., Moody T. W., Brenneman D. E. HIV envelope protein-induced neuronal damage and retardation of behavioral development in rat neonates. Brain Res. 1993 Feb 19;603(2):222–233. doi: 10.1016/0006-8993(93)91241-j. [DOI] [PubMed] [Google Scholar]
  33. Hira S. K., Kamanga J., Bhat G. J., Mwale C., Tembo G., Luo N., Perine P. L. Perinatal transmission of HIV-I in Zambia. BMJ. 1989 Nov 18;299(6710):1250–1252. doi: 10.1136/bmj.299.6710.1250. [DOI] [PMC free article] [PubMed] [Google Scholar]
  34. Koka P., He K., Zack J. A., Kitchen S., Peacock W., Fried I., Tran T., Yashar S. S., Merrill J. E. Human immunodeficiency virus 1 envelope proteins induce interleukin 1, tumor necrosis factor alpha, and nitric oxide in glial cultures derived from fetal, neonatal, and adult human brain. J Exp Med. 1995 Oct 1;182(4):941–951. doi: 10.1084/jem.182.4.941. [DOI] [PMC free article] [PubMed] [Google Scholar]
  35. Kumar R. M., Uduman S. A., Khurranna A. K. Impact of maternal HIV-1 infection on perinatal outcome. Int J Gynaecol Obstet. 1995 May;49(2):137–143. doi: 10.1016/0020-7292(95)02356-h. [DOI] [PubMed] [Google Scholar]
  36. Lallemant M., Lallemant-Le-Coeur S., Cheynier D., Nzingoula S., Jourdain G., Sinet M., Dazza M. C., Blanche S., Griscelli C., Larouzé B. Mother-child transmission of HIV-1 and infant survival in Brazzaville, Congo. AIDS. 1989 Oct;3(10):643–646. doi: 10.1097/00002030-198910000-00004. [DOI] [PubMed] [Google Scholar]
  37. Lepage P., Msellati P., Van de Perre P., Hitimana D. G., Dabis F. Characteristics of newborns and HIV-1 infection in Rwanda. AIDS. 1992 Aug;6(8):882–883. [PubMed] [Google Scholar]
  38. Lipton S. A. HIV-related neuronal injury. Potential therapeutic intervention with calcium channel antagonists and NMDA antagonists. Mol Neurobiol. 1994 Apr-Jun;8(2-3):181–196. doi: 10.1007/BF02780669. [DOI] [PubMed] [Google Scholar]
  39. Lipton S. A. Requirement for macrophages in neuronal injury induced by HIV envelope protein gp120. Neuroreport. 1992 Oct;3(10):913–915. doi: 10.1097/00001756-199210000-00023. [DOI] [PubMed] [Google Scholar]
  40. Lipton S. A., Sucher N. J., Kaiser P. K., Dreyer E. B. Synergistic effects of HIV coat protein and NMDA receptor-mediated neurotoxicity. Neuron. 1991 Jul;7(1):111–118. doi: 10.1016/0896-6273(91)90079-f. [DOI] [PubMed] [Google Scholar]
  41. Mann D. L., Lasane F., Popovic M., Arthur L. O., Robey W. G., Blattner W. A., Newman M. J. HTLV-III large envelope protein (gp120) suppresses PHA-induced lymphocyte blastogenesis. J Immunol. 1987 Apr 15;138(8):2640–2644. [PubMed] [Google Scholar]
  42. Maury W., Potts B. J., Rabson A. B. HIV-1 infection of first-trimester and term human placental tissue: a possible mode of maternal-fetal transmission. J Infect Dis. 1989 Oct;160(4):583–588. doi: 10.1093/infdis/160.4.583. [DOI] [PubMed] [Google Scholar]
  43. McCormick M. C. The contribution of low birth weight to infant mortality and childhood morbidity. N Engl J Med. 1985 Jan 10;312(2):82–90. doi: 10.1056/NEJM198501103120204. [DOI] [PubMed] [Google Scholar]
  44. McKinney R. E., Jr, Robertson J. W. Effect of human immunodeficiency virus infection on the growth of young children. Duke Pediatric AIDS Clinical Trials Unit. J Pediatr. 1993 Oct;123(4):579–582. doi: 10.1016/s0022-3476(05)80955-2. [DOI] [PubMed] [Google Scholar]
  45. Mittler R. S., Hoffmann M. K. Synergism between HIV gp120 and gp120-specific antibody in blocking human T cell activation. Science. 1989 Sep 22;245(4924):1380–1382. doi: 10.1126/science.2571187. [DOI] [PubMed] [Google Scholar]
  46. Mok J. Y., Hague R. A., Yap P. L., Hargreaves F. D., Inglis J. M., Whitelaw J. M., Steel C. M., Eden O. B., Rebus S., Peutherer J. F. Vertical transmission of HIV: a prospective study. Arch Dis Child. 1989 Aug;64(8):1140–1145. doi: 10.1136/adc.64.8.1140. [DOI] [PMC free article] [PubMed] [Google Scholar]
  47. Mollace V., Colasanti M., Persichini T., Bagetta G., Lauro G. M., Nistico G. HIV gp120 glycoprotein stimulates the inducible isoform of no synthase in human cultured astrocytoma cells. Biochem Biophys Res Commun. 1993 Jul 15;194(1):439–445. doi: 10.1006/bbrc.1993.1839. [DOI] [PubMed] [Google Scholar]
  48. Munro H. N. The determination of nucleic acids. Methods Biochem Anal. 1966;14:113–176. doi: 10.1002/9780470110324.ch5. [DOI] [PubMed] [Google Scholar]
  49. Oh S. K., Cruikshank W. W., Raina J., Blanchard G. C., Adler W. H., Walker J., Kornfeld H. Identification of HIV-1 envelope glycoprotein in the serum of AIDS and ARC patients. J Acquir Immune Defic Syndr. 1992;5(3):251–256. [PubMed] [Google Scholar]
  50. Oyaizu N., Chirmule N., Kalyanaraman V. S., Hall W. W., Pahwa R., Shuster M., Pahwa S. Human immunodeficiency virus type 1 envelope glycoprotein gp120 produces immune defects in CD4+ T lymphocytes by inhibiting interleukin 2 mRNA. Proc Natl Acad Sci U S A. 1990 Mar;87(6):2379–2383. doi: 10.1073/pnas.87.6.2379. [DOI] [PMC free article] [PubMed] [Google Scholar]
  51. Pulliam L., West D., Haigwood N., Swanson R. A. HIV-1 envelope gp120 alters astrocytes in human brain cultures. AIDS Res Hum Retroviruses. 1993 May;9(5):439–444. doi: 10.1089/aid.1993.9.439. [DOI] [PubMed] [Google Scholar]
  52. Ryder R. W., Nsa W., Hassig S. E., Behets F., Rayfield M., Ekungola B., Nelson A. M., Mulenda U., Francis H., Mwandagalirwa K. Perinatal transmission of the human immunodeficiency virus type 1 to infants of seropositive women in Zaire. N Engl J Med. 1989 Jun 22;320(25):1637–1642. doi: 10.1056/NEJM198906223202501. [DOI] [PubMed] [Google Scholar]
  53. Said S. I., Berisha H. I., Pakbaz H. Excitotoxicity in the lung: N-methyl-D-aspartate-induced, nitric oxide-dependent, pulmonary edema is attenuated by vasoactive intestinal peptide and by inhibitors of poly(ADP-ribose) polymerase. Proc Natl Acad Sci U S A. 1996 May 14;93(10):4688–4692. doi: 10.1073/pnas.93.10.4688. [DOI] [PMC free article] [PubMed] [Google Scholar]
  54. Sei S., Saito K., Stewart S. K., Crowley J. S., Brouwers P., Kleiner D. E., Katz D. A., Pizzo P. A., Heyes M. P. Increased human immunodeficiency virus (HIV) type 1 DNA content and quinolinic acid concentration in brain tissues from patients with HIV encephalopathy. J Infect Dis. 1995 Sep;172(3):638–647. doi: 10.1093/infdis/172.3.638. [DOI] [PubMed] [Google Scholar]
  55. Sprecher S., Soumenkoff G., Puissant F., Degueldre M. Vertical transmission of HIV in 15-week fetus. Lancet. 1986 Aug 2;2(8501):288–289. doi: 10.1016/s0140-6736(86)92110-0. [DOI] [PubMed] [Google Scholar]
  56. Sundar S. K., Cierpial M. A., Kamaraju L. S., Long S., Hsieh S., Lorenz C., Aaron M., Ritchie J. C., Weiss J. M. Human immunodeficiency virus glycoprotein (gp120) infused into rat brain induces interleukin 1 to elevate pituitary-adrenal activity and decrease peripheral cellular immune responses. Proc Natl Acad Sci U S A. 1991 Dec 15;88(24):11246–11250. doi: 10.1073/pnas.88.24.11246. [DOI] [PMC free article] [PubMed] [Google Scholar]
  57. Tabatabaie T., Stewart C., Pye Q., Kotake Y., Floyd R. A. In vivo trapping of nitric oxide in the brain of neonatal rats treated with the HIV-1 envelope protein gp 120: protective effects of alpha-phenyl-tert-butylnitrone. Biochem Biophys Res Commun. 1996 Apr 16;221(2):386–390. doi: 10.1006/bbrc.1996.0605. [DOI] [PubMed] [Google Scholar]
  58. Taha T. E., Dallabetta G. A., Canner J. K., Chiphangwi J. D., Liomba G., Hoover D. R., Miotti P. G. The effect of human immunodeficiency virus infection on birthweight, and infant and child mortality in urban Malawi. Int J Epidemiol. 1995 Oct;24(5):1022–1029. doi: 10.1093/ije/24.5.1022. [DOI] [PubMed] [Google Scholar]
  59. Toggas S. M., Masliah E., Rockenstein E. M., Rall G. F., Abraham C. R., Mucke L. Central nervous system damage produced by expression of the HIV-1 coat protein gp120 in transgenic mice. Nature. 1994 Jan 13;367(6459):188–193. doi: 10.1038/367188a0. [DOI] [PubMed] [Google Scholar]
  60. Wahl L. M., Corcoran M. L., Pyle S. W., Arthur L. O., Harel-Bellan A., Farrar W. L. Human immunodeficiency virus glycoprotein (gp120) induction of monocyte arachidonic acid metabolites and interleukin 1. Proc Natl Acad Sci U S A. 1989 Jan;86(2):621–625. doi: 10.1073/pnas.86.2.621. [DOI] [PMC free article] [PubMed] [Google Scholar]
  61. 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]
  62. Weinhold K. J., Lyerly H. K., Stanley S. D., Austin A. A., Matthews T. J., Bolognesi D. P. HIV-1 GP120-mediated immune suppression and lymphocyte destruction in the absence of viral infection. J Immunol. 1989 May 1;142(9):3091–3097. [PubMed] [Google Scholar]
  63. Yeung M. C., Pulliam L., Lau A. S. The HIV envelope protein gp120 is toxic to human brain-cell cultures through the induction of interleukin-6 and tumor necrosis factor-alpha. AIDS. 1995 Feb;9(2):137–143. [PubMed] [Google Scholar]

Articles from Journal of Clinical Investigation are provided here courtesy of American Society for Clinical Investigation

RESOURCES