Skip to main content
PMC home page
The Journal of Clinical Investigation logoLink to The Journal of Clinical Investigation
. 1997 Apr 1;99(7):1484–1491. doi: 10.1172/JCI119310

Human chorionic gonadotropin hormone prevents wasting syndrome and death in HIV-1 transgenic mice.

S K De 1, C R Wohlenberg 1, N J Marinos 1, D Doodnauth 1, J L Bryant 1, A L Notkins 1
PMCID: PMC507967  PMID: 9119991

Abstract

At birth, transgenic mice, homozygous for the HIV-1 provirus pNL4-3, deleted in gag/pol, are normal in appearance and weight. Within several days after birth, the pups develop a syndrome characterized by dry, scaly, hyperkeratotic skin, growth failure, and death. The possibility that the homozygous embryos are being protected during gestation by a maternal factor led us to treat the newborn animals with various pregnancy-related hormones including human chorionic gonadotropin (hCG), estrogen, progesterone, and dexamethasone. Treatment with hCG prevented death, led to normal growth, and markedly reduced skin lesions. In contrast to the skin of the untreated homozygous pups, which expressed high levels of HIV mRNA and proteins (i.e., gp120 and Nef), the skin of the hCG-treated pups showed a marked reduction in both HIV mRNA and proteins. Discontinuation of hCG resulted in the reappearance of HIV transcripts and proteins, skin lesions, and growth failure resulting in death. In addition, HIV transcripts and proteins were reduced significantly in heterozygous mothers during pregnancy, but reappeared after parturition. Similarly, hCG treatment resulted in a decrease of HIV proteins in the skin of nonpregnant heterozygous transgenic mice. These findings suggest that the inhibiting effect of hCG on HIV expression may be clinically useful in the treatment of HIV infections, and may be responsible, during pregnancy, for the low transmission of HIV from infected mothers to their offspring.

Full Text

The Full Text of this article is available as a PDF (14.7 MB).

Selected References

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

  1. Ahmad N., Venkatesan S. Nef protein of HIV-1 is a transcriptional repressor of HIV-1 LTR. Science. 1988 Sep 16;241(4872):1481–1485. doi: 10.1126/science.3262235. [DOI] [PubMed] [Google Scholar]
  2. Batzer F. R., Schlaff S., Goldfarb A. F., Corson S. L. Serial beta-subunit human chorionic gonadotropin doubling time as a prognosticator of pregnancy outcome in an infertile population. Fertil Steril. 1981 Mar;35(3):307–312. doi: 10.1016/s0015-0282(16)45376-8. [DOI] [PubMed] [Google Scholar]
  3. Bourinbaiar A. S., Lee-Huang S. Anti-HIV effect of beta subunit of human chorionic gonadotropin (beta hCG) in vitro. Immunol Lett. 1995 Jan;44(1):13–18. doi: 10.1016/0165-2478(94)00191-s. [DOI] [PubMed] [Google Scholar]
  4. Bourinbaiar A. S., Nagorny R. Effect of human chorionic gonadotropin (hCG) on reverse transcriptase activity in HIV-1 infected lymphocytes and monocytes. FEMS Microbiol Lett. 1992 Sep 1;75(1):27–30. doi: 10.1016/0378-1097(92)90451-s. [DOI] [PubMed] [Google Scholar]
  5. Bourinbaiar A. S., Nagorny R. Inhibitory effect of human chorionic gonadotropin (hCG) on HIV-1 transmission from lymphocytes to trophoblasts. FEBS Lett. 1992 Aug 31;309(1):82–84. doi: 10.1016/0014-5793(92)80744-2. [DOI] [PubMed] [Google Scholar]
  6. Bruggeman L. A., Thomson M. M., Nelson P. J., Kopp J. B., Rappaport J., Klotman P. E., Klotman M. E. Patterns of HIV-1 mRNA expression in transgenic mice are tissue-dependent. Virology. 1994 Aug 1;202(2):940–948. doi: 10.1006/viro.1994.1416. [DOI] [PubMed] [Google Scholar]
  7. Carr F. E., Chin W. W. Absence of detectable chorionic gonadotropin subunit messenger ribonucleic acids in the rat placenta throughout gestation. Endocrinology. 1985 Mar;116(3):1151–1157. doi: 10.1210/endo-116-3-1151. [DOI] [PubMed] [Google Scholar]
  8. Chard T., Iles R., Wathen N. Why is there a peak of human chorionic gonadotrophin (HCG) in early pregnancy? Hum Reprod. 1995 Jul;10(7):1837–1840. doi: 10.1093/oxfordjournals.humrep.a136187. [DOI] [PubMed] [Google Scholar]
  9. Chomczynski P., Sacchi N. Single-step method of RNA isolation by acid guanidinium thiocyanate-phenol-chloroform extraction. Anal Biochem. 1987 Apr;162(1):156–159. doi: 10.1006/abio.1987.9999. [DOI] [PubMed] [Google Scholar]
  10. De S. K., McMaster M. T., Andrews G. K. Endotoxin induction of murine metallothionein gene expression. J Biol Chem. 1990 Sep 5;265(25):15267–15274. [PubMed] [Google Scholar]
  11. Dickie P., Felser J., Eckhaus M., Bryant J., Silver J., Marinos N., Notkins A. L. HIV-associated nephropathy in transgenic mice expressing HIV-1 genes. Virology. 1991 Nov;185(1):109–119. doi: 10.1016/0042-6822(91)90759-5. [DOI] [PubMed] [Google Scholar]
  12. Faria T. N., Deb S., Kwok S. C., Talamantes F., Soares M. J. Ontogeny of placental lactogen-I and placental lactogen-II expression in the developing rat placenta. Dev Biol. 1990 Oct;141(2):279–291. doi: 10.1016/0012-1606(90)90384-u. [DOI] [PubMed] [Google Scholar]
  13. Fiddes J. C., Talmadge K. Structure, expression, and evolution of the genes for the human glycoprotein hormones. Recent Prog Horm Res. 1984;40:43–78. doi: 10.1016/b978-0-12-571140-1.50006-2. [DOI] [PubMed] [Google Scholar]
  14. 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]
  15. Fritz M. A., Guo S. M. Doubling time of human chorionic gonadotropin (hCG) in early normal pregnancy: relationship to hCG concentration and gestational age. Fertil Steril. 1987 Apr;47(4):584–589. [PubMed] [Google Scholar]
  16. Furth P. A., Westphal H., Hennighausen L. Expression from the HIV-LTR is stimulated by glucocorticoids and pregnancy. AIDS Res Hum Retroviruses. 1990 Apr;6(4):553–560. doi: 10.1089/aid.1990.6.553. [DOI] [PubMed] [Google Scholar]
  17. Grunfeld C., Feingold K. R. Metabolic disturbances and wasting in the acquired immunodeficiency syndrome. N Engl J Med. 1992 Jul 30;327(5):329–337. doi: 10.1056/NEJM199207303270506. [DOI] [PubMed] [Google Scholar]
  18. Kopp J. B., Klotman M. E., Adler S. H., Bruggeman L. A., Dickie P., Marinos N. J., Eckhaus M., Bryant J. L., Notkins A. L., Klotman P. E. Progressive glomerulosclerosis and enhanced renal accumulation of basement membrane components in mice transgenic for human immunodeficiency virus type 1 genes. Proc Natl Acad Sci U S A. 1992 Mar 1;89(5):1577–1581. doi: 10.1073/pnas.89.5.1577. [DOI] [PMC free article] [PubMed] [Google Scholar]
  19. Kopp J. B., Rooney J. F., Wohlenberg C., Dorfman N., Marinos N. J., Bryant J. L., Katz S. I., Notkins A. L., Klotman P. E. Cutaneous disorders and viral gene expression in HIV-1 transgenic mice. AIDS Res Hum Retroviruses. 1993 Mar;9(3):267–275. doi: 10.1089/aid.1993.9.267. [DOI] [PubMed] [Google Scholar]
  20. Lenton E. A., Grudzinskas G. J., Neal L. M., Chard T., Cooke I. D. Chorionic gonadotropin concentration in early human pregnancy: comparison of specific and nonspecific assays. Fertil Steril. 1981 Jan;35(1):40–45. doi: 10.1016/s0015-0282(16)45256-8. [DOI] [PubMed] [Google Scholar]
  21. Lenton E. A., Neal L. M., Sulaiman R. Plasma concentrations of human chorionic gonadotropin from the time of implantation until the second week of pregnancy. Fertil Steril. 1982 Jun;37(6):773–778. doi: 10.1016/s0015-0282(16)46337-5. [DOI] [PubMed] [Google Scholar]
  22. Lunardi-Iskandar Y., Bryant J. L., Zeman R. A., Lam V. H., Samaniego F., Besnier J. M., Hermans P., Thierry A. R., Gill P., Gallo R. C. Tumorigenesis and metastasis of neoplastic Kaposi's sarcoma cell line in immunodeficient mice blocked by a human pregnancy hormone. Nature. 1995 May 4;375(6526):64–68. doi: 10.1038/375064a0. [DOI] [PubMed] [Google Scholar]
  23. Martin R. H., Glass M. R., Chapman C., Wilson G. D., Woods K. L. Human alpha-lactalbumin and hormonal factors in pregnancy and lactation. Clin Endocrinol (Oxf) 1980 Sep;13(3):223–230. doi: 10.1111/j.1365-2265.1980.tb01046.x. [DOI] [PubMed] [Google Scholar]
  24. Matheson P. B., Weedon J., Cappelli M., Abrams E. J., Shaffer N., Bamji M., Krasinski K., Lambert G., Kaul A., Grimm K. Comparison of methods of estimating the mother-to-child transmission rate of human immunodeficiency virus type 1 (HIV-1). New York City Perinatal HIV Transmission Collaborative Study Group. Am J Epidemiol. 1995 Oct 1;142(7):714–718. doi: 10.1093/oxfordjournals.aje.a117701. [DOI] [PubMed] [Google Scholar]
  25. Minkoff H. L., Henderson C., Mendez H., Gail M. H., Holman S., Willoughby A., Goedett J. J., Rubinstein A., Stratton P., Walsh J. H. Pregnancy outcomes among mothers infected with human immunodeficiency virus and uninfected control subjects. Am J Obstet Gynecol. 1990 Nov;163(5 Pt 1):1598–1604. [PubMed] [Google Scholar]
  26. Miotti P. G., Dallabetta G., Ndovi E., Liomba G., Saah A. J., Chiphangwi J. HIV-1 and pregnant women: associated factors, prevalence, estimate of incidence and role in fetal wastage in central Africa. AIDS. 1990 Aug;4(8):733–736. [PubMed] [Google Scholar]
  27. Ogren L., Talamantes F. Prolactins of pregnancy and their cellular source. Int Rev Cytol. 1988;112:1–65. doi: 10.1016/s0074-7696(08)62005-7. [DOI] [PubMed] [Google Scholar]
  28. Paz I., Seidman D. S., Mashiach S., Stevenson D. K. Maternal transmission of human immunodeficiency virus-1. Obstet Gynecol Surv. 1994 Aug;49(8):577–584. doi: 10.1097/00006254-199408000-00026. [DOI] [PubMed] [Google Scholar]
  29. Pierce J. G., Parsons T. F. Glycoprotein hormones: structure and function. Annu Rev Biochem. 1981;50:465–495. doi: 10.1146/annurev.bi.50.070181.002341. [DOI] [PubMed] [Google Scholar]
  30. Pierce J. G., Parsons T. F. Glycoprotein hormones: structure and function. Annu Rev Biochem. 1981;50:465–495. doi: 10.1146/annurev.bi.50.070181.002341. [DOI] [PubMed] [Google Scholar]
  31. Rizkallah T., Gurpide E., Vande Wiele R. L. Metabolism of HCG in man. J Clin Endocrinol Metab. 1969 Jan;29(1):92–100. doi: 10.1210/jcem-29-1-92. [DOI] [PubMed] [Google Scholar]
  32. Robertson M. C., Friesen H. G. Two forms of rat placental lactogen revealed by radioimmunoassay. Endocrinology. 1981 Jun;108(6):2388–2390. doi: 10.1210/endo-108-6-2388. [DOI] [PubMed] [Google Scholar]
  33. Santoro T. J., Bryant J. L., Pellicoro J., Klotman M. E., Kopp J. B., Bruggeman L. A., Franks R. R., Notkins A. L., Klotman P. E. Growth failure and AIDS-like cachexia syndrome in HIV-1 transgenic mice. Virology. 1994 May 15;201(1):147–151. doi: 10.1006/viro.1994.1276. [DOI] [PubMed] [Google Scholar]
  34. Shannon K. M., Ammann A. J. Acquired immune deficiency syndrome in childhood. J Pediatr. 1985 Feb;106(2):332–342. doi: 10.1016/s0022-3476(85)80320-6. [DOI] [PubMed] [Google Scholar]
  35. Soudeyns H., Geleziunas R., Shyamala G., Hiscott J., Wainberg M. A. Identification of a novel glucocorticoid response element within the genome of the human immunodeficiency virus type 1. Virology. 1993 Jun;194(2):758–768. doi: 10.1006/viro.1993.1317. [DOI] [PubMed] [Google Scholar]
  36. Spinillo A., Iasci A., Dal Maso J., Di Lenardo L., Grella P., Guaschino S. The effect of fetal infection with human immunodeficiency virus type 1 on birthweight and length of gestation. SIGO Study Group of HIV Infection in Pregnancy. Eur J Obstet Gynecol Reprod Biol. 1994 Oct;57(1):13–17. doi: 10.1016/0028-2243(94)90103-1. [DOI] [PubMed] [Google Scholar]
  37. Talmadge K., Vamvakopoulos N. C., Fiddes J. C. Evolution of the genes for the beta subunits of human chorionic gonadotropin and luteinizing hormone. Nature. 1984 Jan 5;307(5946):37–40. doi: 10.1038/307037a0. [DOI] [PubMed] [Google Scholar]
  38. Temmerman M., Plummer F. A., Mirza N. B., Ndinya-Achola J. O., Wamola I. A., Nagelkerke N., Brunham R. C., Piot P. Infection with HIV as a risk factor for adverse obstetrical outcome. AIDS. 1990 Nov;4(11):1087–1093. doi: 10.1097/00002030-199011000-00006. [DOI] [PubMed] [Google Scholar]
  39. Tepper M. A., Roberts J. L. Evidence for only one beta-luteinizing hormone and no beta-chorionic gonadotropin gene in the rat. Endocrinology. 1984 Jul;115(1):385–391. doi: 10.1210/endo-115-1-385. [DOI] [PubMed] [Google Scholar]
  40. Wang X. P., Oyaizu N., Pahwa S. Correlation of maternal cytophilic human immunodeficiency virus (HIV)-1 V3 loop peptide-specific antibodies in infants with vertical HIV transmission. Pediatr Res. 1995 Sep;38(3):384–389. doi: 10.1203/00006450-199509000-00019. [DOI] [PubMed] [Google Scholar]
  41. Weiss G., O'Byrne M., Hochman J. A., Goldsmith L. T., Rifkin I., Steinetz B. G. Secretion of progesterone and relaxin by the humancorpus luteum at midpregnancy and at term. Obstet Gynecol. 1977 Dec;50(6):679–681. [PubMed] [Google Scholar]
  42. Wurzel J. M., Curatola L. M., Gurr J. A., Goldschmidt A. M., Kourides I. A. The luteotropic activity of rat placenta is not due to a chorionic gonadotropin. Endocrinology. 1983 Nov;113(5):1854–1857. doi: 10.1210/endo-113-5-1854. [DOI] [PubMed] [Google Scholar]

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

RESOURCES