Skip to main content
PMC home page
The Journal of Clinical Investigation logoLink to The Journal of Clinical Investigation
. 1997 Jul 1;100(1):32–39. doi: 10.1172/JCI119518

Transgenic dissection of HIV genes involved in lymphoid depletion.

B T Tinkle 1, H Ueda 1, L Ngo 1, P A Luciw 1, K Shaw 1, C A Rosen 1, G Jay 1
PMCID: PMC508162  PMID: 9202054

Abstract

Transgenic mice carrying an HIV provirus, with selective deletion of all three structural genes, developed extensive lymphoid depletion which was detected not only in the spleen and lymph nodes but also in the thymus. Mice with a high level of HIV gene expression developed acute disease which resulted in premature death, and mice with a low level of viral transcripts developed chronic disease with long-term survival. Neither HIV replication nor the envelope glycoprotein (gp120) was required for T cell depletion. Despite abundant viral gene expression early in life, cell death did not become evident until about the time of full lymphoid maturation, suggesting that thymopoiesis was not affected. The more mature T cells in the peripheral lymphoid organs and in the thymic medulla were less sensitive to the apoptotic process than the immature T cells in the thymic cortex. Gradual depletion of the T cell compartment in the peripheral lymphoid organs was intimately accompanied by the reciprocal expansion of the B cell compartment, resulting in the almost complete replacement of T lymphocytes with B immunoblasts in lymph nodes. Unlike T cells, which showed abundant HIV gene expression, B cells did not. The transgenic approach may help identify the HIV nonstructural gene(s) responsible for immune deficiency and help facilitate dissection of its role in inducing apoptosis.

Full Text

The Full Text of this article is available as a PDF (1.2 MB).

Selected References

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

  1. Abramczuk J. W., Pezen D. S., Leonard J. M., Monell-Torrens E., Belcher J. H., Martin M. A., Notkins A. L. Transgenic mice carrying intact HIV provirus: biological effects and organization of a transgene. J Acquir Immune Defic Syndr. 1992;5(2):196–203. [PubMed] [Google Scholar]
  2. Aldrovandi G. M., Feuer G., Gao L., Jamieson B., Kristeva M., Chen I. S., Zack J. A. The SCID-hu mouse as a model for HIV-1 infection. Nature. 1993 Jun 24;363(6431):732–736. doi: 10.1038/363732a0. [DOI] [PubMed] [Google Scholar]
  3. Amadori A., Chieco-Bianchi L. B-cell activation and HIV-1 infection: deeds and misdeeds. Immunol Today. 1990 Oct;11(10):374–379. doi: 10.1016/0167-5699(90)90144-x. [DOI] [PubMed] [Google Scholar]
  4. Ascher M. S., Sheppard H. W., Krowka J. F., Bremermann H. J. AIDS as immune system activation. Key questions that remain. Adv Exp Med Biol. 1995;374:203–210. doi: 10.1007/978-1-4615-1995-9_17. [DOI] [PubMed] [Google Scholar]
  5. Banda N. K., Bernier J., Kurahara D. K., Kurrle R., Haigwood N., Sekaly R. P., Finkel T. H. Crosslinking CD4 by human immunodeficiency virus gp120 primes T cells for activation-induced apoptosis. J Exp Med. 1992 Oct 1;176(4):1099–1106. doi: 10.1084/jem.176.4.1099. [DOI] [PMC free article] [PubMed] [Google Scholar]
  6. Berberian L., Valles-Ayoub Y., Sun N., Martinez-Maza O., Braun J. A VH clonal deficit in human immunodeficiency virus-positive individuals reflects a B-cell maturational arrest. Blood. 1991 Jul 1;78(1):175–179. [PubMed] [Google Scholar]
  7. Bonyhadi M. L., Rabin L., Salimi S., Brown D. A., Kosek J., McCune J. M., Kaneshima H. HIV induces thymus depletion in vivo. Nature. 1993 Jun 24;363(6431):728–732. doi: 10.1038/363728a0. [DOI] [PubMed] [Google Scholar]
  8. Burns B. F., Wood G. S., Dorfman R. F. The varied histopathology of lymphadenopathy in the homosexual male. Am J Surg Pathol. 1985 Apr;9(4):287–297. doi: 10.1097/00000478-198504000-00005. [DOI] [PubMed] [Google Scholar]
  9. Cochrane A. W., Perkins A., Rosen C. A. Identification of sequences important in the nucleolar localization of human immunodeficiency virus Rev: relevance of nucleolar localization to function. J Virol. 1990 Feb;64(2):881–885. doi: 10.1128/jvi.64.2.881-885.1990. [DOI] [PMC free article] [PubMed] [Google Scholar]
  10. Diebold J., Audouin J., Le Tourneau A., Prevot S., Szekeres G. Lymph node reaction patterns in patients with AIDS or AIDS-related complex. Curr Top Pathol. 1991;84(Pt 2):189–221. doi: 10.1007/978-3-642-75522-4_6. [DOI] [PubMed] [Google Scholar]
  11. Emilie D., Fior R., Llorente L., Marfaing-Koka A., Peuchmaur M., Devergne O., Jarrousse B., Wijdenes J., Boue F., Galanaud P. Cytokines from lymphoid organs of HIV-infected patients: production and role in the immune disequilibrium of the disease and in the development of B lymphomas. Immunol Rev. 1994 Aug;140:5–34. doi: 10.1111/j.1600-065x.1994.tb00863.x. [DOI] [PubMed] [Google Scholar]
  12. Estaquier J., Idziorek T., de Bels F., Barré-Sinoussi F., Hurtrel B., Aubertin A. M., Venet A., Mehtali M., Muchmore E., Michel P. Programmed cell death and AIDS: significance of T-cell apoptosis in pathogenic and nonpathogenic primate lentiviral infections. Proc Natl Acad Sci U S A. 1994 Sep 27;91(20):9431–9435. doi: 10.1073/pnas.91.20.9431. [DOI] [PMC free article] [PubMed] [Google Scholar]
  13. Fauci A. S. Multifactorial nature of human immunodeficiency virus disease: implications for therapy. Science. 1993 Nov 12;262(5136):1011–1018. doi: 10.1126/science.8235617. [DOI] [PubMed] [Google Scholar]
  14. Finkel T. H., Tudor-Williams G., Banda N. K., Cotton M. F., Curiel T., Monks C., Baba T. W., Ruprecht R. M., Kupfer A. Apoptosis occurs predominantly in bystander cells and not in productively infected cells of HIV- and SIV-infected lymph nodes. Nat Med. 1995 Feb;1(2):129–134. doi: 10.1038/nm0295-129. [DOI] [PubMed] [Google Scholar]
  15. Gallo R. C., Montagnier L. AIDS in 1988. Sci Am. 1988 Oct;259(4):41–48. [PubMed] [Google Scholar]
  16. Gavrieli Y., Sherman Y., Ben-Sasson S. A. Identification of programmed cell death in situ via specific labeling of nuclear DNA fragmentation. J Cell Biol. 1992 Nov;119(3):493–501. doi: 10.1083/jcb.119.3.493. [DOI] [PMC free article] [PubMed] [Google Scholar]
  17. Gougeon M. L., Laurent-Crawford A. G., Hovanessian A. G., Montagnier L. Direct and indirect mechanisms mediating apoptosis during HIV infection: contribution to in vivo CD4 T cell depletion. Semin Immunol. 1993 Jun;5(3):187–194. doi: 10.1006/smim.1993.1022. [DOI] [PubMed] [Google Scholar]
  18. Ho D. D., Neumann A. U., Perelson A. S., Chen W., Leonard J. M., Markowitz M. Rapid turnover of plasma virions and CD4 lymphocytes in HIV-1 infection. Nature. 1995 Jan 12;373(6510):123–126. doi: 10.1038/373123a0. [DOI] [PubMed] [Google Scholar]
  19. Ioachim H. L., Lerner C. W., Tapper M. L. Lymphadenopathies in homosexual men. Relationships with the acquired immune deficiency syndrome. JAMA. 1983 Sep 9;250(10):1306–1309. doi: 10.1001/jama.250.10.1306. [DOI] [PubMed] [Google Scholar]
  20. Jowett J. B., Planelles V., Poon B., Shah N. P., Chen M. L., Chen I. S. The human immunodeficiency virus type 1 vpr gene arrests infected T cells in the G2 + M phase of the cell cycle. J Virol. 1995 Oct;69(10):6304–6313. doi: 10.1128/jvi.69.10.6304-6313.1995. [DOI] [PMC free article] [PubMed] [Google Scholar]
  21. Laurent-Crawford A. G., Krust B., Muller S., Rivière Y., Rey-Cuillé M. A., Béchet J. M., Montagnier L., Hovanessian A. G. The cytopathic effect of HIV is associated with apoptosis. Virology. 1991 Dec;185(2):829–839. doi: 10.1016/0042-6822(91)90554-o. [DOI] [PubMed] [Google Scholar]
  22. Laurent-Crawford A. G., Krust B., Rivière Y., Desgranges C., Muller S., Kieny M. P., Dauguet C., Hovanessian A. G. Membrane expression of HIV envelope glycoproteins triggers apoptosis in CD4 cells. AIDS Res Hum Retroviruses. 1993 Aug;9(8):761–773. doi: 10.1089/aid.1993.9.761. [DOI] [PubMed] [Google Scholar]
  23. Levy J. A., Hoffman A. D., Kramer S. M., Landis J. A., Shimabukuro J. M., Oshiro L. S. Isolation of lymphocytopathic retroviruses from San Francisco patients with AIDS. Science. 1984 Aug 24;225(4664):840–842. doi: 10.1126/science.6206563. [DOI] [PubMed] [Google Scholar]
  24. Levy J. A. Pathogenesis of human immunodeficiency virus infection. Microbiol Rev. 1993 Mar;57(1):183–289. doi: 10.1128/mr.57.1.183-289.1993. [DOI] [PMC free article] [PubMed] [Google Scholar]
  25. Li C. J., Friedman D. J., Wang C., Metelev V., Pardee A. B. Induction of apoptosis in uninfected lymphocytes by HIV-1 Tat protein. Science. 1995 Apr 21;268(5209):429–431. doi: 10.1126/science.7716549. [DOI] [PubMed] [Google Scholar]
  26. Maldarelli F., Sato H., Berthold E., Orenstein J., Martin M. A. Rapid induction of apoptosis by cell-to-cell transmission of human immunodeficiency virus type 1. J Virol. 1995 Oct;69(10):6457–6465. doi: 10.1128/jvi.69.10.6457-6465.1995. [DOI] [PMC free article] [PubMed] [Google Scholar]
  27. Martínez-Maza O., Crabb E., Mitsuyasu R. T., Fahey J. L., Giorgi J. V. Infection with the human immunodeficiency virus (HIV) is associated with an in vivo increase in B lymphocyte activation and immaturity. J Immunol. 1987 Jun 1;138(11):3720–3724. [PubMed] [Google Scholar]
  28. McGrath M. S., Shiramizu B., Meeker T. C., Kaplan L. D., Herndier B. AIDS-associated polyclonal lymphoma: identification of a new HIV-associated disease process. J Acquir Immune Defic Syndr. 1991;4(4):408–415. [PubMed] [Google Scholar]
  29. Meyaard L., Otto S. A., Jonker R. R., Mijnster M. J., Keet R. P., Miedema F. Programmed death of T cells in HIV-1 infection. Science. 1992 Jul 10;257(5067):217–219. doi: 10.1126/science.1352911. [DOI] [PubMed] [Google Scholar]
  30. Miyazaki Y., Takamatsu T., Nosaka T., Fujita S., Martin T. E., Hatanaka M. The cytotoxicity of human immunodeficiency virus type 1 Rev: implications for its interaction with the nucleolar protein B23. Exp Cell Res. 1995 Jul;219(1):93–101. doi: 10.1006/excr.1995.1209. [DOI] [PubMed] [Google Scholar]
  31. Papadopoulos N. M., Lane H. C., Costello R., Moutsopoulos H. M., Masur H., Gelmann E. P., Fauci A. S. Oligoclonal immunoglobulins in patients with the acquired immunodeficiency syndrome. Clin Immunol Immunopathol. 1985 Apr;35(1):43–46. doi: 10.1016/0090-1229(85)90076-5. [DOI] [PubMed] [Google Scholar]
  32. Reddy M. M., Goetz R. R., Gorman J. M., Grieco M. H., Chess L., Lederman S. Human immunodeficiency virus type-1 infection of homosexual men is accompanied by a decrease in circulating B cells. J Acquir Immune Defic Syndr. 1991;4(4):428–434. [PubMed] [Google Scholar]
  33. Roederer M., Dubs J. G., Anderson M. T., Raju P. A., Herzenberg L. A., Herzenberg L. A. CD8 naive T cell counts decrease progressively in HIV-infected adults. J Clin Invest. 1995 May;95(5):2061–2066. doi: 10.1172/JCI117892. [DOI] [PMC free article] [PubMed] [Google Scholar]
  34. Rogel M. E., Wu L. I., Emerman M. The human immunodeficiency virus type 1 vpr gene prevents cell proliferation during chronic infection. J Virol. 1995 Feb;69(2):882–888. doi: 10.1128/jvi.69.2.882-888.1995. [DOI] [PMC free article] [PubMed] [Google Scholar]
  35. Sanchez-Pescador R., Power M. D., Barr P. J., Steimer K. S., Stempien M. M., Brown-Shimer S. L., Gee W. W., Renard A., Randolph A., Levy J. A. Nucleotide sequence and expression of an AIDS-associated retrovirus (ARV-2). Science. 1985 Feb 1;227(4686):484–492. doi: 10.1126/science.2578227. [DOI] [PubMed] [Google Scholar]
  36. Sandstrom P. A., Roberts B., Folks T. M., Buttke T. M. HIV gene expression enhances T cell susceptibility to hydrogen peroxide-induced apoptosis. AIDS Res Hum Retroviruses. 1993 Nov;9(11):1107–1113. doi: 10.1089/aid.1993.9.1107. [DOI] [PubMed] [Google Scholar]
  37. Schwartz S., Felber B. K., Benko D. M., Fenyö E. M., Pavlakis G. N. Cloning and functional analysis of multiply spliced mRNA species of human immunodeficiency virus type 1. J Virol. 1990 Jun;64(6):2519–2529. doi: 10.1128/jvi.64.6.2519-2529.1990. [DOI] [PMC free article] [PubMed] [Google Scholar]
  38. Shirai A., Cosentino M., Leitman-Klinman S. F., Klinman D. M. Human immunodeficiency virus infection induces both polyclonal and virus-specific B cell activation. J Clin Invest. 1992 Feb;89(2):561–566. doi: 10.1172/JCI115621. [DOI] [PMC free article] [PubMed] [Google Scholar]
  39. Skowronski J., Parks D., Mariani R. Altered T cell activation and development in transgenic mice expressing the HIV-1 nef gene. EMBO J. 1993 Feb;12(2):703–713. doi: 10.1002/j.1460-2075.1993.tb05704.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  40. Stanley S. K., McCune J. M., Kaneshima H., Justement J. S., Sullivan M., Boone E., Baseler M., Adelsberger J., Bonyhadi M., Orenstein J. Human immunodeficiency virus infection of the human thymus and disruption of the thymic microenvironment in the SCID-hu mouse. J Exp Med. 1993 Oct 1;178(4):1151–1163. doi: 10.1084/jem.178.4.1151. [DOI] [PMC free article] [PubMed] [Google Scholar]
  41. Vellutini C., Horschowski N., Philippon V., Gambarelli D., Nave K. A., Filippi P. Development of lymphoid hyperplasia in transgenic mice expressing the HIV tat gene. AIDS Res Hum Retroviruses. 1995 Jan;11(1):21–29. doi: 10.1089/aid.1995.11.21. [DOI] [PubMed] [Google Scholar]
  42. Wei X., Ghosh S. K., Taylor M. E., Johnson V. A., Emini E. A., Deutsch P., Lifson J. D., Bonhoeffer S., Nowak M. A., Hahn B. H. Viral dynamics in human immunodeficiency virus type 1 infection. Nature. 1995 Jan 12;373(6510):117–122. doi: 10.1038/373117a0. [DOI] [PubMed] [Google Scholar]
  43. Weiss R. A. How does HIV cause AIDS? Science. 1993 May 28;260(5112):1273–1279. doi: 10.1126/science.8493571. [DOI] [PubMed] [Google Scholar]

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

RESOURCES