Skip to main content
Proceedings of the National Academy of Sciences of the United States of America logoLink to Proceedings of the National Academy of Sciences of the United States of America
. 1988 May;85(10):3570–3574. doi: 10.1073/pnas.85.10.3570

Cytopathic effect of human immunodeficiency virus in T4 cells is linked to the last stage of virus infection.

R Leonard 1, D Zagury 1, I Desportes 1, J Bernard 1, J F Zagury 1, R C Gallo 1
PMCID: PMC280255  PMID: 3259321

Abstract

A principal feature of acquired immunodeficiency syndrome is depletion of T4 lymphocytes, which is partly due to a direct cytopathic effect of the virus. Both syncytial formation (viral-induced cell fusion) and premature cell death have been cited as the major cause for this phenomenon. By kinetic analysis of cell proliferation and cell lysis we show that the cytopathic effect correlates chiefly with virus production from infected cells, including giant syncytial cells. Most T4 cells were, at least transiently, infected by human immunodeficiency virus (human T-lymphotropic virus type IIIB strain); however, after phytohemagglutinin activation, only 10-30% of infected cells express virus (and die) at any one time, indicating that virus production, followed by cell killing, is linked to immune activation and cell differentiation. We also show that an interval exists before viral release, in which expression of viral antigens occurs on the cell surface, suggesting that infected cells are immunogenic before viral production. If so, they may induce a cell-mediated immune response that could minimize dissemination of human immunodeficiency virus, a possibility that has influenced our approaches to the development of a vaccine for prevention of acquired immunodeficiency syndrome.

Full text

PDF
3570

Images in this article

Selected References

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

  1. Barré-Sinoussi F., Chermann J. C., Rey F., Nugeyre M. T., Chamaret S., Gruest J., Dauguet C., Axler-Blin C., Vézinet-Brun F., Rouzioux C. Isolation of a T-lymphotropic retrovirus from a patient at risk for acquired immune deficiency syndrome (AIDS). Science. 1983 May 20;220(4599):868–871. doi: 10.1126/science.6189183. [DOI] [PubMed] [Google Scholar]
  2. Dalgleish A. G., Beverley P. C., Clapham P. R., Crawford D. H., Greaves M. F., Weiss R. A. The CD4 (T4) antigen is an essential component of the receptor for the AIDS retrovirus. Nature. 1984 Dec 20;312(5996):763–767. doi: 10.1038/312763a0. [DOI] [PubMed] [Google Scholar]
  3. De Rossi A., Franchini G., Aldovini A., Del Mistro A., Chieco-Bianchi L., Gallo R. C., Wong-Staal F. Differential response to the cytopathic effects of human T-cell lymphotropic virus type III (HTLV-III) superinfection in T4+ (helper) and T8+ (suppressor) T-cell clones transformed by HTLV-I. Proc Natl Acad Sci U S A. 1986 Jun;83(12):4297–4301. doi: 10.1073/pnas.83.12.4297. [DOI] [PMC free article] [PubMed] [Google Scholar]
  4. Erard F., Corthesy P., Nabholz M., Lowenthal J. W., Zaech P., Plaetinck G., MacDonald H. R. Interleukin 2 is both necessary and sufficient for the growth and differentiation of lectin-stimulated cytolytic T lymphocyte precursors. J Immunol. 1985 Mar;134(3):1644–1652. [PubMed] [Google Scholar]
  5. Feinberg M. B., Jarrett R. F., Aldovini A., Gallo R. C., Wong-Staal F. HTLV-III expression and production involve complex regulation at the levels of splicing and translation of viral RNA. Cell. 1986 Sep 12;46(6):807–817. doi: 10.1016/0092-8674(86)90062-0. [DOI] [PubMed] [Google Scholar]
  6. Fisher A. G., Ratner L., Mitsuya H., Marselle L. M., Harper M. E., Broder S., Gallo R. C., Wong-Staal F. Infectious mutants of HTLV-III with changes in the 3' region and markedly reduced cytopathic effects. Science. 1986 Aug 8;233(4764):655–659. doi: 10.1126/science.3014663. [DOI] [PubMed] [Google Scholar]
  7. Gartner S., Markovits P., Markovitz D. M., Kaplan M. H., Gallo R. C., Popovic M. The role of mononuclear phagocytes in HTLV-III/LAV infection. Science. 1986 Jul 11;233(4760):215–219. doi: 10.1126/science.3014648. [DOI] [PubMed] [Google Scholar]
  8. Harper M. E., Marselle L. M., Gallo R. C., Wong-Staal F. Detection of lymphocytes expressing human T-lymphotropic virus type III in lymph nodes and peripheral blood from infected individuals by in situ hybridization. Proc Natl Acad Sci U S A. 1986 Feb;83(3):772–776. doi: 10.1073/pnas.83.3.772. [DOI] [PMC free article] [PubMed] [Google Scholar]
  9. Hoxie J. A., Alpers J. D., Rackowski J. L., Huebner K., Haggarty B. S., Cedarbaum A. J., Reed J. C. Alterations in T4 (CD4) protein and mRNA synthesis in cells infected with HIV. Science. 1986 Nov 28;234(4780):1123–1127. doi: 10.1126/science.3095925. [DOI] [PubMed] [Google Scholar]
  10. Klatzmann D., Champagne E., Chamaret S., Gruest J., Guetard D., Hercend T., Gluckman J. C., Montagnier L. T-lymphocyte T4 molecule behaves as the receptor for human retrovirus LAV. Nature. 1984 Dec 20;312(5996):767–768. doi: 10.1038/312767a0. [DOI] [PubMed] [Google Scholar]
  11. Klatzmann D., Montagnier L. Approaches to AIDS therapy. Nature. 1986 Jan 2;319(6048):10–11. doi: 10.1038/319010a0. [DOI] [PubMed] [Google Scholar]
  12. Laurence J., Gottlieb A. B., Kunkel H. G. Soluble suppressor factors in patients with acquired immune deficiency syndrome and its prodrome. Elaboration in vitro by T lymphocyte-adherent cell interactions. J Clin Invest. 1983 Dec;72(6):2072–2081. doi: 10.1172/JCI111172. [DOI] [PMC free article] [PubMed] [Google Scholar]
  13. Lifson J. D., Feinberg M. B., Reyes G. R., Rabin L., Banapour B., Chakrabarti S., Moss B., Wong-Staal F., Steimer K. S., Engleman E. G. Induction of CD4-dependent cell fusion by the HTLV-III/LAV envelope glycoprotein. Nature. 1986 Oct 23;323(6090):725–728. doi: 10.1038/323725a0. [DOI] [PubMed] [Google Scholar]
  14. Lyerly H. K., Matthews T. J., Langlois A. J., Bolognesi D. P., Weinhold K. J. Human T-cell lymphotropic virus IIIB glycoprotein (gp120) bound to CD4 determinants on normal lymphocytes and expressed by infected cells serves as target for immune attack. Proc Natl Acad Sci U S A. 1987 Jul;84(13):4601–4605. doi: 10.1073/pnas.84.13.4601. [DOI] [PMC free article] [PubMed] [Google Scholar]
  15. Morein B., Barz D., Koszinowski U., Schirrmacher V. Integration of a virus membrane protein into the lipid bilayer of target cells as a prerequisite for immune cytolysis. Specific cytolysis after virosome-target cell fusion. J Exp Med. 1979 Dec 1;150(6):1383–1398. doi: 10.1084/jem.150.6.1383. [DOI] [PMC free article] [PubMed] [Google Scholar]
  16. Nabel G., Baltimore D. An inducible transcription factor activates expression of human immunodeficiency virus in T cells. Nature. 1987 Apr 16;326(6114):711–713. doi: 10.1038/326711a0. [DOI] [PubMed] [Google Scholar]
  17. Pahwa S., Pahwa R., Saxinger C., Gallo R. C., Good R. A. Influence of the human T-lymphotropic virus/lymphadenopathy-associated virus on functions of human lymphocytes: evidence for immunosuppressive effects and polyclonal B-cell activation by banded viral preparations. Proc Natl Acad Sci U S A. 1985 Dec;82(23):8198–8202. doi: 10.1073/pnas.82.23.8198. [DOI] [PMC free article] [PubMed] [Google Scholar]
  18. Popovic M., Sarngadharan M. G., Read E., Gallo R. C. Detection, isolation, and continuous production of cytopathic retroviruses (HTLV-III) from patients with AIDS and pre-AIDS. Science. 1984 May 4;224(4648):497–500. doi: 10.1126/science.6200935. [DOI] [PubMed] [Google Scholar]
  19. Salahuddin S. Z., Markham P. D., Popovic M., Sarngadharan M. G., Orndorff S., Fladagar A., Patel A., Gold J., Gallo R. C. Isolation of infectious human T-cell leukemia/lymphotropic virus type III (HTLV-III) from patients with acquired immunodeficiency syndrome (AIDS) or AIDS-related complex (ARC) and from healthy carriers: a study of risk groups and tissue sources. Proc Natl Acad Sci U S A. 1985 Aug;82(16):5530–5534. doi: 10.1073/pnas.82.16.5530. [DOI] [PMC free article] [PubMed] [Google Scholar]
  20. Salahuddin S. Z., Rose R. M., Groopman J. E., Markham P. D., Gallo R. C. Human T lymphotropic virus type III infection of human alveolar macrophages. Blood. 1986 Jul;68(1):281–284. [PubMed] [Google Scholar]
  21. Sodroski J., Goh W. C., Rosen C., Campbell K., Haseltine W. A. Role of the HTLV-III/LAV envelope in syncytium formation and cytopathicity. 1986 Jul 31-Aug 6Nature. 322(6078):470–474. doi: 10.1038/322470a0. [DOI] [PubMed] [Google Scholar]
  22. Walker C. M., Moody D. J., Stites D. P., Levy J. A. CD8+ lymphocytes can control HIV infection in vitro by suppressing virus replication. Science. 1986 Dec 19;234(4783):1563–1566. doi: 10.1126/science.2431484. [DOI] [PubMed] [Google Scholar]
  23. Wong-Staal F., Gallo R. C. Human T-lymphotropic retroviruses. Nature. 1985 Oct 3;317(6036):395–403. doi: 10.1038/317395a0. [DOI] [PubMed] [Google Scholar]
  24. Zagury D., Bernard J., Leonard R., Cheynier R., Feldman M., Sarin P. S., Gallo R. C. Long-term cultures of HTLV-III--infected T cells: a model of cytopathology of T-cell depletion in AIDS. Science. 1986 Feb 21;231(4740):850–853. doi: 10.1126/science.2418502. [DOI] [PubMed] [Google Scholar]
  25. Zagury D., Gagne I., Réveil B., Bernard J., Zagury J. F., Saimot A. G., Sarin P. S., Gallo R. C. Repairing the T-cell defect in AIDS. Lancet. 1985 Aug 24;2(8452):449–449. doi: 10.1016/s0140-6736(85)92770-9. [DOI] [PubMed] [Google Scholar]

Articles from Proceedings of the National Academy of Sciences of the United States of America are provided here courtesy of National Academy of Sciences

RESOURCES