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. 1987 Mar;84(5):1429–1433. doi: 10.1073/pnas.84.5.1429

Fusion as a mediator of cytolysis in mixtures of uninfected CD4+ lymphocytes and cells infected by human immunodeficiency virus.

B Yoffe, D E Lewis, B L Petrie, C A Noonan, J L Melnick, F B Hollinger
PMCID: PMC304444  PMID: 2950525

Abstract

We describe an unusual type of cytopathology in which uninfected CD4+ (helper/inducer) cells (cells expressing the human leukocyte antigen CD4) interact with cells persistently infected with the human immunodeficiency virus (HIV). Prior antigenic stimulation was not required, since CD4+ cells taken either from healthy persons without anti-HIV antibodies or from individuals with anti-HIV antibodies were capable of inducing cytolysis. Neither CD8+ (suppressor/cytotoxic) nor CD16+ (natural killer) cells mediated the reaction. Light microscopic and autoradiographic studies revealed that, prior to cytolysis, multinucleated giant cells were formed from fusions between HIV-infected cells and large numbers of uninfected CD4+ lymphocytes. These data may explain the paradox that exists in vivo in which a dramatic depletion of CD4+ lymphocytes occurs in the presence of a small number of HIV-infected CD4+ cells. These new insights into the pathogenesis of acquired immunodeficiency syndrome (AIDS) may lead to future therapeutic strategies.

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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. Brynes R. K., Chan W. C., Spira T. J., Ewing E. P., Jr, Chandler F. W. Value of lymph node biopsy in unexplained lymphadenopathy in homosexual men. JAMA. 1983 Sep 9;250(10):1313–1317. [PubMed] [Google Scholar]
  3. Budka H. Multinucleated giant cells in brain: a hallmark of the acquired immune deficiency syndrome (AIDS). Acta Neuropathol. 1986;69(3-4):253–258. doi: 10.1007/BF00688301. [DOI] [PubMed] [Google Scholar]
  4. Casali P., Oldstone M. B. Mechanisms of killing of measles virus-infected cells by human lymphocytes: interferon associated and unassociated cell-mediated cytotoxicity. Cell Immunol. 1982 Jul 1;70(2):330–344. doi: 10.1016/0008-8749(82)90334-3. [DOI] [PubMed] [Google Scholar]
  5. 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]
  6. Essex M., McLane M. F., Lee T. H., Falk L., Howe C. W., Mullins J. I., Cabradilla C., Francis D. P. Antibodies to cell membrane antigens associated with human T-cell leukemia virus in patients with AIDS. Science. 1983 May 20;220(4599):859–862. doi: 10.1126/science.6342136. [DOI] [PubMed] [Google Scholar]
  7. Finberg R., Benacerraf B. Induction, control and consequences of virus specific cytotoxic T cells. Immunol Rev. 1981;58:157–180. doi: 10.1111/j.1600-065x.1981.tb00353.x. [DOI] [PubMed] [Google Scholar]
  8. Gallo R. C., Salahuddin S. Z., Popovic M., Shearer G. M., Kaplan M., Haynes B. F., Palker T. J., Redfield R., Oleske J., Safai B. Frequent detection and isolation of cytopathic retroviruses (HTLV-III) from patients with AIDS and at risk for AIDS. Science. 1984 May 4;224(4648):500–503. doi: 10.1126/science.6200936. [DOI] [PubMed] [Google Scholar]
  9. 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]
  10. Gonda M. A., Wong-Staal F., Gallo R. C., Clements J. E., Narayan O., Gilden R. V. Sequence homology and morphologic similarity of HTLV-III and visna virus, a pathogenic lentivirus. Science. 1985 Jan 11;227(4683):173–177. doi: 10.1126/science.2981428. [DOI] [PubMed] [Google Scholar]
  11. 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]
  12. Hoxie J. A., Flaherty L. E., Haggarty B. S., Rackowski J. L. Infection of T4 lymphocytes by HTLV-III does not require expression of the OKT4 epitope. J Immunol. 1986 Jan;136(2):361–363. [PubMed] [Google Scholar]
  13. Jenkins R. N., Rich R. R. Characterization of determinants encoded by four Qa-1 genotypes and their recognition by cloned cytotoxic T lymphocytes. J Immunol. 1983 Nov;131(5):2147–2153. [PubMed] [Google Scholar]
  14. Joshi V. V., Oleske J. M., Minnefor A. B., Singh R., Bokhari T., Rapkin R. H. Pathology of suspected acquired immune deficiency syndrome in children: a study of eight cases. Pediatr Pathol. 1984;2(1):71–87. doi: 10.3109/15513818409041189. [DOI] [PubMed] [Google Scholar]
  15. 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]
  16. 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]
  17. Lifson J. D., Reyes G. R., McGrath M. S., Stein B. S., Engleman E. G. AIDS retrovirus induced cytopathology: giant cell formation and involvement of CD4 antigen. Science. 1986 May 30;232(4754):1123–1127. doi: 10.1126/science.3010463. [DOI] [PubMed] [Google Scholar]
  18. McDougal J. S., Kennedy M. S., Sligh J. M., Cort S. P., Mawle A., Nicholson J. K. Binding of HTLV-III/LAV to T4+ T cells by a complex of the 110K viral protein and the T4 molecule. Science. 1986 Jan 24;231(4736):382–385. doi: 10.1126/science.3001934. [DOI] [PubMed] [Google Scholar]
  19. McDougal J. S., Mawle A., Cort S. P., Nicholson J. K., Cross G. D., Scheppler-Campbell J. A., Hicks D., Sligh J. Cellular tropism of the human retrovirus HTLV-III/LAV. I. Role of T cell activation and expression of the T4 antigen. J Immunol. 1985 Nov;135(5):3151–3162. [PubMed] [Google Scholar]
  20. Meuer S. C., Schlossman S. F., Reinherz E. L. Clonal analysis of human cytotoxic T lymphocytes: T4+ and T8+ effector T cells recognize products of different major histocompatibility complex regions. Proc Natl Acad Sci U S A. 1982 Jul;79(14):4395–4399. doi: 10.1073/pnas.79.14.4395. [DOI] [PMC free article] [PubMed] [Google Scholar]
  21. Miyasaka N., Darnell B., Baron S., Talal N. Interleukin 2 enhances natural killing of normal lymphocytes. Cell Immunol. 1984 Mar;84(1):154–162. doi: 10.1016/0008-8749(84)90086-8. [DOI] [PubMed] [Google Scholar]
  22. Ortaldo J. R., Mason A. T., Gerard J. P., Henderson L. E., Farrar W., Hopkins R. F., 3rd, Herberman R. B., Rabin H. Effects of natural and recombinant IL 2 on regulation of IFN gamma production and natural killer activity: lack of involvement of the Tac antigen for these immunoregulatory effects. J Immunol. 1984 Aug;133(2):779–783. [PubMed] [Google Scholar]
  23. 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]
  24. Santoli D., Trinchieri G., Koprowski H. Cell-mediated cytotoxicity against virus-infected target cells in humans. II. Interferon induction and activation of natural killer cells. J Immunol. 1978 Aug;121(2):532–538. [PubMed] [Google Scholar]
  25. Schroff R. W., Gottlieb M. S., Prince H. E., Chai L. L., Fahey J. L. Immunological studies of homosexual men with immunodeficiency and Kaposi's sarcoma. Clin Immunol Immunopathol. 1983 Jun;27(3):300–314. doi: 10.1016/0090-1229(83)90083-1. [DOI] [PubMed] [Google Scholar]
  26. Seligmann M., Chess L., Fahey J. L., Fauci A. S., Lachmann P. J., L'Age-Stehr J., Ngu J., Pinching A. J., Rosen F. S., Spira T. J. AIDS--an immunologic reevaluation. N Engl J Med. 1984 Nov 15;311(20):1286–1292. doi: 10.1056/NEJM198411153112005. [DOI] [PubMed] [Google Scholar]
  27. Shaw G. M., Harper M. E., Hahn B. H., Epstein L. G., Gajdusek D. C., Price R. W., Navia B. A., Petito C. K., O'Hara C. J., Groopman J. E. HTLV-III infection in brains of children and adults with AIDS encephalopathy. Science. 1985 Jan 11;227(4683):177–182. doi: 10.1126/science.2981429. [DOI] [PubMed] [Google Scholar]
  28. 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]
  29. Sonigo P., Alizon M., Staskus K., Klatzmann D., Cole S., Danos O., Retzel E., Tiollais P., Haase A., Wain-Hobson S. Nucleotide sequence of the visna lentivirus: relationship to the AIDS virus. Cell. 1985 Aug;42(1):369–382. doi: 10.1016/s0092-8674(85)80132-x. [DOI] [PubMed] [Google Scholar]
  30. Stein G. H., Yanishevsky R. Autoradiography. Methods Enzymol. 1979;58:279–292. doi: 10.1016/s0076-6879(79)58143-9. [DOI] [PubMed] [Google Scholar]
  31. Swain S. L., Dennert G., Wormsley S., Dutton R. W. The Lyt phenotype of a long-term allospecific T cell line. Both helper and killer activities to IA are mediated by Ly-1 cells. Eur J Immunol. 1981 Mar;11(3):175–180. doi: 10.1002/eji.1830110304. [DOI] [PubMed] [Google Scholar]
  32. Swain S. L. T cell subsets and the recognition of MHC class. Immunol Rev. 1983;74:129–142. doi: 10.1111/j.1600-065x.1983.tb01087.x. [DOI] [PubMed] [Google Scholar]
  33. Thomas Y., Sosman J., Irigoyen O., Friedman S. M., Kung P. C., Goldstein G., Chess L. Functional analysis of human T cell subsets defined by monoclonal antibodies. I. Collaborative T-T interactions in the immunoregulation of B cell differentiation. J Immunol. 1980 Dec;125(6):2402–2408. [PubMed] [Google Scholar]
  34. Wain-Hobson S., Alizon M., Montagnier L. Relationship of AIDS to other retroviruses. 1985 Feb 28-Mar 6Nature. 313(6005):743–743. doi: 10.1038/313743a0. [DOI] [PubMed] [Google Scholar]
  35. West W. H., Cannon G. B., Kay H. D., Bonnard G. D., Herberman R. B. Natural cytotoxic reactivity of human lymphocytes against a myeloid cell line: characterization of effector cells. J Immunol. 1977 Jan;118(1):355–361. [PubMed] [Google Scholar]
  36. 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]

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