Abstract
During human immunodeficiency virus (HIV) infection there is a profound and selective decrease in the CD4+ population of T lymphocytes. The mechanism of this depletion is not understood, as only a small fraction of all CD4+ cells appear to be productively infected with HIV-1 in seropositive individuals. In the present study, crosslinking of bound gp120 on human CD4+ T cells followed by signaling through the T cell receptor for antigen was found to result in activation-dependent cell death by a form of cell suicide termed apoptosis, or programmed cell death. The data indicate that even picomolar concentrations of gp120 prime T cells for activation-induced cell death, suggesting a mechanism for CD4+ T cell depletion in acquired immune deficiency syndrome (AIDS), particularly in the face of concurrent infection and antigenic challenge with other organisms. These results also provide an explanation for the enhancement of infection by certain antibodies against HIV, and for the paradox that HIV appears to cause AIDS after the onset of antiviral immunity.
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- 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]
- Blumberg R. S., Paradis T., Hartshorn K. L., Vogt M., Ho D. D., Hirsch M. S., Leban J., Sato V. L., Schooley R. T. Antibody-dependent cell-mediated cytotoxicity against cells infected with the human immunodeficiency virus. J Infect Dis. 1987 Dec;156(6):878–884. doi: 10.1093/infdis/156.6.878. [DOI] [PubMed] [Google Scholar]
- Borst J., van Dongen J. J., de Vries E., Comans-Bitter W. M., van Tol M. J., Vossen J. M., Kurrle R. BMA031, a monoclonal antibody suited to identify the T-cell receptor alpha beta/CD3 complex on viable human T lymphocytes in normal and disease states. Hum Immunol. 1990 Nov;29(3):175–188. doi: 10.1016/0198-8859(90)90113-4. [DOI] [PubMed] [Google Scholar]
- Cheng-Mayer C., Homsy J., Evans L. A., Levy J. A. Identification of human immunodeficiency virus subtypes with distinct patterns of sensitivity to serum neutralization. Proc Natl Acad Sci U S A. 1988 Apr;85(8):2815–2819. doi: 10.1073/pnas.85.8.2815. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Choi Y., Kappler J. W., Marrack P. A superantigen encoded in the open reading frame of the 3' long terminal repeat of mouse mammary tumour virus. Nature. 1991 Mar 21;350(6315):203–207. doi: 10.1038/350203a0. [DOI] [PubMed] [Google Scholar]
- Church G. M., Gilbert W. Genomic sequencing. Proc Natl Acad Sci U S A. 1984 Apr;81(7):1991–1995. doi: 10.1073/pnas.81.7.1991. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Cohen J. J. Programmed cell death in the immune system. Adv Immunol. 1991;50:55–85. doi: 10.1016/s0065-2776(08)60822-6. [DOI] [PubMed] [Google Scholar]
- Cole B. C., Atkin C. L. The Mycoplasma arthritidis T-cell mitogen, MAM: a model superantigen. Immunol Today. 1991 Aug;12(8):271–276. doi: 10.1016/0167-5699(91)90125-D. [DOI] [PubMed] [Google Scholar]
- Cruikshank W. W., Center D. M., Pyle S. W., Kornfeld H. Biologic activities of HIV-1 envelope glycoprotein: the effects of crosslinking. Biomed Pharmacother. 1990;44(1):5–11. doi: 10.1016/0753-3322(90)90062-e. [DOI] [PubMed] [Google Scholar]
- 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]
- Duesberg P. H. Retroviruses as carcinogens and pathogens: expectations and reality. Cancer Res. 1987 Mar 1;47(5):1199–1220. [PubMed] [Google Scholar]
- Duke R. C., Cohen J. J. IL-2 addiction: withdrawal of growth factor activates a suicide program in dependent T cells. Lymphokine Res. 1986 Fall;5(4):289–299. [PubMed] [Google Scholar]
- Fauci A. S. The human immunodeficiency virus: infectivity and mechanisms of pathogenesis. Science. 1988 Feb 5;239(4840):617–622. doi: 10.1126/science.3277274. [DOI] [PubMed] [Google Scholar]
- Halstead S. B. Pathogenesis of dengue: challenges to molecular biology. Science. 1988 Jan 29;239(4839):476–481. doi: 10.1126/science.3277268. [DOI] [PubMed] [Google Scholar]
- 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]
- Ho D. D., Sarngadharan M. G., Hirsch M. S., Schooley R. T., Rota T. R., Kennedy R. C., Chanh T. C., Sato V. L. Human immunodeficiency virus neutralizing antibodies recognize several conserved domains on the envelope glycoproteins. J Virol. 1987 Jun;61(6):2024–2028. doi: 10.1128/jvi.61.6.2024-2028.1987. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Homsy J., Meyer M., Tateno M., Clarkson S., Levy J. A. The Fc and not CD4 receptor mediates antibody enhancement of HIV infection in human cells. Science. 1989 Jun 16;244(4910):1357–1360. doi: 10.1126/science.2786647. [DOI] [PubMed] [Google Scholar]
- Hügin A. W., Vacchio M. S., Morse H. C., 3rd A virus-encoded "superantigen" in a retrovirus-induced immunodeficiency syndrome of mice. Science. 1991 Apr 19;252(5004):424–427. doi: 10.1126/science.1850169. [DOI] [PubMed] [Google Scholar]
- Imberti L., Sottini A., Bettinardi A., Puoti M., Primi D. Selective depletion in HIV infection of T cells that bear specific T cell receptor V beta sequences. Science. 1991 Nov 8;254(5033):860–862. doi: 10.1126/science.1948066. [DOI] [PubMed] [Google Scholar]
- Kessler H. A., Blaauw B., Spear J., Paul D. A., Falk L. A., Landay A. Diagnosis of human immunodeficiency virus infection in seronegative homosexuals presenting with an acute viral syndrome. JAMA. 1987 Sep 4;258(9):1196–1199. [PubMed] [Google Scholar]
- 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]
- Lane H. C., Depper J. M., Greene W. C., Whalen G., Waldmann T. A., Fauci A. S. Qualitative analysis of immune function in patients with the acquired immunodeficiency syndrome. Evidence for a selective defect in soluble antigen recognition. N Engl J Med. 1985 Jul 11;313(2):79–84. doi: 10.1056/NEJM198507113130204. [DOI] [PubMed] [Google Scholar]
- Lasky L. A., Groopman J. E., Fennie C. W., Benz P. M., Capon D. J., Dowbenko D. J., Nakamura G. R., Nunes W. M., Renz M. E., Berman P. W. Neutralization of the AIDS retrovirus by antibodies to a recombinant envelope glycoprotein. Science. 1986 Jul 11;233(4760):209–212. doi: 10.1126/science.3014647. [DOI] [PubMed] [Google Scholar]
- Lasky L. A., Nakamura G., Smith D. H., Fennie C., Shimasaki C., Patzer E., Berman P., Gregory T., Capon D. J. Delineation of a region of the human immunodeficiency virus type 1 gp120 glycoprotein critical for interaction with the CD4 receptor. Cell. 1987 Sep 11;50(6):975–985. doi: 10.1016/0092-8674(87)90524-1. [DOI] [PubMed] [Google Scholar]
- 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]
- Ljunggren K., Böttiger B., Biberfeld G., Karlson A., Fenyö E. M., Jondal M. Antibody-dependent cellular cytotoxicity-inducing antibodies against human immunodeficiency virus. Presence at different clinical stages. J Immunol. 1987 Oct 1;139(7):2263–2267. [PubMed] [Google Scholar]
- Lum L. G., Orcutt-Thordarson N., Seigneuret M. C., Hansen J. A. In vitro regulation of immunoglobulin synthesis by T-cell subpopulations defined by a new human T-cell antigen (9.3). Cell Immunol. 1982 Sep 1;72(1):122–129. doi: 10.1016/0008-8749(82)90289-1. [DOI] [PubMed] [Google Scholar]
- 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]
- Maddon P. J., Dalgleish A. G., McDougal J. S., Clapham P. R., Weiss R. A., Axel R. The T4 gene encodes the AIDS virus receptor and is expressed in the immune system and the brain. Cell. 1986 Nov 7;47(3):333–348. doi: 10.1016/0092-8674(86)90590-8. [DOI] [PubMed] [Google Scholar]
- 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]
- 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]
- Newell M. K., Haughn L. J., Maroun C. R., Julius M. H. Death of mature T cells by separate ligation of CD4 and the T-cell receptor for antigen. Nature. 1990 Sep 20;347(6290):286–289. doi: 10.1038/347286a0. [DOI] [PubMed] [Google Scholar]
- 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]
- Ojo-Amaize E. A., Nishanian P., Keith D. E., Jr, Houghton R. L., Heitjan D. F., Fahey J. L., Giorgi J. V. Antibodies to human immunodeficiency virus in human sera induce cell-mediated lysis of human immunodeficiency virus-infected cells. J Immunol. 1987 Oct 1;139(7):2458–2463. [PubMed] [Google Scholar]
- Pellegrino M. A., Ferrone S., Theofilopoulos A. N. Isolation of human T and B lymphocytes by rosette formation with 2-aminoethylisothiquronium bromide (AET) -treated sheep red blood cells with monkey red blood cells. J Immunol Methods. 1976;11(3-4):273–279. doi: 10.1016/0022-1759(76)90120-4. [DOI] [PubMed] [Google Scholar]
- Pyle S. W., Bess J. W., Jr, Robey W. G., Fischinger P. J., Gilden R. V., Arthur L. O. Purification of 120,000 dalton envelope glycoprotein from culture fluids of human immunodeficiency virus (HIV)-infected H9 cells. AIDS Res Hum Retroviruses. 1987;3(4):387–400. doi: 10.1089/aid.1987.3.387. [DOI] [PubMed] [Google Scholar]
- Ranki A., Valle S. L., Krohn M., Antonen J., Allain J. P., Leuther M., Franchini G., Krohn K. Long latency precedes overt seroconversion in sexually transmitted human-immunodeficiency-virus infection. Lancet. 1987 Sep 12;2(8559):589–593. doi: 10.1016/s0140-6736(87)92985-0. [DOI] [PubMed] [Google Scholar]
- Reed K. C., Mann D. A. Rapid transfer of DNA from agarose gels to nylon membranes. Nucleic Acids Res. 1985 Oct 25;13(20):7207–7221. doi: 10.1093/nar/13.20.7207. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Richman D. D., McCutchan J. A., Spector S. A. Detecting human immunodeficiency virus RNA in peripheral blood mononuclear cells by nucleic acid hybridization. J Infect Dis. 1987 Nov;156(5):823–827. doi: 10.1093/infdis/156.5.823. [DOI] [PubMed] [Google Scholar]
- Robinson W. E., Jr, Montefiori D. C., Mitchell W. M. Antibody-dependent enhancement of human immunodeficiency virus type 1 infection. Lancet. 1988 Apr 9;1(8589):790–794. doi: 10.1016/s0140-6736(88)91657-1. [DOI] [PubMed] [Google Scholar]
- Rook A. H., Lane H. C., Folks T., McCoy S., Alter H., Fauci A. S. Sera from HTLV-III/LAV antibody-positive individuals mediate antibody-dependent cellular cytotoxicity against HTLV-III/LAV-infected T cells. J Immunol. 1987 Feb 15;138(4):1064–1067. [PubMed] [Google Scholar]
- 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]
- Sattentau Q. J., Dalgleish A. G., Weiss R. A., Beverley P. C. Epitopes of the CD4 antigen and HIV infection. Science. 1986 Nov 28;234(4780):1120–1123. doi: 10.1126/science.2430333. [DOI] [PubMed] [Google Scholar]
- Schneider J., Kaaden O., Copeland T. D., Oroszlan S., Hunsmann G. Shedding and interspecies type sero-reactivity of the envelope glycopolypeptide gp120 of the human immunodeficiency virus. J Gen Virol. 1986 Nov;67(Pt 11):2533–2538. doi: 10.1099/0022-1317-67-11-2533. [DOI] [PubMed] [Google Scholar]
- Schnittman S. M., Psallidopoulos M. C., Lane H. C., Thompson L., Baseler M., Massari F., Fox C. H., Salzman N. P., Fauci A. S. The reservoir for HIV-1 in human peripheral blood is a T cell that maintains expression of CD4. Science. 1989 Jul 21;245(4915):305–308. doi: 10.1126/science.2665081. [DOI] [PubMed] [Google Scholar]
- Sellins K. S., Cohen J. J. Gene induction by gamma-irradiation leads to DNA fragmentation in lymphocytes. J Immunol. 1987 Nov 15;139(10):3199–3206. [PubMed] [Google Scholar]
- Shearer G. M., Bernstein D. C., Tung K. S., Via C. S., Redfield R., Salahuddin S. Z., Gallo R. C. A model for the selective loss of major histocompatibility complex self-restricted T cell immune responses during the development of acquired immune deficiency syndrome (AIDS). J Immunol. 1986 Oct 15;137(8):2514–2521. [PubMed] [Google Scholar]
- Shepp D. H., Chakrabarti S., Moss B., Quinnan G. V., Jr Antibody-dependent cellular cytotoxicity specific for the envelope antigens of human immunodeficiency virus. J Infect Dis. 1988 Jun;157(6):1260–1264. doi: 10.1093/infdis/157.6.1260. [DOI] [PubMed] [Google Scholar]
- Shi Y. F., Sahai B. M., Green D. R. Cyclosporin A inhibits activation-induced cell death in T-cell hybridomas and thymocytes. Nature. 1989 Jun 22;339(6226):625–626. doi: 10.1038/339625a0. [DOI] [PubMed] [Google Scholar]
- Siliciano R. F., Lawton T., Knall C., Karr R. W., Berman P., Gregory T., Reinherz E. L. Analysis of host-virus interactions in AIDS with anti-gp120 T cell clones: effect of HIV sequence variation and a mechanism for CD4+ cell depletion. Cell. 1988 Aug 12;54(4):561–575. doi: 10.1016/0092-8674(88)90078-5. [DOI] [PubMed] [Google Scholar]
- Smith C. A., Williams G. T., Kingston R., Jenkinson E. J., Owen J. J. Antibodies to CD3/T-cell receptor complex induce death by apoptosis in immature T cells in thymic cultures. Nature. 1989 Jan 12;337(6203):181–184. doi: 10.1038/337181a0. [DOI] [PubMed] [Google Scholar]
- Smith D. H., Byrn R. A., Marsters S. A., Gregory T., Groopman J. E., Capon D. J. Blocking of HIV-1 infectivity by a soluble, secreted form of the CD4 antigen. Science. 1987 Dec 18;238(4834):1704–1707. doi: 10.1126/science.3500514. [DOI] [PubMed] [Google Scholar]
- Spiegel H., Herbst H., Niedobitek G., Foss H. D., Stein H. Follicular dendritic cells are a major reservoir for human immunodeficiency virus type 1 in lymphoid tissues facilitating infection of CD4+ T-helper cells. Am J Pathol. 1992 Jan;140(1):15–22. [PMC free article] [PubMed] [Google Scholar]
- Takeda A., Tuazon C. U., Ennis F. A. Antibody-enhanced infection by HIV-1 via Fc receptor-mediated entry. Science. 1988 Oct 28;242(4878):580–583. doi: 10.1126/science.2972065. [DOI] [PubMed] [Google Scholar]
- Terai C., Kornbluth R. S., Pauza C. D., Richman D. D., Carson D. A. Apoptosis as a mechanism of cell death in cultured T lymphoblasts acutely infected with HIV-1. J Clin Invest. 1991 May;87(5):1710–1715. doi: 10.1172/JCI115188. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Waldmann H. Manipulation of T-cell responses with monoclonal antibodies. Annu Rev Immunol. 1989;7:407–444. doi: 10.1146/annurev.iy.07.040189.002203. [DOI] [PubMed] [Google Scholar]
- 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]
- Wyllie A. H. Glucocorticoid-induced thymocyte apoptosis is associated with endogenous endonuclease activation. Nature. 1980 Apr 10;284(5756):555–556. doi: 10.1038/284555a0. [DOI] [PubMed] [Google Scholar]