viewpoint
Programmed cell death and AIDS: from hypothesis to experiment Jean Claude Ameisen Here, Jean Claude Ameisen discusses new findings supporting the hypothesis that abnormal induction of programmed cell death (PCD) is relevant to AIDS patbogenesis. Recent evidence also suggests that the prevention of PCD is a factor in oncogenesis. Together, these ideas provide a framework for the reinterpretation of cell survival disorders in terms of PCD dysregulation, and suggest that in vivo control of cell signalling has wide-ranging therapeutic potential. Programmed cell death (PCD, also known as apoptosis), an active cell suicide process, has long been recognized as an important feature in embryonic development, in particular in shaping the immune and nervous systems 1-3. It also occurs in adult tissues. PCD is regulated by signals provided by the local environment2.3; unlike cell degeneration or necrosis, PCD can be induced or suppressed by the withdrawal or addition of defined activation signals 2,3. In a previous paper in this journal 4, submitted in May 1990, it was proposed that inappropriate induction of PCD may play a central role in the pathogenesis of acquired immune deficiency syndrome (MDS). The idea presented was that most immunological and nonimmunological defects leading to AIDS, including brain atrophy and dementia, could be related to an activation-induced suicide process in CD4 + T cells and neurons, caused by indirect interference of human immunodeficiency virus (HIV) with inter: and intracellular signalling. The hypothesis made several testable predictions, based on the assumption that both early in vitro dysfunction and late in vivo depletion of CD4+ T cells are due to PCD, and that modulation of cell signalling may prevent death and restore normal CD4 + T-cell functions 4. During the last two years, a series of experimental observations have provided support for this model, by indicating that Tcell receptor (TCR) stimulation can lead to PCD in mature T cells in several circumstances, including mouse and human acquired immune deficiencies of retroviral origin.
proliferation to the stimuli, including proliferation of memory T cells to a recall antigen (tetanus) not encountered by the patients since they become infected by HW. Secondly, Montagnier's group reported that poor in vitro survival of lymphocytes from HIV-infected individuals is due to PCD induction 7, and observed activation-induced PCD of CD4 ÷ and CD8* T cells in response to calcium ionophore and of CD4 ÷ T cells in response to superantigens. Third, Miedema and colleagues reported that the failure of T cells from HIVinfected individuals to proliferate in response to suboptimal doses of a particular CD3 mAb of IgE isotype was related to CD4 * and CD8* T-cell PCD induction 8. Fourth, the in vitro cytopathic effect on CD4+ T cells of HIV itself was shown by Carson et al.9 and Hovanessian et al? ° to be due to PCD, a finding that provided an explanation for the previous observation that death of HIV-infected CD4 + T cells in vitro is preceded by the accumulation of histones ~, a consequence of internucleosome cleavage during PCD. Fifth, and finally, extending the observation of Newell et al.~2 on the effect of CD4 crosslinking on murine T cells, FinkeW reported that CD4 ligation by gpl20 plus anti-gpl20 antibodies primes normal human CD4+ T cells for PCD in response to subsequent TCR stimulation. This suggests that both the HIV envelope protein and the immune response to it may play a role in PCD induction in AIDS. PCD induction and AIDS
HIV and CD4* T-cell PCD T-cell PCD and AIDS Several lines of evidence suggest a relationship between T-cell dysfunction, T-cell PCD and AIDS. First, we observed that CD4 + T cells from HIV-infected asymptomatic individuals undergo PCD upon in vitro stimulation by pokeweed mitogen or by TCR stimulation by self major histocompatibility complex (MHC) class II-dependent superantigens s,6. The death of the cells is an active process that can be prevented by protein synthesis inhibitors or by cyclosporin A. Furthermore, the addition of a co-signal, in the form of an anti-CD28 monoclonal antibody (mAb), prevents both CD4 • T-cell suicide and restores normal T-cell
The HIV proteins gpl20 (Ref. 13) and tat (Ref. 14), as well as anti-envelope antibodies that crossreact with MHC class II molecules ~s, inhibit antigen-specific proliferation of normal CD4 + T cells in vitro. Of these, gp120 has been reevaluated in terms of PCD induction; it therefore provides the first, but perhaps not the only, candidate for PCD induction in AIDS. An important question is whether co-signals, such as that provided by anti-CD28 mAb (Ref. 6) or cytokines 7, which prevent PCD in T cells from HIV-infected individuals, also prevent gp120-mediated PCD induction in normal CD4 + T cells. If so, then it is possible that HIV envelope proteins, rather than HIV superinfection 9, accounts for
© 1992, Elsevier Science Publishers Ltd, UK.
Immunology Today
388
vol 13 No. 10 1992
viewpoint PCD in productively infected CD4 + T-cell cultures: envelope proteins expressed on the surface of HIVinfected cells may lead to PCD in neighbouring activated but uninfected cells by crosslinking the CD4 molecule, thus interfering with activation signals that prevent T-cell death. Support for this hypothesis comes from the recent finding that the cytopathic effects of the envelope-CD4 interaction between infected and uninfected CD4* T cells requires intracellular signalling~6; and that such envelope-CD4 interaction leads to PCD (A. Hovanessian, abstract presented at the VIII International Conference on AIDS, Amsterdam, July 1992). A far reaching implication of these findings is that modulation of cell signalling may prevent PCD and allow HIV infection to proceed in the absence of T-cell death. Additional mechanisms, which are not mutually exclusive, may contribute to PCD induction in HIV infection. For example, two series of findings have led Janeway ~" to propose that variable H1V-encoded superantigens exist. First, superantigens induce PCD, in vivo, of CI)4 + T cells that express the appropriate Vb TCR molecule js (after an initial phase of intense T-cell proliferation) leading to T-cell depletion rather than Tcell memory. Secondly, the selective depletion of T cells bearing particular VI, families in murine retroviral (MMTV) infection is caused by retrovirus-encoded superantigens I~. Selective T-cell depletion has been reported in AIDS patients >, but HIV-encoded superantigens have not yet been identified. The possible role of autoimmunity in AIDS pathogenesis-'* should also be taken into consideration. The finding that antibodies against T-cell surface molecules, such as Fas (Ref. 22) induce apoptosis in normal, acti-rated T cells, provides a rationale for the involvement of autoantibodies in PCI) induction. On the basis of similarities between AIDS and graft versus host diseases2~, it has been suggested that autoimmune mechanisms may involve molecular mimicry between gpl60 and MHC class II molecules Is,2
Programmed cell death and AIDS: from hypothesis to experiment Jean Claude Ameisen Here, Jean Claude Ameisen discusses new findings supporting the hypothesis that abnormal induction of programmed cell death (PCD) is relevant to AIDS patbogenesis. Recent evidence also suggests that the prevention of PCD is a factor in oncogenesis. Together, these ideas provide a framework for the reinterpretation of cell survival disorders in terms of PCD dysregulation, and suggest that in vivo control of cell signalling has wide-ranging therapeutic potential. Programmed cell death (PCD, also known as apoptosis), an active cell suicide process, has long been recognized as an important feature in embryonic development, in particular in shaping the immune and nervous systems 1-3. It also occurs in adult tissues. PCD is regulated by signals provided by the local environment2.3; unlike cell degeneration or necrosis, PCD can be induced or suppressed by the withdrawal or addition of defined activation signals 2,3. In a previous paper in this journal 4, submitted in May 1990, it was proposed that inappropriate induction of PCD may play a central role in the pathogenesis of acquired immune deficiency syndrome (MDS). The idea presented was that most immunological and nonimmunological defects leading to AIDS, including brain atrophy and dementia, could be related to an activation-induced suicide process in CD4 + T cells and neurons, caused by indirect interference of human immunodeficiency virus (HIV) with inter: and intracellular signalling. The hypothesis made several testable predictions, based on the assumption that both early in vitro dysfunction and late in vivo depletion of CD4+ T cells are due to PCD, and that modulation of cell signalling may prevent death and restore normal CD4 + T-cell functions 4. During the last two years, a series of experimental observations have provided support for this model, by indicating that Tcell receptor (TCR) stimulation can lead to PCD in mature T cells in several circumstances, including mouse and human acquired immune deficiencies of retroviral origin.
proliferation to the stimuli, including proliferation of memory T cells to a recall antigen (tetanus) not encountered by the patients since they become infected by HW. Secondly, Montagnier's group reported that poor in vitro survival of lymphocytes from HIV-infected individuals is due to PCD induction 7, and observed activation-induced PCD of CD4 ÷ and CD8* T cells in response to calcium ionophore and of CD4 ÷ T cells in response to superantigens. Third, Miedema and colleagues reported that the failure of T cells from HIVinfected individuals to proliferate in response to suboptimal doses of a particular CD3 mAb of IgE isotype was related to CD4 * and CD8* T-cell PCD induction 8. Fourth, the in vitro cytopathic effect on CD4+ T cells of HIV itself was shown by Carson et al.9 and Hovanessian et al? ° to be due to PCD, a finding that provided an explanation for the previous observation that death of HIV-infected CD4 + T cells in vitro is preceded by the accumulation of histones ~, a consequence of internucleosome cleavage during PCD. Fifth, and finally, extending the observation of Newell et al.~2 on the effect of CD4 crosslinking on murine T cells, FinkeW reported that CD4 ligation by gpl20 plus anti-gpl20 antibodies primes normal human CD4+ T cells for PCD in response to subsequent TCR stimulation. This suggests that both the HIV envelope protein and the immune response to it may play a role in PCD induction in AIDS. PCD induction and AIDS
HIV and CD4* T-cell PCD T-cell PCD and AIDS Several lines of evidence suggest a relationship between T-cell dysfunction, T-cell PCD and AIDS. First, we observed that CD4 + T cells from HIV-infected asymptomatic individuals undergo PCD upon in vitro stimulation by pokeweed mitogen or by TCR stimulation by self major histocompatibility complex (MHC) class II-dependent superantigens s,6. The death of the cells is an active process that can be prevented by protein synthesis inhibitors or by cyclosporin A. Furthermore, the addition of a co-signal, in the form of an anti-CD28 monoclonal antibody (mAb), prevents both CD4 • T-cell suicide and restores normal T-cell
The HIV proteins gpl20 (Ref. 13) and tat (Ref. 14), as well as anti-envelope antibodies that crossreact with MHC class II molecules ~s, inhibit antigen-specific proliferation of normal CD4 + T cells in vitro. Of these, gp120 has been reevaluated in terms of PCD induction; it therefore provides the first, but perhaps not the only, candidate for PCD induction in AIDS. An important question is whether co-signals, such as that provided by anti-CD28 mAb (Ref. 6) or cytokines 7, which prevent PCD in T cells from HIV-infected individuals, also prevent gp120-mediated PCD induction in normal CD4 + T cells. If so, then it is possible that HIV envelope proteins, rather than HIV superinfection 9, accounts for
© 1992, Elsevier Science Publishers Ltd, UK.
Immunology Today
388
vol 13 No. 10 1992
viewpoint PCD in productively infected CD4 + T-cell cultures: envelope proteins expressed on the surface of HIVinfected cells may lead to PCD in neighbouring activated but uninfected cells by crosslinking the CD4 molecule, thus interfering with activation signals that prevent T-cell death. Support for this hypothesis comes from the recent finding that the cytopathic effects of the envelope-CD4 interaction between infected and uninfected CD4* T cells requires intracellular signalling~6; and that such envelope-CD4 interaction leads to PCD (A. Hovanessian, abstract presented at the VIII International Conference on AIDS, Amsterdam, July 1992). A far reaching implication of these findings is that modulation of cell signalling may prevent PCD and allow HIV infection to proceed in the absence of T-cell death. Additional mechanisms, which are not mutually exclusive, may contribute to PCD induction in HIV infection. For example, two series of findings have led Janeway ~" to propose that variable H1V-encoded superantigens exist. First, superantigens induce PCD, in vivo, of CI)4 + T cells that express the appropriate Vb TCR molecule js (after an initial phase of intense T-cell proliferation) leading to T-cell depletion rather than Tcell memory. Secondly, the selective depletion of T cells bearing particular VI, families in murine retroviral (MMTV) infection is caused by retrovirus-encoded superantigens I~. Selective T-cell depletion has been reported in AIDS patients >, but HIV-encoded superantigens have not yet been identified. The possible role of autoimmunity in AIDS pathogenesis-'* should also be taken into consideration. The finding that antibodies against T-cell surface molecules, such as Fas (Ref. 22) induce apoptosis in normal, acti-rated T cells, provides a rationale for the involvement of autoantibodies in PCI) induction. On the basis of similarities between AIDS and graft versus host diseases2~, it has been suggested that autoimmune mechanisms may involve molecular mimicry between gpl60 and MHC class II molecules Is,2
