Programmed cell death and AIDS: significance of T-cell apoptosis in pathogenic and nonpathogenic primate lentiviral infections.

Estaquier, Jérǒme; Idziorek, Thierry; Bels, Frédéric De; Barré‐Sinoussi, Françoise; Hurtrel, Bruno; Aubertin, Anne-Marie; Venet, Alain; Mehtali, Majid; Muchmore, Elizabeth; Michel, Philippe

doi:10.1073/pnas.91.20.9431

Cited by 241 publications

(187 citation statements)

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“…1,2,[8][9][10] The third proposed mechanism is excessive, ongoing immune activation caused by a high, persistent viral antigen load and leading to the activation-induced death of various uninfected immune cells, including CD4 þ T cells. 1,2,4,8,9 Evidence for the involvement of indirect mechanisms of CD4 þ T-cell killing has been provided by the identification in vivo [11][12][13][14][15][16] and ex vivo [17][18][19] of increased number of dying, uninfected immune cells, including CD4 þ T cells, both in HIV1-infected persons and in non-human primate models of pathogenic simian immunodeficiency virus (SIV) infection, that are closely related to HIV. An important question is whether HIV1 may only cause death in activated, cycling CD4 þ T cells, or also in unstimulated noncycling CD4 þ T cells, which represent at any given time point the vast majority of the CD4 þ T cells in HIV1-infected persons.…”

Section: Introductionmentioning

confidence: 99%

A novel mechanism for HIV1-mediated bystander CD4+ T-cell death: neighboring dying cells drive the capacity of HIV1 to kill noncycling primary CD4+ T cells

et al. 2004

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CD4 þ T-cell death is a crucial feature of AIDS pathogenesis, but the mechanisms involved remain unclear. Here, we present in vitro findings that identify a novel process of HIV1 mediated killing of bystander CD4 þ T cells, which does not require productive infection of these cells but depends on the presence of neighboring dying cells. X4-tropic HIV1 strains, which use CD4 and CXCR4 as receptors for cell entry, caused death of unstimulated noncycling primary CD4 þ T cells only if the viruses were produced by dying, productively infected T cells, but not by living, chronically infected T cells or by living HIV1-transfected HeLa cells. Inducing cell death in HIV1-transfected HeLa cells was sufficient to obtain viruses that caused CD4 þ T-cell death. The addition of supernatants from dying control cells, including primary T cells, allowed viruses produced by living HIV1-transfected cells to cause CD4 þ Tcell death. CD4 þ T-cell killing required HIV1 fusion and/or entry into these cells, but neither HIV1 envelope-mediated CD4 or CXCR4 signaling nor the presence of the HIV1 Nef protein in the viral particles. Supernatants from dying control cells contained CD95 ligand (CD95L), and antibody-mediated neutralization of CD95L prevented these supernatants from complementing HIV1 in inducing CD4 þ T-cell death. Our in vitro findings suggest that the very extent of cell death induced in vivo during HIV1 infection by either virus cytopathic effects or immune activation may by itself provide an amplification loop in AIDS pathogenesis. More generally, they provide a paradigm for pathogen-mediated killing processes in which the extent of cell death occurring in the microenvironment might drive the capacity of the pathogen to induce further cell death.

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Section: Introductionmentioning

confidence: 99%

A novel mechanism for HIV1-mediated bystander CD4+ T-cell death: neighboring dying cells drive the capacity of HIV1 to kill noncycling primary CD4+ T cells

et al. 2004

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“…The activation-induced cell death mechanism that explains the proliferative defects observed in vitro might also account for the progressive in vivo deletion of CD4 T cells. Indeed, studies performed on different models of primates have shown that induction of cell death in CD4 T cells was detected only when T cells were isolated from animals infected with a type of retrovirus that induces an AIDS-like disease [8]. This correlation prompted us to analyse further the mechanism of HIV-induced activation cell death to determine the specificity and rate of induction of cell death.…”

Section: Discussionmentioning

confidence: 99%

“…Moreover, studies performed on various primate models that allow one to discriminate between biological features associated with pathogenic or non-pathogenic chronic lentiviral infections have shown that activation-induced cell death (AICD) of CD4 T cells was only observed in the model leading to AIDS [8]. In contrast, enhanced spontaneous cell death that affects mainly CD8 T cells was observed in both pathogenic and non-pathogenic models of chronic lentiviral infections [8].…”

Section: Introductionmentioning

confidence: 99%

Selective CD4+ T cell deletion after specific activation in HIV-infected individuals; protection by anti-CD28 monoclonal antibodies

Cottrez

Càpron

Groux

1996

Clinical and Experimental Immunology

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SUMMARYAIDS is characterized by a progressive decline in the number of CD4 T cells. This is preceded by an early selective defect in the proliferation of these cells to recall antigens [1][2][3], pokeweed mitogen (PWM) [4][5][6] and to superantigens (SAg) [4,7]. In contrast, the proliferative response to phytohaemagglutinin (PHA) remains intact [1,2,5]. We and others have shown that the proliferative defect in response to some stimuli was in fact due to the induction of cell death [4,7]. The activation-induced cell death mechanism that explains the proliferative defects observed in vitro might also account for the progressive in vivo deletion of CD4 T cells. Indeed, studies performed on different models of primates have shown that induction of cell death in CD4 T cells was detected only when T cells were isolated from animals infected with a type of retrovirus that induces an AIDS-like disease [8]. This correlation prompted us to analyse further the mechanism of HIV-induced activation cell death to determine the specificity and rate of induction of cell death. T cells from HIV-infected individuals were activated with superantigens and the V¯T cell receptor (TCR) expression analysed. Data presented here show that cell death is restricted to activated CD4 T cells, and does not affect bystander cells. More importantly, addition of anti-CD28 MoAb specifically inhibited the induction of apoptosis, raising possibilities for therapy.

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“…Au cours de l'infection par le VIH, les lymphocytes T CD8 sont activés en périphérie, mais cependant leur état de maturation ne leur permet pas d'acquérir une activité importante vis-à-vis du VIH-1 [5]. L'une des hypothèses est que, au cours de la différenciation lymphocytaire, les lymphocytes T sont anormalement sensibles à un processus apoptotique, conduisant de ce fait à un profil de différenciation abortif, expliquant cet état d'immaturité [6][7][8]. L'apoptose est un mécanisme physiologique de suicide cellulaire, essentiel au cours du développement et au contrôle de l'homéostasie des tissus adultes.…”

Section: Inefficacité Du Contrôle Du Virus Par Les Lymphocytes T Cd8unclassified

Sanctuaire du virus de l’immunodéficience humaine et mécanismes d’échappement

Estaquier

Hurtrel

2008

Med Sci (Paris)

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Persistance virale chez les patients VIH : l'hypothèse d'un réservoir cellulaire viralLes avancées dans le traitement de l'infection par le VIH ont permis au cours de ces dernières années de ralentir la progression de la maladie et d'en prévenir les conséquences pathologiques chez une grande majorité de patients. L'introduction des multi-thérapies, associant en particulier des anti-protéases, a réduit de façon considérable la charge virale plasmatique, jusqu'à un niveau indétectable [1]. En dépit d'une diminution rapide, en quelques jours, de cette réplication virale, il existe une seconde phase caractérisée par une réduction de la réplication virale beaucoup plus lente, cette seconde phase pouvant refléter l'existence d'un réservoir cellulaire. Deux types cellulaires peuvent expliquer cette dynamique, le macrophage et le lymphocyte T CD4 au repos ayant intégré le génome viral. Cette persistance virale explique pourquoi les interruptions de traitement conduisent en quelques jours à une réplication virale intense. La charge virale plasmatique atteint alors un niveau équivalent à celui qui préexistait à l'institution de la thérapie, et ce quelle que soit la durée du traitement. Dans la mesure où la multiplication du VIH est la résultante d'un équilibre entre l'infection de nouvelles cibles -les cellules CD4 -, la production de virions et la réponse immunitaire Inefficacité du contrôle du virus par les lymphocytes T CD8À l'époque où ces observations étaient publiées, de nombreux travaux montraient que les lymphocytes T CD8 cytotoxiques -cellules capables de lyser une cellule infectée via l'expression de granzyme B et de perforinesont une arme indispensable au contrôle des agents > Depuis 25 années, l'identification du réservoir du virus de l'immunodéficience humaine (VIH) est source de questions. Dans un travail récent, nous montrons que les ganglions mésentériques drainant la région intestinale pourraient constituer un réservoir majeur du virus. Ce concept a été établi chez un modèle animal, le macaque Rhésus. De plus, parmi les mécanismes susceptibles de participer à la dissémination du virus dans l'ensemble de l'organisme, certains éléments suggèrent le rôle majeur de la mort par apoptose des lymphocytes T CD8. Cette mort cellulaire programmée est associée à une augmentation de l'expression, dans les ganglions, de facteurs immunosuppresseurs comme le TGF-β (transforming growth factor-b), ainsi que des molécules IDO (indoléamine 2, 3 dioxygénase) et PD-1 (programmed death molecule 1) impliquées dans la régulation du métabolisme des lymphocytes T. Ainsi, ces facteurs immunosuppresseurs offrent au virus les conditions favorables à sa persistance au sein de ce sanctuaire. < À la mémoire de Bruno Hurtrel

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Programmed cell death and AIDS: significance of T-cell apoptosis in pathogenic and nonpathogenic primate lentiviral infections.

Cited by 241 publications

References 35 publications

A novel mechanism for HIV1-mediated bystander CD4+ T-cell death: neighboring dying cells drive the capacity of HIV1 to kill noncycling primary CD4+ T cells

A novel mechanism for HIV1-mediated bystander CD4+ T-cell death: neighboring dying cells drive the capacity of HIV1 to kill noncycling primary CD4+ T cells

Selective CD4+ T cell deletion after specific activation in HIV-infected individuals; protection by anti-CD28 monoclonal antibodies

Sanctuaire du virus de l’immunodéficience humaine et mécanismes d’échappement

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