Induction of Apoptosis in Uninfected Lymphocytes by HIV-1 Tat Protein

Li, Chiang J.; Friedman, David J.; Wang, Chuanlin; Metelev, Valeri; Pardee, Arthur B.

doi:10.1126/science.7716549

Cited by 555 publications

(373 citation statements)

References 37 publications

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“…Our findings also indicate that the Nef protein, present in small amounts in the HIV1 particles 45 and reported to either induce or repress cell death, [46][47][48][49] is not required for the killing of noncycling CD4 þ T cells in our model. Tat, another HIV1 protein that has been found to either induce 21,56,57 or repress 58 cell death in vitro, is not present in the viral particles, but is released by HIV1-producing cells. 59 Therefore, it is possible that Tat was present in the 100-450 nm fractions purified from supernatants of living, HIV1-transfected HeLa cells that we used as a source of virus.…”

Section: Discussionmentioning

confidence: 99%

“…The 39-40 kDa band corresponds to the described MW of the unprocessed, microvesicle-bound form of CD95L. 52,56 (d) Purified unstimulated primary CD4 þ T cells (10 6 /ml) were incubated with viruses (500 ng p24/ml) purified from living HeLa cells transfected with NL4-3 or with NL4-3/Denv, and with either supernatants from the Neuro-2a FasL cell line (Neuro-2a FasL), which contain microvesicle-bound, unprocessed CD95L, 57 51,[53][54][55] Western blot analysis of the purified supernatants of living or dying (serum deprived) control HeLa cells, using a CD95L-specific antibody, showed the presence of a 39-40 kDa CD95L in the latter (as in the positive control Jurkat cell cytoplasmic lysates) and no detectable CD95L in the former (Figure 5c). To further investigate the potential role of CD95L, we incubated CD4 þ T cells with supernatants from the Neuro-2a FasL cell line, which contain microvesicle-bound, unprocessed CD95L released by these cells.…”

Section: Cd95l Released By Dying Cells Is One Of the Cellular Factorsmentioning

confidence: 99%

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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: Discussionmentioning

confidence: 99%

Section: Cd95l Released By Dying Cells Is One Of the Cellular Factorsmentioning

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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“…of three independent experiments cells. To study this point, we chose the Jurkat derived cell clone, Jhan-Tat, which undergoes apoptosis upon serum withdrawal more rapidly than K562-Tat cells (Li et al, 1995;Westendorp et al, 1995a). Thus, Jhan-Tat cells and the parental Jhan cell line were incubated with the cell-permeable caspase-3 inhibitor z-DEVDcmk, and half of the cells were cultured in medium containing 10% FCS, and the other half cultured under low serum conditions (0.1% FCS) for 6 h. Then, ROS generation and Dc m dissipation were detected as described above for K562 cells.…”

Section: Loss Of Mitochondrial Membrane Potential (Dc M ) and Reactivmentioning

confidence: 99%

“…The molecular mechanism of apoptosis in HIV-1 infection is largely unknown but several reports indicate that T cell apoptosis might be a ected by viral proteins such as HIV-Tat (Li et al, 1995;McCloskey et al, 1997;Patki and Lederman, 1996;Sastry et al, 1996;Westendorp et al, 1995a;Zauli et al, 1996), and gp120 (Banda et al, 1992;Herbein et al, 1998;Tuosto et al, 1995;Westendorp et al, 1995a). It has been shown that HIV-1-Tat upregulates the expression of CD95L in human peripheral T cells and accelerates CD95-mediated apoptosis (Westendorp et al, 1995a), and that this viral protein can downregulate not only the bcl-2 gene expression in a variety of hematopoietic cell types, but also increase the expression of the proapoptotic gene Bax (Sastry et al, 1996).…”

Section: Introductionmentioning

confidence: 99%

Susceptibility of HIV-1-TAT transfected cells to undergo apoptosis. Biochemical mechanisms

Macho¹,

Calzado²,

Jiménez‐Reina³

et al. 1999

Oncogene

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The e ects of HIV-1 Tat protein on mitochondria membrane permeability and apoptosis were analysed in lymphoid cells. In this report we show that stabletransfected HIV-Tat cells are primed to undergo apoptosis upon serum withdrawal. This e ect was observed in both the Jhan T cell line and the K562 cells, the latter expressing the bcr-abl chimeric gene, which confers resistance to apoptosis induced by di erent stimuli. Using a cyto¯uorimetric approach we have determined that serum withdrawal induces a disruption of the transmembrane mitochondrial potential (Dc m ) followed by an increase of reactive oxygen species (ROS) and the subsequent DNA nuclear loss in K562-Tat cells but not in the K562-pcDNA cell line. These pre-apoptotic events were associated with the cleavage of the caspase-3, while the expression of Bcl-2, Bcl-X L and Bax proteins was not a ected by the presence of Tat. Regardless of the steady state of the Bax protein, we found that in both K562 and K562-Tat cells, this protein is located in the nucleus, but after serum withdrawal its localization was mainly in the cytoplasm. The activity of caspase-3 detected in K562-Tat cells after serum withdrawal paralleled with the mitochondria permeability transition. Nevertheless, in Jhan-Tat cells the inhibition of this caspase with the speci®c inhibitor, z-DEVD-cmk, did not a ect the disruption of the mitochondria potential induced by serum withdrawal. Interestingly, we found that HIV-Tat protein accumulates at the mitochondria in the K562-Tat cells cultured under low serum conditions, and this mitochondrial localization correlated with the Dc m disruption detected in these cells. In addition, HIV-1 Tat protein synergies with protoporphyrin IX (PPIX), a ligand of the mitochondrial benzodiazepine receptor, in the induction of apoptosis in both Jhan and K562 cells. Thus, HIV-1 Tat protein may induce apoptosis by a mechanism that involves mitochondrial PT and may contribute to the lymphocyte depletion seen in AIDS patients.

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“…In addition, Tat can modulate the expression of cytokines and cellular genes [6][7][8][9][10][11], and chemokine receptors [12][13][14][15], which are responsible for the transmission of macrophageand T-cell-tropic HIV-1 strains, respectively. In addition, the Tat protein also plays key roles in viral pathogenesis and in the pathogenesis of acquired immune deficiency syndrome (AIDS)-associated Kaposi's sarcoma [8,[16][17][18][19][20][21][22].…”

Section: Introductionmentioning

confidence: 99%

Long-term protection against SHIV89.6P replication in HIV-1 Tat vaccinated cynomolgus monkeys

Maggiorella

Baroncelli

Michelini

et al. 2004

Vaccine

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Vaccination with a biologically active Tat protein or tat DNA contained infection with the highly pathogenic SHIV89.6P virus, preventing CD4 T-cell decline and disease onset. Here we show that protection was prolonged, since neither CD4 T-cell decline nor active virus replication was observed in all vaccinated animals that controlled virus replication up to week 104 after the challenge. In contrast, virus persisted and replicated in peripheral blood mononuclear cells and lymph nodes of infected animals, two of which died. Tat-specific antibody, CD4 and CD8 T-cell responses were high and stable only in the animals controlling the infection. In contrast, Gag-specific antibody production and CD4 and CD8 T-cell responses were consistently and persistently positive only in the monkeys that did not control primary virus replication. These results indicate that vaccination with Tat protein or DNA induced long-term memory Tat-specific immune responses and controlled primary infection at its early stages allowing a long-term containment of virus replication and spread in blood and tissues.

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Induction of Apoptosis in Uninfected Lymphocytes by HIV-1 Tat Protein

Cited by 555 publications

References 37 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

Susceptibility of HIV-1-TAT transfected cells to undergo apoptosis. Biochemical mechanisms

Long-term protection against SHIV89.6P replication in HIV-1 Tat vaccinated cynomolgus monkeys

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