The HIV-1-Specific Protein Casp8p41 Induces Death of Infected Cells through Bax/Bak

Sainski, Amy M.; Natesampillai, Sekar; Cummins, Nathan W.; Bren, Gary D.; Taylor, Julie; Saenz, Dyana T.; Poeschla, Eric M.; Badley, Andrew D.

doi:10.1128/jvi.02515-10

Cited by 35 publications

(36 citation statements)

References 62 publications

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“…Similarly, we failed to detect cleavage of pro-caspase 8 (Figure 5). Recent studies of the Casp8p41 fragment suggest that it could independently induce apoptosis via its interaction with mitochondria, resulting in rapid mitochondrial depolarization mediated by Bax/Bak, cytochrome c release and activation of caspase 9 and 3 [19,23,24]. These findings agree with our results showing that HIV-1 PR activates caspase 9 both in vivo and in vitro (Figure 5).…”

Section: Discussionsupporting

confidence: 93%

HIV-1 protease-induced apoptosis

et al. 2014

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BackgroundApoptosis is one of the presumptive causes of CD4+ T cell depletion during HIV infection and progression to AIDS. However, the precise role of HIV-1 in this process remains unexplained. HIV-1 protease (PR) has been suggested as a possible factor, but a direct link between HIV-1 PR enzymatic activity and apoptosis has not been established.ResultsHere, we show that expression of active HIV-1 PR induces death in HeLa and HEK-293 cells via the mitochondrial apoptotic pathway. This conclusion is based on in vivo observations of the direct localization of HIV-1 PR in mitochondria, a key player in triggering apoptosis. Moreover, we observed an HIV-1 PR concentration-dependent decrease in mitochondrial membrane potential and the role of HIV-1 PR in activation of caspase 9, PARP cleavage and DNA fragmentation. In addition, in vitro data demonstrated that HIV-1 PR mediates cleavage of mitochondrial proteins Tom22, VDAC and ANT, leading to release of AIF and Hsp60 proteins. By using yeast two-hybrid screening, we also identified a new HIV-1 PR interaction partner, breast carcinoma-associated protein 3 (BCA3). We found that BCA3 accelerates p53 transcriptional activity on the bax promoter, thus elevating the cellular level of pro-apoptotic Bax protein.ConclusionIn summary, our results describe the involvement of HIV-1 PR in apoptosis, which is caused either by a direct effect of HIV-1 PR on mitochondrial membrane integrity or by its interaction with cellular protein BCA3.

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Section: Discussionsupporting

confidence: 93%

HIV-1 protease-induced apoptosis

et al. 2014

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“…HIV replication is known to exert a direct lethal effect on CD4 ϩ T cells (1,2,3,4). Protease generation of Casp8p41 and an integrase-mediated DNA damage response are important mechanisms that initiate apoptosis of HIV-infected cells (5,6). In addition, CD8 T cells exert contact-dependent death of HIV-infected cells.…”

Section: H Uman Immunodeficiency Virus (Hiv) Infection Causes a Declimentioning

confidence: 99%

The Majority of CD4 ⁺ T-Cell Depletion during Acute Simian-Human Immunodeficiency Virus SHIV89.6P Infection Occurs in Uninfected Cells

Matrajt

Younan

Kiem

et al. 2014

J Virol

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Untreated human immunodeficiency virus (HIV) infection is characterized by depletion of CD4؉ T cells, ultimately leading to the impairment of host immune defenses and death. HIV-infected CD4 ؉ T cells die from direct virus-induced apoptosis and CD8 T-cell-mediated elimination, but a broader and more profound depletion occurs in uninfected CD4؉ T cells via multiple indirect effects of infection. We fit mathematical models to data from experiments that tested an HIV eradication strategy in which five macaques with a proportion of CD4 ؉ T cells resistant to simian-human immunodeficiency virus (SHIV) entry were challenged with SHIV89.6P, a highly pathogenic dual-tropic chimeric SIV-HIV viral strain that results in rapid loss of both SHIV-susceptible and SHIV-resistant CD4 ؉ T cells. Our results suggest that uninfected (bystander) cell death accounts for the majority of CD4 ؉ T-lymphocyte loss, with at least 60% and 99% of CD4 ؉ T cell death occurring in uninfected cells during acute and established infection, respectively. Mechanisms to limit the profound indirect killing effects associated with HIV infection may be associated with immune preservation and improved long-term survival. IMPORTANCE HIV infection induces a massive depletion of CD4 ؉ T cells, leading to profound immunodeficiency, opportunistic infections, and eventually death. While HIV induces apoptosis (programmed cell death) by directly entering and replicating in CD4؉ T cells, uninfected CD4 ؉ T cells also undergo apoptosis due to ongoing toxic inflammation in the region of infection. In this paper, we use mathematical models in conjunction with data from simian-human immunodeficiency virus SHIV89.6P infection in macaques (a model of HIV infection in humans) to estimate the percentage of cell death that occurs in uninfected cells during the initial period of infection. We reveal that the vast majority of cell death occurs in these cells, which are not infected. The "bystander effects" that lead to enormous reductions in the number of uninfected CD4 ؉ T cells may be a target for future interventions that aim to limit the extent of damage caused by HIV.

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“…Beads were washed three times with 10 volumes of lysis buffer. Bound protein was eluted and subjected to SDS-PAGE, followed by immunoblotting as previously described (16). The primary antibodies used were anti-HA peroxidase high-affinity 3F10 (Roche, St. Louis, MO) and the antibodies listed above.…”

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confidence: 99%

Prime, Shock, and Kill: Priming CD4 T Cells from HIV Patients with a BCL-2 Antagonist before HIV Reactivation Reduces HIV Reservoir Size

Cummins

Sainski

Dai

et al. 2016

J Virol

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105

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Understanding how some HIV-infected cells resist the cytotoxicity of HIV replication is crucial to enabling HIV cure efforts. HIV killing of CD4 T cells that replicate HIV can involve HIV protease-mediated cleavage of procaspase 8 to generate a fragment (Casp8p41) that directly binds and activates the mitochondrial proapoptotic protein BAK. Here, we demonstrate that Casp8p41 also binds with nanomolar affinity to the antiapoptotic protein Bcl-2, which sequesters Casp8p41 and prevents apoptosis. Intense activity is focused on identifying a clinical intervention that results in a long term, drug free remission of HIV-1 infection. Latently infected CD4 T cells harbor transcriptionally silent, replication-competent HIV. Because these cells persist long term and are unaffected by current therapies, the cells represent an HIV reservoir that remains undiminished by current approaches. Pilot clinical trials have tested whether reactivation of HIV-1 from latency will decrease the number of cells containing HIV DNA due to viral cytopathic effect or immune-mediated clearance. The latency reversal agents vorinostat, panobinostat, and romidepsin result in HIV reactivation, as measured by increases in cell-associated HIV RNA, but no change in cell-associated HIV DNA, indicating that the reactivating cells do not die (1-4). Multiple ongoing studies are testing augmentation of the anti-HIV immune response in combination with viral reactivation as a strategy for HIV eradication.In an effort to inform these attempts to eradicate the HIV reservoir, we and others have been examining the mechanistic basis for HIV-induced killing of CD4 T cells under different circumstances of activation and HIV replication. Although numerous pathways may contribute to the decline of uninfected CD4 T cells during uncontrolled HIV infection (5), fewer pathways have been implicated in the demise of cells directly infected by HIV. After HIV attachment, at least three distinct pathways can initiate the death of infected cells: (i) RIG-I-mediated sensing of HIV RNA (6, 7), (ii) IFI-16 sensing of unintegrated HIV DNA (8, 9), and (iii) DNA-PK-sensing of HIV integrase nicking of host DNA (10). Once integrated into host DNA, HIV can remain in a latent state

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The HIV-1-Specific Protein Casp8p41 Induces Death of Infected Cells through Bax/Bak

Cited by 35 publications

References 62 publications

HIV-1 protease-induced apoptosis

HIV-1 protease-induced apoptosis

The Majority of CD4 ⁺ T-Cell Depletion during Acute Simian-Human Immunodeficiency Virus SHIV89.6P Infection Occurs in Uninfected Cells

Prime, Shock, and Kill: Priming CD4 T Cells from HIV Patients with a BCL-2 Antagonist before HIV Reactivation Reduces HIV Reservoir Size

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The HIV-1-Specific Protein Casp8p41 Induces Death of Infected Cells through Bax/Bak

Cited by 35 publications

References 62 publications

HIV-1 protease-induced apoptosis

HIV-1 protease-induced apoptosis

The Majority of CD4 + T-Cell Depletion during Acute Simian-Human Immunodeficiency Virus SHIV89.6P Infection Occurs in Uninfected Cells

Prime, Shock, and Kill: Priming CD4 T Cells from HIV Patients with a BCL-2 Antagonist before HIV Reactivation Reduces HIV Reservoir Size

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The Majority of CD4 ⁺ T-Cell Depletion during Acute Simian-Human Immunodeficiency Virus SHIV89.6P Infection Occurs in Uninfected Cells