Induction of Apoptosis by HIV-1 vpr

HIV-1 vpr 诱导细胞凋亡

• 批准号: 8138037
• 负责人: VICENTE PLANELLES
• 金额: $ 14.26万
• 依托单位: UNIVERSITY OF UTAH
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-09-20 至 2011-09-19
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8138037
• 关键词: Affect; Agreement; Amino Acids; Apoptosis; Apoptotic; BRCA1 gene; CD4 Positive T Lymphocytes; Cell Cycle; Cell Cycle Arrest; Cells; Complex; DNA; DNA biosynthesis; G2 Phase; Gene Expression; HIV-1; In Vitro; Induction of Apoptosis; Interphase Cell; Kinetics; Life; Mediating; Modeling; Pathogenesis; Phase; Phosphorylation; Phosphotransferases; Proteins; Refractory; Signal Transduction; Stimulus; Surveys; T-Lymphocyte; Transactivation; Viral; Viral Genes; in vivo; macrophage; monocyte; promoter; vpr Genes

The HIV-1 accessory gene vpr encodes a conserved 96-amino acid protein that induces block of the cell cycle at the 62 phase. Expression of Vpr in CD4+ lymphocytes also induces apoptosis. We have identified the ATR kinase as the cellular factor that mediates Vpr-induced cell cycle arrest and apoptosis. We have also demonstrated that induction of G2 arrest and apoptosis require phosphorylation of downstream targets of ATR, such as Chk1, BRCA1 and GADD45a. Therefore, the ATR, kinase represents a key determinant of Vpr-induced pathogenesis. The major focus of this proposal will be to elucidate the precise mechanism by which Vpr activates ATR. Macrophages infected with HIV-1 in vivo and in vitro are long-lived, when compared to infected, activated T-cells. We find that expression of Vpr in macrophages is unable to induce apoptosis, and we hypothesize that the underlying cause is that Vpr is unable to activate ATR in these cells. The differential ability of Vpr to induce apoptosis in activated T-cells versus macrophages is in complete agreement with an emerging model in which activation of ATR requires ongoing cellular DMA replication. Activation of ATR by Vpr also leads to an enhancement viral gene expression, which explains the moderate transactivation activity ascribed to Vpr in T- cells. The specific Aims of this proposal are: Specific Aim 1. To elucidate the mechanism by which Vpr activates ATR. The function of ATR is to survey cellular DNA replication and to detect stalled replication forks. We will examine whether Vpr causes activation of ATR by affecting the integrity of DNA, by hindering host cell replication, or by activating the ATR signaling complex directly. Specific Aim 2. To explore the effect of Vpr on ATR in monocyte-derived macrophages (MDM). We have observed that MDM are refractory to Vpr-induced apoptosis, but not to other pro-apoptotic stimuli. We hypothesize that Vpr is unable to activate ATR in MDM due to their non-dividing status. We also hypothesize that Vpr-induced transactivation, which is dependent on ATR activation, does not occur in MDM. Aim 3. To evaluate the contribution of ATR activation to the kinetics of replication of HIV-1. We have shown that inhibition of ATR leads to complete supression of Vpr's ability to transactivate the viral promoter. Therefore, we hypothesize that Vpr will be able to induce transactivation in dividing cells (activated T-cells) but not innon- dividing cells (MDM). We also hypothesize that ATR activation by Vpr, when allowed, will result in enhanced rate of viral replication.

HIV-1辅助基因vpr编码一个保守的96个氨基酸的蛋白，诱导细胞阻滞

项目成果

Human immunodeficiency virus type 1 Vpr-mediated G2 arrest requires Rad17 and Hus1 and induces nuclear BRCA1 and gamma-H2AX focus formation.

人类免疫缺陷病毒 1 型 Vpr 介导的 G2 停滞需要 Rad17 和 Hus1，并诱导核 BRCA1 和 γ-H2AX 病灶形成。

• DOI: 10.1128/mcb.24.21.9286-9294.2004
• 发表时间: 2004
• 期刊: Molecular and cellular biology
• 影响因子: 5.3
• 作者: Zimmerman,ErikS;Chen,Junjie;Andersen,JoshuaL;Ardon,Orly;Dehart,JasonL;Blackett,Jana;Choudhary,ShaileshK;Camerini,David;Nghiem,Paul;Planelles,Vicente
• 通讯作者: Planelles,Vicente

Characterizing the anti-HIV activity of papuamide A.

• DOI: 10.3390/md20080027
• 发表时间: 2008
• 期刊: Marine drugs
• 影响因子: 5.4
• 作者: Andjelic CD;Planelles V;Barrows LR
• 通讯作者: Barrows LR

Degranulation of natural killer cells following interaction with HIV-1-infected cells is hindered by downmodulation of NTB-A by Vpu.

• DOI: 10.1016/j.chom.2010.10.008
• 发表时间: 2010-11-18
• 期刊: Cell host & microbe
• 影响因子: 30.3
• 作者: Shah AH;Sowrirajan B;Davis ZB;Ward JP;Campbell EM;Planelles V;Barker E
• 通讯作者: Barker E

Epigenetic regulation of HIV-1 latency by cytosine methylation.

• DOI: 10.1371/journal.ppat.1000495
• 发表时间: 2009-06
• 期刊: PLoS pathogens
• 影响因子: 6.7
• 作者: Kauder SE;Bosque A;Lindqvist A;Planelles V;Verdin E
• 通讯作者: Verdin E

Understanding the molecular manipulation of DCAF1 by the lentiviral accessory proteins Vpr and Vpx.

了解慢病毒辅助蛋白 Vpr 和 Vpx 对 DCAF1 的分子操作。

• DOI: 10.1016/j.virol.2014.11.024
• 发表时间: 2015
• 期刊: Virology
• 影响因子: 3.7
• 作者: Cassiday,PatrickA;DePaula-Silva,AnaBeatriz;Chumley,Jeffrey;Ward,Jeffrey;Barker,Edward;Planelles,Vicente
• 通讯作者: Planelles,Vicente