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On this note, given that only part of GFP? cells contain Vpr, this issue of sorting for Vpr-positive GFP? cells becomes even more essential in this type of analysis
On this note, given that only part of GFP? cells contain Vpr, this issue of sorting for Vpr-positive GFP? cells becomes even more essential in this type of analysis. Given that a large body of evidence has already clearly demonstrated that induced expression of NKG2DL triggers lysis of target T cells by NK cells (Cerboni et al., 2007; Fogli Avitinib (AC0010) et al., 2008; Norman et al., 2011; Pham et al., 2011; Richard et al., 2010; Shah et al., 2010; Ward et al., 2007, 2009), it is conceivable that Vpr-induced upregulation of ULBP2 on uninfected cells, would render these cells highly susceptible to NK cell killing. conditions known to promote NK cell-mediated killing. Overall, these findings suggest that Vpr could contribute to CD4+ T cell loss by rendering uninfected bystander cells susceptible to NK cell-mediated killing. infection of immortalized T cell linesit is direct killing of CD4+ T cells that prevails. In contrast, in more physiological systems, such as HIV-1 infection of lymphoid tissues or lymph nodes from HIV-1 infected individuals, it is primarily uninfected bystander CD4+ T cells that are killed (Finkel et al., 1995; Jekle et al., 2003), underscoring the potentially important contribution of this loss to the overall depletion of CD4+ T cells. Over the years, several indirect mechanisms have been proposed to contribute to the killing of uninfected bystander CD4+ T cells, including those mediated by HIV-1-encoded proteins Tat, Nef, gp120 or viral protein R (Vpr), since these viral proteins can induce apoptosis of neighbouring uninfected cells upon their release from infected cells (Varbanov et al., 2006). Moreover, HIV-1 defective virus particles, which represent the majority of virions that are released during productive infection (Dimitrov et al., 1993; Piatak et al., 1993), have also been suggested to play a part in CD4+ T cell loss either by interacting with uninfected bystander cells or/and by transducing these cells (Esser et al., 2001; Herbeuval et al., 2005; Richard et al., 2010). More recently, abortive HIV infections, such as those occurring in nonpermissive resting CD4+ T cells, were shown to activate proapoptotic and inflammatory responses as a result of the sensing of incomplete reverse transcripts that are accumulating in these conditions, thus contributing to the killing of bystander cells (Doitsh et al., 2010). The HIV-1 Vpr accessory protein can be found not only as an intracellular or intravirion protein but also in an extracellular soluble form. Indeed, Vpr is efficiently packaged into viral particles via an interaction with the p6 domain of Gag (Bachand et al., 1999; Lu et al., 1995) and can be detected as a soluble protein in the serum and cerebrospinal fluid of HIV-1-infected individuals (Hoshino et al., 2007; Levy et al., 1994) as well as in the extracellular medium of virus-producing cells (Xiao et al., 2008). Importantly, the fact that recombinant soluble Vpr displays natural-transducing properties on multiple cell types (Sherman et al., 2002), suggests that Vpr could transduce uninfected bystander cells not only as a defective virion-associated protein but also as a secreted protein. One of the most studied biological activities of Vpr is its ability to promote a cell cycle arrest at the G2 phase when expressed alone or in the context Rabbit Polyclonal to GABRD of HIV-1 infection (He et al., 1995; Jowett et al., 1995; Re et al., 1995). Interestingly, soluble and virion-associated Vpr molecules were also found to have the ability to induce a cell cycle Avitinib (AC0010) arrest (Hrimech et al., 1999; Poon et al., 1998; Sherman et al., 2002), suggesting that Vpr could exert this biological activity on Avitinib (AC0010) uninfected bystander cells. Accumulating evidence indicates that Vpr-mediated cell cycle arrest relies on the recruitment of a cullin-ring E3 ubiquitin ligase, namely DDB1-CUL4A (VprBP also designated DCAF1) by Vpr, and on the activation of a cellular DNA damage response (DDR) initiated by the ataxia telangiectasia-mutated and Rad3-mutated (ATR) kinase (review in (Romani and Cohen, 2012)). Indeed, expression of Vpr induces the phosphorylation of several effector molecules regulated by ATR, including the checkpoint kinase 1 (Chk1) and the histone 2A variant X (H2AX), and the formation of DNA repair foci containing phosphorylated H2AX (-H2AX) and p53 binding protein 1 (53BP1) through a process that is dependent on the engagement of DDB1-CUL4A (VprBP) (Belzile et al., 2010a; Lai et al., 2005; Zimmerman et al., 2004). Recently, we and others reported that activation of ATR by Vpr leads to the augmentation of specific ligands of the activating natural killer group 2, member D (NKG2D) receptor, which is constitutively expressed on Natural Killer (NK) cells (Richard et al., 2010; Ward et al., 2009). Indeed, ULBP2, a member of the human cytomegalovirus UL16 binding protein (ULBP) family, was the most predominantly upregulated NKG2D ligand (NKG2DL) during infection of primary CD4+ T cells with Vpr-proficient virus. Paradoxically, increased expression of ULBP2 at the surface of infected.