The dose-dependent H2O2 stress response promotes increased survival forSchizosaccharomyces pombe cells expressing HIV-1 Vpr

Abstract

Human immunodeficiency virus type 1 (HIV-1) viral protein R (Vpr) exerts multiple effects on viral and host cellular activities during infection, including induction of the cell cycle G2 arrest, and cell death in both human cells and the fission yeast Schizosaccharomyces pombe. We show that treament of exponential-phase wild-type Vpr-expressing S. pombe cells with a low, subinhibitory concentration (0.15 mmol/L) of hydrogen peroxide and 0.1 mmol/L thiamine significantly increased both cell proliferation and survival rates and decreased the number of elongated G2-arrested cells. Short-term, H2O2-induced adaptive stress increased the survival of the cells while acute stress conditions interrupted the Vpr-mediated death of the cells; however, no changes in cell length or cell phase were detected. The results suggest the importance of the oxidative status of the cells in Vpr-mediated processes. Our findings contribute to the development of a new approach via which to investigate the contribution of Vpr to HIV pathogenesis and to reduce the Vpr-mediated effects in HIV-infected patients.

Regulation of unbalanced redox homeostasis induced by the expression of wild-type HIV-1 viral protein R (NL4-3Vpr) in fission yeast

“…These data are in agreement with earlier observations [3,32]. For comparison, the multiplication of the mutant F341Vpr-expressing cells stopped at 20 h and started again at 26 h [28].…”

“…For comparison, the multiplication of the mutant F341Vpr-expressing cells stopped at 20 h and started again at 26 h [28]. Table 2 It has been demonstrated previously that the expression of wild-type NL4-3Vpr in S. pombe induces elongated cells that are delayed or arrested at the G2/M cell cycle transition [3,29,30]. The G2 arrest mediated by Vpr utilizes the cellular signaling pathway whose physiological function is to recognize replication stress and which is strongly associated with the oxido-reduction balance of cells [33].…”

“…Taking this into account, we used the parental strain SP223 as a control. Other conditions and the microscopic examination of cells were as described earlier by Antal and Pesti [3]. …”

“…The wild-type Vpr (NL4-3Vpr) is localized in the mitochondria, nucleus and cytoplasm [7], where it destroys the cellular regulation of the host: (i) it alters the cell morphology (elongated "cdc" phenotype cells) [24], (ii) it prevents cell proliferation by arresting cells in the G2 phase of the cell cycle [13,24], (iii) it causes apoptosis through binding to the inner mitochondrial membrane and the release of cytochromes responsible for apoptosis [12], (iv) it activates caspase 8, the main effector of the receptor-mediated apoptotic pathway [27], (v) it causes oxidative stress in HIV-1-infected host cells [22,28] and (vi) it stimulates the replication of HIV and the development of immunodeficiency [5,14,26]. We demonstrated earlier that the internal oxidative stress caused by wild-type Vpr in Schizosaccharomyces pombe (S. pombe) is partly suppressed by hydrogen peroxide (H 2 O 2 )-induced adaptive processes [3]. A mutation of wild-type Vpr may cause altered pathways and target molecules during HIV pathogenesis [16], indicating its structural importance.…”

Activation of the Oxidative Stress Pathway by HIV-1 Vpr Leads to Induction of Hypoxia-inducible Factor 1α Expression

“…In addition to Tat, HIV-1 gp120 protein has been shown to cause reactive oxygen species (ROS) production in glial cells leading to neurodegeneration and apoptosis (10). Finally, in a recent study, HIV-1 Vpr protein was shown to be involved in OS pathway (11).…”