HIV-1 Tat protein induces DNA damage in human peripheral blood B-lymphocytes via mitochondrial ROS production

Abstract

Human immunodeficiency virus (HIV) infection is associated with B-cell malignancies in patients though HIV-1 is not able to infect B-cells. The rate of B-cell lymphomas in HIV-infected individuals remains high even under the combined antiretroviral therapy (cART) that reconstitutes the immune function. Thus, the contribution of HIV-1 to B-cell oncogenesis remains enigmatic. HIV-1 induces oxidative stress and DNA damage in infected cells via multiple mechanisms, including viral Tat protein. We have detected elevated levels of reactive oxygen species (ROS) and DNA damage in B-cells of HIV-infected individuals. As Tat is present in blood of infected individuals and is able to transduce cells, we hypothesized that it could induce oxidative DNA damage in B-cells promoting genetic instability and malignant transformation. Indeed, incubation of B-cells isolated from healthy donors with purified Tat protein led to oxidative stress, a decrease in the glutathione (GSH) levels, DNA damage and appearance of chromosomal aberrations. The effects of Tat relied on its transcriptional activity and were mediated by NF-κB activation. Tat stimulated oxidative stress in B-cells mostly via mitochondrial ROS production which depended on the reverse electron flow in Complex I of respiratory chain. We propose that Tat-induced oxidative stress, DNA damage and chromosomal aberrations are novel oncogenic factors favoring B-cell lymphomas in HIV-1 infected individuals.

Benzo(a)pyrene in Cigarette Smoke Enhances HIV-1 Replication through NF-κB Activation via CYP-Mediated Oxidative Stress Pathway

“…In addition to the ROS generated via the CYP-mediated metabolism of BaP, there are other factors such as HIV-1 proteins whose contribution to ROS production cannot be ruled out. HIV-1 proteins such as tat, gp120, Nef, and Vpr are known to cause oxidative stress in the infected cells 70 – 74 . These HIV-1 proteins generate ROS via different mechanisms: tat via upregulation of spermine oxidases 75 or by activating the NADPH oxidase pathways 76 ; gp120 via upregulation of CYP2E1, NADPH oxidases 72 , and proline oxidase 77 ; Vpr via interaction with adenine nucleotide translocator or NADPH oxidases 73 ; and Nef via direct interaction with NADPH oxidases 78 .…”

HDAC6 inhibition induces the failure of mouse early embryonic development

“…Excessive ROS could react with the cellular macromolecules, change their biochemical and physical properties, and eventually destroy their cellular function, resulting in cell dysfunction or death (H. J. Kim et al, ). In aerobic cells, mitochondrial deficiency due to the overproduction of ROS leads to oxidative DNA damage (El‐Amine et al, ). If the damage is excessive or DNA repair is ineffective, then the activation of cell death is the normal physiological response (Rahal et al, ).…”

“…Kim et al, 2015). In aerobic cells, mitochondrial deficiency due to the overproduction of ROS leads to oxidative DNA damage (El-Amine et al, 2018). If the damage is excessive or DNA repair is ineffective, then the activation of cell death is the normal physiological response (Rahal et al, 2016).…”

Ripk3 promotes ER stress-induced necroptosis in cardiac IR injury: A mechanism involving calcium overload/XO/ROS/mPTP pathway

“…LDH release was measured using an LDH release kit (Beyotime, Beijing, China). The 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay was used to measure cell viability as previously described [33] . Cells were plated onto 96-well plates (10 4 cells/well).…”