Reactive Oxygen Species Hydrogen Peroxide Mediates Kaposi's Sarcoma-Associated Herpesvirus Reactivation from Latency

Abstract

Kaposi's sarcoma-associated herpesvirus (KSHV) establishes a latent infection in the host following an acute infection. Reactivation from latency contributes to the development of KSHV-induced malignancies, which include Kaposi's sarcoma (KS), the most common cancer in untreated AIDS patients, primary effusion lymphoma and multicentric Castleman's disease. However, the physiological cues that trigger KSHV reactivation remain unclear. Here, we show that the reactive oxygen species (ROS) hydrogen peroxide (H2O2) induces KSHV reactivation from latency through both autocrine and paracrine signaling. Furthermore, KSHV spontaneous lytic replication, and KSHV reactivation from latency induced by oxidative stress, hypoxia, and proinflammatory and proangiogenic cytokines are mediated by H2O2. Mechanistically, H2O2 induction of KSHV reactivation depends on the activation of mitogen-activated protein kinase ERK1/2, JNK, and p38 pathways. Significantly, H2O2 scavengers N-acetyl-L-cysteine (NAC), catalase and glutathione inhibit KSHV lytic replication in culture. In a mouse model of KSHV-induced lymphoma, NAC effectively inhibits KSHV lytic replication and significantly prolongs the lifespan of the mice. These results directly relate KSHV reactivation to oxidative stress and inflammation, which are physiological hallmarks of KS patients. The discovery of this novel mechanism of KSHV reactivation indicates that antioxidants and anti-inflammation drugs could be promising preventive and therapeutic agents for effectively targeting KSHV replication and KSHV-related malignancies.

Modulation of host ROS metabolism is essential for viral infection of a bloom-forming coccolithophore in the ocean

“…U Sheyn et al virus, hepatitis C virus and HIV (Perl and Banki, 2000;Ye et al, 2011;Bottero et al, 2013;Ma et al, 2013). On the other hand, in plants, during tobacco mosaic virus infection, ROS signaling was found to initiate plant defense hypersensitive response (Allan et al, 2001;Yoda et al, 2003;Love et al, 2005).…”

Multivariate discriminant analysis of redox and progression indexes in Cuban AIDS patients with Kaposis sarcoma

“…CAT alterations could indicate altered peroxide generation which has been associated to KS lytic replication through both paracrine and autocrine mechanisms [18]. Depletion of GSH and antioxidant capacity evaluated as PP could be related to consumption by increased chronic generation of ROS.…”

“…Data that support the contribution of oxidative stress in AIDS-KS pathogenesis has also been accrued at the cellular biochemical level [16][17][18][19]. In vitro studies conducted by Ye et al showed that AIDS-KS strains demonstrate enhanced susceptibility to oxidative stress as induced by either physiologically relevant levels of hydrogen peroxide [18] or conducted by Li et al who show activation through a drug capable of undergoing redox cycling (doxorubicin) [19].…”

“…In vitro studies conducted by Ye et al showed that AIDS-KS strains demonstrate enhanced susceptibility to oxidative stress as induced by either physiologically relevant levels of hydrogen peroxide [18] or conducted by Li et al who show activation through a drug capable of undergoing redox cycling (doxorubicin) [19]. AIDS-KS cells also show an acute hyperresponsiveness to a pro-inflammatory cytokine that signals by redox-mediated pathways (interleukin 6) [20] and possess an inherent perturbation in their thiol redox status characterized by significantly lower levels of both glutathione (GSH) and the GSH reductase co-factor, nicotinamide adenine dinucleotide phosphate [21].…”

A novel role of hydrogen peroxide in Kaposi sarcoma-associated herpesvirus reactivation

“…this question, two recent studies from Dr. Ren Sun's laboratory and our group independently discovered that the ROS H 2 O 2 plays a pivotal role in this viral event. 6,7 We observed a dose-dependent induction of KSHV lytic gene expression and virion production from latently infected human primary effusion lymphoma ( Previously, 12-O-tetradecanoyl phorbol-13-acetate (TPA), hypoxia and inflammatory cytokines have been shown to induce KSHV lytic replication. [9][10][11] We found that these stimuli also increased intracellular H 2 O 2 and that antioxidants such as catalase, reduced glutathione and N-acetyle-cysteine (NAC) attenuated viral reactivation induced by these factors.…”