RNA Viruses: ROS-Mediated Cell Death

Reshi, Mohammad Latif; Su, Yi Che; Hong, Jiann Ruey

doi:10.1155/2014/467452

Cited by 245 publications

(268 citation statements)

References 211 publications

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“…Similarly, previous observations showed that oxidative stress is responsible for the induction of apoptosis in several cell types, including natural killer cells, enterocytes, podocytes, and astrocytes, during HIV-1 infection (44,(48)(49)(50). Recent studies, such as those conducted by Kalinowska et al (14) and Trautmann et al (16), also showed that decreased IL-7-induced pSTAT5 levels in CD8 T cells during HIV-1 infection were associated with oxidative stress.…”

Section: Ccr7mentioning

confidence: 62%

Kynurenine Reduces Memory CD4 T-Cell Survival by Interfering with Interleukin-2 Signaling Early during HIV-1 Infection

Dagenais-Lussier

Aounallah

Mehraj

et al. 2016

J Virol

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Early HIV-1 infection is characterized by enhanced tryptophan catabolism, which contributes to immune suppression and disease progression. However, the mechanism by which kynurenine, a tryptophan-related metabolite, induces immune suppression remains poorly understood. Herein, we show that the increased production of kynurenine correlates with defective interleukin-2 (IL-2) signaling in memory CD4 T cells from HIV-infected subjects. Defective IL-2 signaling in these subjects, which drives reduced protection from Fas-mediated apoptosis, was also associated with memory CD4 T-cell loss. Treatment of memory CD4 T cells with the concentration of kynurenine found in plasma inhibited IL-2 signaling through the production of reactive oxygen species. We further show that IL-2 signaling in memory CD4 T cells is improved by the antioxidant N-acetylcysteine. Early initiation of antiretroviral therapy restored the IL-2 response in memory CD4 T cells by reducing reactive oxygen species and kynurenine production. The study findings provide a kynurenine-dependent mechanism through IL-2 signaling for reduced CD4 T-cell survival, which can be reversed by early treatment initiation in HIV-1 infection. IMPORTANCE The persistence of functional memory CD4 T cells represents the basis for long-lasting immune protection in individuals after exposure to HIV-1. Unfortunately, primary HIV-1 infection results in the massive loss of these cells within weeks of infection, which is mainly driven by inflammation and massive infection by the virus. These new findings show that the enhanced production of kynurenine, a metabolite related to tryptophan catabolism, also impairs memory CD4 T-cell survival and interferes with IL-2 signaling early during HIV-1 infection.P rogressive depletion of CD4 T cells by pyroptosis and activation-related apoptosis is the hallmark of HIV-1 infection (1-4). The loss of memory CD4 T cells and, in particular, central memory CD4 T cells (T CM cells), which are critical to ensure longlasting immune protection, occurs from the onset of infection and independently predicts disease progression (5-8). Memory T-cell survival depends on signals provided by the gamma-chain-receptor cytokines, such as interleukin-2 (IL-2) and IL-7 (9-12). Previous data showed an impaired response to these cytokines in T cells during HIV-1 infection (13-16). However, our knowledge of the molecular mechanisms responsible for these immune defects is still incomplete.CD4 T-cell depletion is also linked with persistent inflammation, which takes place in the gut and lymphoid tissues early after infection and in the bloodstream later after infection (17-19). This inflammation is clinically relevant, since it has not been fully abrogated by long-term antiretroviral therapy (ART) (20)(21)(22)(23). Persistent inflammation during HIV-1 infection is associated with enhanced metabolic activity, which drives a Warburg-like effect on lipid, glucose, and amino acid pathways (22,(24)(25)(26)(27). The catabolism of an essential amino acid like tryptoph...

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Section: Ccr7mentioning

confidence: 62%

Kynurenine Reduces Memory CD4 T-Cell Survival by Interfering with Interleukin-2 Signaling Early during HIV-1 Infection

Dagenais-Lussier

Aounallah

Mehraj

et al. 2016

J Virol

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“…This was first shown for the Sendai virus model and mouse splenocytes, which enhance the production of FR in response to contact with the virus, not only intact, but also inactivated by ultraviolet irradiation [49]. Later the increase of oxidative activity in cells leading to their death was shown for many viruses, both RNA and DNA genomic [44,50,52].…”

Section: Suppression Of Virus Reproduction Due To Antioxidant Activitymentioning

confidence: 90%

Protective Activity of Ascorbic Acid at Influenza Infection

Zarubaev

Slita

Lavrentyeva

et al. 2018

Russian Journal of Infection and Immunity

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Abstract. Ascorbic acid (vitamin C, AA) is an essential nutrient of the human diet due to its participation on numerous regulatory and enzymatic processes. AA takes part in such vital physiological processes as hormone production, collagen synthesis, stimulation of the immune system, etc. In the present review the activities of AA are considered that provide its protective effect at influenza infection. This effect can be result of direct virus-inhibiting activity of AA as well as of anti-inflammatory and antioxidant properties. Oxidative stress during influenza infection leads to nonspecific damage of the pulmonary tissue and subsequent inflammation of the lungs. The antioxidant activity of AA results in alleviation of infection due to suppression of tissue damage as well as in inhibition of reactive oxygen species-mediated signal transduction and regulatory reactions. After oxidation by ROS, AA is converted to dehydroascorbic acid (DAA) and inhibits the key enzymes of NF-κB pathway, such as kinases IKKα and IKKβ. AA itself blocks the activity of another component of the NF-kB pathway, kinase IKKβ(SS/EE), whose activity is directed to the phosphorylation of the factor IκBα. As a result, activation of NF-κB and its transport to the nucleus does not occur. Thus, AA performs a dual function: first, it neutralizes free radicals, preventing them from activating NF-κB, and secondly, the product of its oxidation, DAA, further blocks the activation of this pathway. In addition, in some cases AA results in the decrease in the infectious activity of influenza virus that is not due to the antioxidant activity of AA, but to direct virus-inhibiting activity. Taken together, the presented data suggests that the use of drugs with antiviral and antioxidant activity, as a combination of individual drugs or, as in the case of AA, as a single drug with complex activity, for treatment of influenza has advantages over the etiotropic drug monotherapy scheme. Резюме. Аскорбиновая кислота (витамин C, АК) является важным пищевым компонентом для человека благо-даря ее роли в различных регуляторных и ферментативных процессах. АК принимает участие в таких жизненно важных физиологических процессах, как продукция гормонов, синтез коллагена, стимуляция иммунной си-стемы и пр. В настоящем обзоре рассмотрена активность АК, обеспечивающая ее протективный эффект при гриппозной инфекции. Этот эффект может быть обусловлен прямой вирусингибирующей активностью АК, а также ее противовоспалительными и антиоксидантными свойствами. Окислительный стресс при гриппе ведет к неспецифическому повреждению ткани легких и развитию воспаления. Антиоксидантная активность АК приводит к облегчению течения инфекции вследствие снижения уровня повреждения ткани и ингибиро-

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“…[4][5][6][7][8] Relationships between viruses and DDR in the host are well described and show that viruses modulate cell metabolism and interact with cellular molecules to activate or deactivate different pathways in DNA damage repair. [9][10][11][12] Virus-induced dysfunction in DNA repair may result from up-or downregulation of key factors involved in DDR. There is also growing evidence that HIV-1 influences DDR during active infection, with most studies focusing on the accessory protein Vpr targeting different factors essential for host genome integrity and cell cycle arrest.…”

Section: Introductionmentioning

confidence: 99%

Deficiency in DNA damage response, a new characteristic of cells infected with latent HIV-1

et al. 2017

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Viruses can interact with host cell molecules responsible for the recognition and repair of DNA lesions, resulting in dysfunctional DNA damage response (DDR). Cells with inefficient DDR are more vulnerable to therapeutic approaches that target DDR, thereby raising DNA damage to a threshold that triggers apoptosis. Here, we demonstrate that 2 Jurkat-derived cell lines with incorporated silent HIV-1 provirus show increases in DDR signaling that responds to formation of double strand DNA breaks (DSBs). We found that phosphorylation of histone H2AX on Ser139 (gamma-H2AX), a biomarker of DSBs, and phosphorylation of ATM at Ser1981, Chk2 at Thr68, and p53 at Ser15, part of signaling pathways associated with DSBs, are elevated in these cells. These results indicate a DDR defect even though the virus is latent. DDR-inducing agents, specifically high doses of nucleoside RT inhibitors (NRTIs), caused greater increases in gamma-H2AX levels in latently infected cells. Additionally, latently infected cells are more susceptible to long-term exposure to G-quadruplex stabilizing agents, and this effect is enhanced when the agent is combined with an inhibitor targeting DNA-PK, which is crucial for DSB repair and telomere maintenance. Moreover, exposing these cells to the cancer drug etoposide resulted in formation of DSBs at a higher rate than in un-infected cells. Similar effects of etoposide were also observed in population of primary memory T cells infected with latent HIV-1. Sensitivity to these agents highlights a unique vulnerability of latently infected cells, a new feature that could potentially be used in developing therapies to eliminate HIV-1 reservoirs.

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RNA Viruses: ROS-Mediated Cell Death

Cited by 245 publications

References 211 publications

Kynurenine Reduces Memory CD4 T-Cell Survival by Interfering with Interleukin-2 Signaling Early during HIV-1 Infection

Kynurenine Reduces Memory CD4 T-Cell Survival by Interfering with Interleukin-2 Signaling Early during HIV-1 Infection

Protective Activity of Ascorbic Acid at Influenza Infection

Deficiency in DNA damage response, a new characteristic of cells infected with latent HIV-1

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