Human Immunodeficiency Virus Type 1 Tat Protein Inhibits the SIRT1 Deacetylase and Induces T Cell Hyperactivation

Gladstone Institute of Virology and Immunology, University of California, San Francisco, CA 94158, USA.
Cell host & microbe (Impact Factor: 12.33). 04/2008; 3(3):158-67. DOI: 10.1016/j.chom.2008.02.002
Source: PubMed


Symptoms of T cell hyperactivation shape the course and outcome of HIV-1 infection, but the mechanism(s) underlying this chronic immune activation are not well understood. We find that the viral transactivator Tat promotes hyperactivation of T cells by blocking the nicotinamide adenine dinucleotide (NAD(+))-dependent deacetylase SIRT1. Tat directly interacts with the deacetylase domain of SIRT1 and blocks the ability of SIRT1 to deacetylate lysine 310 in the p65 subunit of NF-kappaB. Because acetylated p65 is more active as a transcription factor, Tat hyperactivates the expression of NF-kappaB-responsive genes, a function lost in SIRT1-/- cells. These results support a model where the normal function of SIRT1 as a negative regulator of T cell activation is suppressed by Tat during HIV infection. These events likely contribute to the state of immune cell hyperactivation found in HIV-infected individuals.

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    • "Furthermore, the increase in HSV1-specific T-cell responses induced by the HSV1-Tat vector may reflect Tat’s ability to modulate T-cell functionality. This is supported by several in vitro and in vivo studies demonstrating that the biologically active clade-B Tat protein modulates the various signals orchestrating the first phases of the immune response through enhancement of the co-stimulation provided by IL-2 [75], [76], CD40 [37], [38], CD28 [76] and other pro-inflammatory cytokines [77]–[81]. Moreover, Tat is known to target immature DCs, inducing their maturation towards a Th1-polarizing phenotype through the transcriptional activation of TNF-alpha gene expression, leading to more efficient presentation of both allogeneic and heterologous antigens [37], [38]. "
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    ABSTRACT: Herpes simplex virus types 1 and 2 (HSV1 and HSV2) are common infectious agents in both industrialized and developing countries. They cause recurrent asymptomatic and/or symptomatic infections, and life-threatening diseases and death in newborns and immunocompromised patients. Current treatment for HSV relies on antiviral medications, which can halt the symptomatic diseases but cannot prevent the shedding that occurs in asymptomatic patients or, consequently, the spread of the viruses. Therefore, prevention rather than treatment of HSV infections has long been an area of intense research, but thus far effective anti-HSV vaccines still remain elusive. One of the key hurdles to overcome in anti-HSV vaccine development is the identification and effective use of strategies that promote the emergence of Th1-type immune responses against a wide range of epitopes involved in the control of viral replication. Since the HIV1 Tat protein has several immunomodulatory activities and increases CTL recognition of dominant and subdominant epitopes of heterologous antigens, we generated and assayed a recombinant attenuated replication-competent HSV1 vector containing the tat gene (HSV1-Tat). In this proof-of-concept study we show that immunization with this vector conferred protection in 100% of mice challenged intravaginally with a lethal dose of wild-type HSV1. We demonstrate that the presence of Tat within the recombinant virus increased and broadened Th1-like and CTL responses against HSV-derived T-cell epitopes and elicited in most immunized mice detectable IgG responses. In sharp contrast, a similarly attenuated HSV1 recombinant vector without Tat (HSV1-LacZ), induced low and different T cell responses, no measurable antibody responses and did not protect mice against the wild-type HSV1 challenge. These findings strongly suggest that recombinant HSV1 vectors expressing Tat merit further investigation for their potential to prevent and/or contain HSV1 infection and dissemination.
    Full-text · Article · Jul 2014 · PLoS ONE
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    • "The Tat protein of HIV is known to exit infected cells [9,10,12] and exert immunomodulatory effects in both non-infected and non HIV-specific T cells [14-16,18,20-22,29,77]. It is interesting to note that several Tat-mediated effects like the activation of DCs [15,16], CD4+ [6,19] and CD8+ T cells, the induction of an effector memory phenotype and the loss of B cells, as reported here, are hallmarks of the chronic immune activation observed in HIV-infected patients [2,3,79-81,83-85]. Although further studies are needed to better characterize the molecular pathways involved, we propose a key role of Tat in T cell dysfunctions and hyperactivation which may lead to an impaired control of co-infections and thus to AIDS progression. "
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    ABSTRACT: T cells are functionally compromised during HIV infection despite their increased activation and proliferation. Although T cell hyperactivation is one of the best predictive markers for disease progression, its causes are poorly understood. Anti-tat natural immunity as well as anti-tat antibodies induced by Tat immunization protect from progression to AIDS and reverse signs of immune activation in HIV-infected patients suggesting a role of Tat in T cell dysfunctionality. The Tat protein of HIV-1 is known to induce, in vitro, the activation of CD4(+) T lymphocytes, but its role on CD8(+) T cells and how these effects modulate, in vivo, the immune response to pathogens are not known. To characterize the role of Tat in T cell hyperactivation and dysfunction, we examined the effect of Tat on CD8(+) T cell responses and antiviral immunity in different ex vivo and in vivo models of antigenic stimulation, including HSV infection. We demonstrate for the first time that the presence of Tat during priming of CD8(+) T cells favors the activation of antigen-specific CTLs. Effector CD8(+) T cells generated in the presence of Tat undergo an enhanced and prolonged expansion that turns to a partial dysfunctionality at the peak of the response, and worsens HSV acute infection. Moreover, Tat favors the development of effector memory CD8(+) T cells and a transient loss of B cells, two hallmarks of the chronic immune activation observed in HIV-infected patients. Our data provide evidence that Tat affects CD8(+) T cell responses to co-pathogens and suggest that Tat may contribute to the CD8(+) T cell hyperactivation observed in HIV-infected individuals.
    Full-text · Article · Nov 2013 · PLoS ONE
    • "Studies reveal that SIRT1 exerts effects on the immune system by regulating the activity of T cells. Kwon et al. (2008) reported that blocking SIRT1 induces T cell hyperactivation, suggesting that SIRT1 acts as a negative regulator of T cell activation. Zhang et al. (2009) also found that the loss of SIRT1 functionality resulted in abnormally increased T cell activation and a breakdown of CD4þ T cell tolerance and that conversely, the upregulation of SIRT1 expression led to T cell anergy. "
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    ABSTRACT: Silent information regulator 1 (SIRT1) is a type of histone deacetylase whose activity is dependent on nicotinamide adenine dinucleotide. SIRT1 plays a key role in the longevity effects elicited by calorie restriction. Recently, a neuroprotective effect of SIRT1 was reported for neurological diseases. The focus of this review is to summarize the protective effects of SIRT1 in cerebral ischemia. First, the posttranslational modifications of SIRT1 are illustrated; then, we discuss the roles of SIRT1 in cerebral immune homeostasis. Next, we introduce the deacetylase activity of SIRT1 in cerebral ischemia and provide some examples of relevant studies. In addition, we discuss several activated mediators of SIRT1, such as resveratrol, caloric restriction, ischemic preconditioning, and other proteins and compounds. Finally, we highlight a few SIRT1-related signaling pathways, such as the peroxisome proliferator-activated receptor γ coactivator 1α, nuclear transcription factor κB, uncoupling protein 2, and forkhead box O pathways. Taken together, the information compiled in this article will serve as a comprehensive reference for the actions of SIRT1 in the nervous system and will help in the design of future experimental research and promote SIRT1 as a new therapeutic target.
    No preview · Article · Jul 2013 · Neurobiology of aging
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