Hepatitis C virus infection (HCV) represents a unique model to characterize, from early to late stages of infection, the T cell differentiation process leading to exhaustion of human CD8+ T cells. ...Here we show that in early HCV infection, exhaustion-committed virus-specific CD8+ T cells display a marked upregulation of transcription associated with impaired glycolytic and mitochondrial functions, that are linked to enhanced ataxia-telangiectasia mutated (ATM) and p53 signaling. After evolution to chronic infection, exhaustion of HCV-specific T cell responses is instead characterized by a broad gene downregulation associated with a wide metabolic and anti-viral function impairment, which can be rescued by histone methyltransferase inhibitors. These results have implications not only for treatment of HCV-positive patients not responding to last-generation antivirals, but also for other chronic pathologies associated with T cell dysfunction, including cancer.
Background & Aims In patients with chronic hepatitis B virus (HBV) infection, persistent exposure to high concentrations of antigen can disrupt T-cell functions. It is not clear to what extent ...long-term suppression of HBV by nucleos(t)ide analogues can restore antiviral T-cell functions. We compared HBV-specific T-cell responses of patients treated with nucleos(t)ide analogues with those detected in other conditions of HBV control. Methods We analyzed intracellular levels of interferon gamma, interleukin-2, and tumor necrosis factor α in HBV-specific T cells after 10 days of stimulation with peptides covering the overall HBV genotype D sequence and ex vivo with selected CD8 epitopes and the corresponding HLA-A2 dextramers. Findings from patients treated with nucleos(t)ide analogues who had complete (HBV DNA negative/antibody to hepatitis B surface antigen positive) or partial (HBV DNA negative/hepatitis B surface antigen positive) control of their infections were compared with those of patients with spontaneous or interferon alfa–induced resolution of acute or chronic infections, inactive HBV carriers, or untreated hepatitis B e antigen–negative patients with chronic infections. Results Although HBV-specific T cells from nucleos(t)ide analogue–treated patients with complete control of infection were dysfunctional ex vivo, they had efficient responses after in vitro expansion. These responses were comparable to those of patients who spontaneously resolved acute HBV infection. Nucleos(t)ide analogue–treated patients who were HBV DNA negative but hepatitis B surface antigen positive had lower levels of T-cell responses but responses greater than those of untreated patients with chronic infection. Conclusions In vitro reactivity can be restored to T cells from patients with suppressed HBV infection following long-term treatment with nucleos(t)ide analogues, despite prolonged exposure to large loads of antigen. Immune therapies that increase the antiviral T-cell response might increase the likelihood of complete HBV control in patients undergoing long-term nucleos(t)ide analogue treatment.
We describe a case of relapsing hypersensitivity pneumonitis (HP) manifesting as a reconstitution inflammatory syndrome (IRIS) in a HIV infected patient receiving antiretroviral therapy (HAART). The ...patient, who works as a farmer since the early 20s, was diagnosed with HP at age 23: after an initial steroid therapy, a long lasting clinical regression followed. At age 32, HIV positivity was diagnosed, with HAART starting only at age 38 (initially, lamivudine 300 mg/daily + zidovudine 300 mg b.i.d.). In the following 15 years, CD4+ count remained <500 cells/μL until therapy was shifted to ritonavir 100 mg b.i.d + fosamprenavir 700 mg b.i.d. A six-months long increase in the CD4+ count (>600 cells/μL) with undetectable viral load then followed. Eventually, the patient developed cough and slowly worsening dyspnoea. Laboratory exams (serum T cell lymphocyte count 83%, CD8+ 45-51%; serum IgG for
M faeni
=78 mg/L and
P notatum
>200 mg/L) and high-resolution computer tomography (HRCT) were compatible with relapsing HP. The working tasks were modified avoiding any contact with allergens, then achieving a 6 months long clinical regression. Detectable HIV load (62 copies/mL) was identified at follow-up, and emtricitabine 200 mg/tenofovir disoproxil fumarate 245 mg s.i.d. was added to HAART. Respiratory involvement newly relapsed. HAART was shifted to emtricitabine 200 mg/tenofovir disoproxil fumarate 245 mg s.i.d. and raltegravir 400 mg b.i.d. Within several weeks, signs and symptoms resolved almost completely (peripheral oxygen saturation >95%: CD4+ count remained >600 cells/μL with CD8+ count steadily <50% and CD4+/CD8+ ratio >55%). (
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In chronic HBV infection, elevated reactive oxygen species levels derived from dysfunctional mitochondria can cause increased protein oxidation and DNA damage in exhausted virus-specific CD8 T cells. ...The aim of this study was to understand how these defects are mechanistically interconnected to further elucidate T cell exhaustion pathogenesis and, doing so, to devise novel T cell-based therapies.
DNA damage and repair mechanisms, including parylation, CD38 expression, and telomere length were studied in HBV-specific CD8 T cells from chronic HBV patients. Correction of intracellular signalling alterations and improvement of antiviral T cell functions by the NAD precursor nicotinamide mononucleotide and by CD38 inhibition was assessed.
Elevated DNA damage was associated with defective DNA repair processes, including NAD-dependent parylation, in HBV-specific CD8 cells of chronic HBV patients. NAD depletion was indicated by the overexpression of CD38, the major NAD consumer, and by the significant improvement of DNA repair mechanisms, and mitochondrial and proteostasis functions by NAD supplementation, which could also improve the HBV-specific antiviral CD8 T cell function.
Our study delineates a model of CD8 T cell exhaustion whereby multiple interconnected intracellular defects, including telomere shortening, are causally related to NAD depletion suggesting similarities between T cell exhaustion and cell senescence. Correction of these deregulated intracellular functions by NAD supplementation can also restore antiviral CD8 T cell activity and thus represents a promising potential therapeutic strategy for chronic HBV infection.
Correction of HBV-specific CD8 T cell dysfunction is believed to represent a rational strategy to cure chronic HBV infection, which however requires a deep understanding of HBV immune pathogenesis to identify the most important targets for functional T cell reconstitution strategies. This study identifies a central role played by NAD depletion in the intracellular vicious circle that maintains CD8 T cell exhaustion, showing that its replenishment can correct impaired intracellular mechanisms and reconstitute efficient antiviral CD8 T cell function, with implications for the design of novel immune anti-HBV therapies. As these intracellular defects are likely shared with other chronic virus infections where CD8 exhaustion can affect virus clearance, these results can likely also be of pathogenetic relevance for other infection models.
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•In chronic HBV infection elevated ROS production is associated with high DNA damage in HBV-specific CD8 T cells.•Response to DNA damage is dysfunctional.•Upregulation of CD38 and persistent activation of poly-ADP-ribose polymerases contribute to NAD consumption.•NAD depletion maintains and amplifies cellular dysfunction in exhausted HBV-specific T cells.•NAD replenishment can restore T-cell function.
July 17, 1998, can be considered as one of the most important milestones of the international judicial structure: it is the day when the Rome Statute of the International Criminal Court was adopted ...by 120 states out of 148. Article 86 of Statute explicitly states that „States Parties shall … cooperate fully with the Court in its investigation and prosecution of crimes within the jurisdiction of the Court.” As in the case of every international treaty, the principle of pacta sunt servanda enshrined in Article 26 of the 1969 Vienna Convention on the Law of the Treaties states applies, which explicitly states that “every treaty in force is binding upon the parties to it and must be performed by them in good faith.” As has been pointed out by the Permanent Court of International Justice, contracting states must make all the necessary internal measures which are required to fulfil its international obligations rising from a binding treaty. One could ask, why is this quite obvious argument important in the case of Hungary? Well, Hungary has ratified the Statute but still has not implemented it in its internal legislation. This can be considered as a serious constitutional omission, since if the Court would require the cooperation of Hungary – e.g. in the case of an arrest warrant – and it would not be able to fulfil it because of the lack of the internal legal norms, it would be considered as international legal responsibility of Hungary. In this article, I try to explore the reasons behind this omission and outline the possible solutions.
1998. július 17-e a nemzetközi igazszolgáltatási struktúra egyik legfontosabb mérföldköve: ezen a napon született meg a Római Statútum, amelyet a kodifikálásban résztvevő 148 államból 120 támogatott. A Statútum 86. cikke expressis verbis rögzíti, hogy „a Részes Államok kötelesek … teljes mértékben együttműködni a Bírósággal a Bíróság joghatóságába tartozó bűntettek miatti nyomozás és büntetőeljárás során.” Mint minden nemzetközi szerződés, úgy a Statútum esetében is érvényesül a pacta sunt servanda elve, amelyről explicit formában a szerződések jogáról szóló 1969. évi Bécsi Egyezmény 26. cikke rendelkezik, rögzítve, hogy „minden hatályos szerződés kötelezi a részes feleket amelyeket jóhiszeműen kell végrehajtaniuk.” Ahogy arra az Állandó Nemzetközi Bíróság is rávilágított, egy érvényes és hatályos nemzetközi kötelezettség esetében az érintett állam köteles megtenni minden olyan belső jogi intézkedést, amely annak végrehajtásához szükséges. Miért is fontos mindez? Magyarország ugyan ratifikálta a Statútumot, azonban azt a mai napi napig nem hirdette ki, amely azért tekinthető jelentős mulasztásnak, mert ha a Bíróság együttműködésre hívná fel hazánkat – például egy elfogatási parancs kibocsátása útján – és azt a belső jogi mulasztásunk miatt nem tudnánk teljesíteni, úgy a 86. cikkben rögzített együttműködési kötelezettség megsértése megalapozhatná Magyarország nemzetközi jogi felelősségét. A tanulmányban annak a kérdésnek a megválaszolását kísérlem meg, hogy vajon milyen okok vezethettek idáig, és milyen megoldási lehetőségek állnak rendelkezésre.
Az államfői immunitás kérdése a nemzetközi büntetőjog egyik legfontosabb területe, hiszen a nemzetközi bűncselekmények elkövetői gyakorta az állami hierarchia csúcsán helyezkednek el. Ebből ...kifolyólag hivatali idejük alatt főszabály szerint nincs lehetőség az általuk véghezvitt cselekmények büntetőjogi szempontból történő elbírálására. Ezt a problémát felismerve a Nürnbergi Törvényszéktől kezdve, az Egyesült Nemzetek Szervezetének keretében felállított ad-hoc törvényszékek továbbá a Nemzetközi Büntetőbíróság Statútuma is expressis verbis rögzítik a hivatalos minőség irrelevanciáját. Ugyanakkor látnunk kell azt is, hogy a jelenleg hatályos nemzetközi közjog normarendszere alapján főszabály szerint nem állapítható meg kötelezettség egy olyan államra nézve, amely nem részese az adott szerződésnek. Tekintettel arra, hogy a Nemzetközi Büntetőbíróságnak önálló erőszakszervezete nincs a tagállamok együttműködésére van utalva a letartóztatási parancsok foganatosításának tekintetében. Ebből kifolyólag kérdésként merül fel, hogy vajon mit tehet a Nemzetközi Büntetőbíróság amennyiben egy olyan állam hivatalban lévő államfőjével szemben kíván eljárást folytatni, amely nem ratifikálta a Római Statútumot? Ezzel a problémával szembesült Omar Hassan Ahmad Al Bashir esetében, amelynek leltároztatását számos tagállam megtagadta az őt megillető államfői immunitásból adódóan. Jelen írás keretében a vonatkozó esetjogon keresztül mutatom be a kortárs nemzetközi büntetőjog korlátait és teszek kísérletet egy megoldási javaslatra.
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