Showing papers by "Nina Le Bert published in 2023"
TL;DR: Chisari et al. as discussed by the authors measured the capacity of the HB-specific CD8T cells in either acute and CHB patients, and found that the ability of these cells to recover after functional cure was inversely correlated with their ability to produce cytokines directly ex vivo.
Abstract: Control of hepatitis B virus (HBV) infection requires functional virusspecific T cells, yet clinical management of patients with chronic HBV infection (CHB) relies exclusively on the assessment of virological (HBVDNA, HBsAg) and biochemical (alanine transaminase (ALT)) biomarkers. There is, however, a growing recognition of the necessity to categorise CHB patients based on their profile of HBVspecific immunity. Such immunological biomarkers might guide when to start or stop nucleos(t)ide analogue (NA) therapy, and/or identify patients who would benefit from novel therapeutic strategies designed to modify host–virus interaction by restoring HBVspecific immunity, either directly (therapeutic vaccines or check point inhibitors) or indirectly (antisense nucleotides, siRNA) (figure 1). In Gut, Ferrari and Boni’s group present findings which could potentially help address this unmet clinical need. Their study in treatment naïve CHB patients shows that simple phenotypic analysis of total circulating CD8T cells can predict HBVspecific CD8 T cell response to immunomodulatory compounds. For three decades, we have known that HBVspecific T cell immunity differs between patients with acute and CHB (reviewed in Chisari and Ferrari ). More recent works have shown that HBVspecific T cells recover, even though often only partially, 4 after functional cure. 6 Such data support the idea that restoration of functional HBVspecific T cell immunity can achieve HBV control but fails to take into account a key characteristic of HBVspecific T cells in CHB patients: their extreme heterogeneity. 7–9 Although extremely low levels of HBsAg and HBcrAg can predict superior responsiveness to PDL1 blockade, it is now clear that the HBVspecific T cell response does not preferentially segregate into the classical CHB definitions (ie, immune tolerant, chronic active, asymptomatic carriers), which are based on virological and biochemical profiles. 12 HBsAg quantity is not associated with frequency and/or function of HBVspecific T cells. 13 Levels of transaminases, the other biomarker used to categorise CHB patients, do not correlate with HBVspecific T cell responses; ALT levels are not proportional to HBVspecific T cell frequency both in the periphery and the liver. Indeed, hepatic damage in CHB is primarily caused by inflammatory and necrotic events supported by myeloid and nonantigenspecific CD8T cells. Thus, since virological and clinical biomarkers cannot predict the level of HBVspecific T cell immunity, its direct assessment is necessary. Unfortunately, such assessment is highly complex, and has thus far prevented its application in the clinic. It is therefore of great practical importance that Rossi et al showed that a phenotypic analysis of circulating total CD8T cells, performed by analysing exhaustion (PD1, TOX) and memory (CD127, BCL2) markers, can generate an ‘exhaustion score’ that predicts HBVspecific T cell responsiveness to immunomodulatory therapy. The authors first measured the expression of exhaustion and memory markers in selected core and polymeraseHLAA2 restricted CD8T cells in treatment naïve CHB patients with liver inflammation (HBeAg+ and HBeAg− chronic hepatitis). In line with previously described HBVspecific CD8T cell heterogeneity, they found variable levels of expression among patients. The expression of these markers was then quantified to calculate an exhaustion score (EI, a numeric value of the zstandard medium fluorescent values of PD1, TOX, CD39, CD127, BCl2). The authors found that EI scores of HBcorespecific CD8T cells varied across the cohort. The EI score was independent of viral load and HBsAg quantity but positively correlated with ALT. Importantly, the score was inversely correlated with the ability of HBcorespecific CD8T cells to produce cytokines directly ex vivo. To expand on this observation, the authors measured the capacity of the HBcorespecific CD8T cells to proliferate in vitro after peptidespecific stimulation, either in the presence of antioxidant, polyphenolic or PD1/PDL1 targeting compounds or of a tolllike receptor 8 (TLR8) agonist—all agents proposed to restore exhausted T cell function. The ability of the HBcore CD8T cells to proliferate in vitro in the presence of these
TL;DR: In this paper , the authors studied serological and cellular immune responses in residents of rural Kenya who had not experienced any respiratory symptom nor had contact with COVID-19 cases, and detected anti-spike antibodies in 41.0% and T cell responses against SARS-CoV-2 proteins in 82.5%.
Abstract: Antibodies are used to estimate prevalence of past infection. However, T cell responses against SARS-CoV-2 may more accurately define prevalence because SARS-CoV-2-specific antibodies wane. In November-December 2021, we studied serological and cellular immune responses in residents of rural Kenya who had not experienced any respiratory symptom nor had contact with COVID-19 cases. Among participants we detected anti-spike antibodies in 41.0% and T cell responses against [≥]2 SARS-CoV-2 proteins in 82.5%, which implies that serosurveys underestimate SARS-CoV-2 prevalence in settings where asymptomatic infections prevail. Distinct from cellular immunity in European and Asian COVID-19 convalescents, strong T cell immunogenicity was observed against viral accessory proteins in these asymptomatic Africans, as well as a higher IL-10/IFN-{gamma} ratio cytokine profile, suggesting that environmental or genetic factors modulate pro-inflammatory responses.
TL;DR: In this article , the authors analyzed spike-specific antibodies and T cells specific for SARS-CoV-2 structural (membrane, nucleocapsid, and spike) and accessory (ORF3a, ORF7, orF8) proteins.
Abstract: Background SARS-CoV-2 infection in Africa has been characterized by a less severe disease profile than what has been observed elsewhere, but the profile of SARS-CoV-2–specific adaptive immunity in these mainly asymptomatic patients has not, to our knowledge, been analyzed. Methods We collected blood samples from residents of rural Kenya (n = 80), who had not experienced any respiratory symptoms or had contact with individuals with COVID-19 and had not received COVID-19 vaccines. We analyzed spike-specific antibodies and T cells specific for SARS-CoV-2 structural (membrane, nucleocapsid, and spike) and accessory (ORF3a, ORF7, ORF8) proteins. Pre-pandemic blood samples collected in Nairobi (n = 13) and blood samples from mild-to-moderately symptomatic COVID-19 convalescent patients (n = 36) living in the urban environment of Singapore were also studied. Results Among asymptomatic Africans, we detected anti-spike antibodies in 41.0% of the samples and T cell responses against 2 or more SARS-CoV-2 proteins in 82.5% of samples examined. Such a pattern was absent in the pre-pandemic samples. Furthermore, distinct from cellular immunity in European and Asian COVID-19 convalescents, we observed strong T cell immunogenicity against viral accessory proteins (ORF3a, ORF8) but not structural proteins, as well as a higher IL-10/IFN-γ cytokine ratio profile. Conclusions The high incidence of T cell responses against different SARS-CoV-2 proteins in seronegative participants suggests that serosurveys underestimate SARS-CoV-2 prevalence in settings where asymptomatic infections prevail. The functional and antigen-specific profile of SARS-CoV-2–specific T cells in African individuals suggests that environmental factors can play a role in the development of protective antiviral immunity. Funding US Centers for Disease Control and Prevention, Division of Global Health Protection; the Singapore Ministry of Health’s National Medical Research Council (COVID19RF3-0060, COVID19RF-001, COVID19RF-008, MOH-StaR17Nov-0001).
TL;DR: In this article , a discussion about integrating virological and clinical parameters with immunological ones to better select patients for novel immunotherapies and manage their treatments is presented. But the authors focus on the clinical management of CHB.