Innate Sensing of HIV-Infected Cells

Cell-free HIV-1 virions are poor stimulators of type I interferon (IFN) production. We examined here how HIV-infected cells are recognized by plasmacytoid dendritic cells (pDCs) and by other cells. We show that infected lymphocytes are more potent inducers of IFN than virions. There are target cell-type differences in the recognition of infected lymphocytes. In primary pDCs and pDC-like cells, recognition occurs in large part through TLR7, as demonstrated by the use of inhibitors and by TLR7 silencing. Donor cells expressing replication-defective viruses, carrying mutated reverse transcriptase, integrase or nucleocapsid proteins induced IFN production by target cells as potently as wild-type virus. In contrast, Env-deleted or fusion defective HIV-1 mutants were less efficient, suggesting that in addition to TLR7, cytoplasmic cellular sensors may also mediate sensing of infected cells. Furthermore, in a model of TLR7-negative cells, we demonstrate that the IRF3 pathway, through a process requiring access of incoming viral material to the cytoplasm, allows sensing of HIV-infected lymphocytes. Therefore, detection of HIV-infected lymphocytes occurs through both endosomal and cytoplasmic pathways. Characterization of the mechanisms of innate recognition of HIV-infected cells allows a better understanding of the pathogenic and exacerbated immunologic events associated with HIV infection

IL28B genetic variations are associated with high sustained virological response (SVR) of interferon-α plus ribavirin therapy in Taiwanese chronic HCV infection

Chronic hepatitis C virus (HCV) infection patients exhibit different sustained virological responses (SVRs) following the treatment with pegylated interferon-α (IFN-α) and ribavirin. Genome-wide association studies consistently linked SVR of IFN-α-based therapy to the IL28B single-nucleotide polymorphisms (SNPs) on chromosome 19q.13 in various populations. This study was undertaken to investigate the association of IL28B SNPs with SVR in a cohort of Taiwanese chronic HCV patients. Ten SNPs of IL28B were genotyped in 728 chronic HCV patients and 960 healthy controls. Genotype distributions, allele frequencies and haplotypes were tested for SVR and susceptibility in Taiwanese chronic HCV patients. Non-genotype 1 infection (adjusted P=3.3 × 10−12, odds ratio (OR) 0.179; 95% confidence interval (CI): 0.110–0.290) and low HCV viral load (<400 000 IU ml–1) (adjusted P=3.5 × 10−9, OR 0.299; 95% CI: 0.200–0.446) were two major factors identified for high SVR. Notably, eight IL28B SNPs including previously described disease-associated SNPs (Trend test P=0.005) were significantly associated with SVR. Our data indicate that IL28B polymorphisms are the essential contributing factors for high SVR in Taiwanese chronic HCV patients. Combination of virus genotyping and host genetic data may be used to select the optimal treatment regimes in IFN-based therapy

Inhibition of DPP4 activity in humans establishes its in vivo role in CXCL10 post‐translational modification: prospective placebo‐controlled clinical studies

International audienceBiochemical experiments, animal models, and observational studies in humans all support a role of dipeptidyl peptidase 4 (DPP4) in the N-terminal truncation of CXCL10, which results in the generation of an antagonist form of the chemokine that limits T-cell and NK cell migration. Motivated by the ability to regulate lymphocyte trafficking in vivo, we conducted two prospective clinical trials to test the effects of DPP4 inhibition on CXCL10 processing in healthy donors and in chronic hepatitis C patients, a disease in which DPP4 levels are found to be elevated. Participants were treated daily with 100 mg sitagliptin, a clinically approved DPP4 inhibitor. Plasma samples were analyzed using an ultrasensitive single-molecule assay (Simoa) to distinguish the full-length CXCL101-77 from the NH2-truncated CXCL103-77, as compared to the total CXCL10 levels. Sitagliptin treatment resulted in a significant decrease in CXCL103-77 concentration, a reciprocal increase in CXCL101-77, with only minimal effects on total levels of the chemokine. These data provide the first direct evidence that in vivo DPP4 inhibition in humans can preserve the bioactive form of CXCL10, offering new therapeutic opportunities for DPP4 inhibitors

“ TANGO

Background The aim of this study is to evaluate the validity and reliability of the Targeting the Individual's Aetiology of Nocturia to Guide Outcomes (TANGO) screening tool, which is used to determine nocturia etiology. Methods Patients hospitalized in urology, orthopedics, and general surgery clinics between September 2019 and January 2020 were included in the study. Demographic characteristics of the participants such as age, gender, drug use, and nocturia severity were assessed by the researchers. The Turkish version of the TANGO questionnaire consisting of 22 questions was filled in by the patients. The patients were asked to repeat the same test 4 weeks later. Results A total of 124 patients were included in the study. The mean age of the patients participating in the study was 51.20 +/- 18.50 (38-82). The result of the reliability assessment showed that the total score intraclass correlation coefficient was 0.715 (individual item score weighted kappa coefficients, 0.696-0.731) and the Cronbach's alpha coefficient was 0.727. A total of 112 patients filled in the TANGO screening tool again after 4 weeks. The test-retest reliability analysis kappa value was 0.75 (0.68-0.83). In the validity analysis, a moderately positive correlation was observed between the TANGO-Urinary Incontinence Score and the number of nocturia (r = 0.452,P= .003). Conclusion According to the validation study, the TANGO screening tool is valid and reliable to determine the nocturia etiology for the Turkish population

HMGB1 Is Involved in IFN-α Production and TRAIL Expression by HIV-1-Exposed Plasmacytoid Dendritic Cells: Impact of the Crosstalk with NK Cells.

Plasmacytoid dendritic cells (pDCs) are innate sensors of viral infections and important mediators of antiviral innate immunity through their ability to produce large amounts of IFN-α. Moreover, Toll-like receptor 7 (TLR7) and 9 (TLR9) ligands, such as HIV and CpG respectively, turn pDCs into TRAIL-expressing killer pDCs able to lyse HIV-infected CD4+ T cells. NK cells can regulate antiviral immunity by modulating pDC functions, and pDC production of IFN-α as well as cell-cell contact is required to promote NK cell functions. Impaired pDC-NK cell crosstalk was reported in the setting of HIV-1 infection, but the impact of HIV-1 on TRAIL expression and innate antiviral immunity during this crosstalk is unknown. Here, we report that low concentrations of CCR5-tropic HIV-1Ba-L promote the release of pro-inflammatory cytokines such as IFN-α, TNF-α, IFN-γ and IL-12, and CCR5-interacting chemokines (MIP-1α and MIP-1β) in NK-pDCs co-cultures. At high HIV-1BaL concentrations, the addition of NK cells did not promote the release of these mediators, suggesting that once efficiently triggered by the virus, pDCs could not integrate new activating signals delivered by NK cells. However, high HIV-1BaL concentrations were required to trigger IFN-α-mediated TRAIL expression at the surface of both pDCs and NK cells during their crosstalk. Interestingly, we identified the alarmin HMGB1, released at pDC-NK cell synapse, as an essential trigger for the secretion of IFN-α and IFN-related soluble mediators during the interplay of HIV-1 exposed pDCs with NK cells. Moreover, HMGB1 was found crucial for mTRAIL translocation to the plasma membrane of both pDCs and NK cells during their crosstalk following pDC exposure to HIV-1. Data from serum analyses of circulating HMGB1, HMGB1-specific antibodies, sTRAIL and IP-10 in a cohort of 67 HIV-1+ patients argue for the in vivo relevance of these observations. Altogether, these findings identify HMGB1 as a trigger for IFN-α-mediated TRAIL expression at the surface of pDCs and NK cells, and they suggest a novel mechanism of innate control of HIV-1 infection

A look behind closed doors: interaction of persistent viruses with dendritic cells.

International audiencePersistent infections with HIV, hepatitis B virus and hepatitis C virus are major causes of morbidity and mortality worldwide. As sentinels of the immune system, dendritic cells (DCs) are crucial for the generation of protective antiviral immunity. Recent advances in our understanding of the role of DCs during infection with these viruses provide insights into the mechanisms used by these viruses to exploit DC function and evade innate and adaptive immunity. In this Review we highlight the current knowledge about the interaction between DCs and these viruses and the underlying mechanisms that might influence the outcome of viral infections