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Introduction: Combined anti-retroviral therapy (cART) transformed HIV-1 from a deadly disease into a chronic infection, but does not cure HIV infection. It also does not fully restore HIV-induced gut damage unless administered extremely early after infection. Additional biomarkers are needed to evaluate the capacity of therapies aimed at HIV remission/cure to restore HIV-induced intestinal immune damage and limit chronic inflammation. Herein, we aimed to identify a systemic surrogate marker whose levels would reflect gut immune damage such as intestinal Th17 cell loss starting from primary HIV-1 infection. Methods: Biomarker discovery approaches were performed in four independent cohorts, covering HIV-1 primary and chronic infection in 496 naive or cART-treated patients (Amsterdam cohort (ACS), ANRS PRIMO, COPANA and CODEX cohorts). The concentration and activity of soluble Dipeptidylpeptidase 4 (sDPP4) were quantified in the blood from these patients, including pre- and post-infection samples in the ACS cohort. For quantification of DPP4 in the gut, we utilized two non-human primate models, representing pathogenic (macaque) and non-pathogenic (African green monkey) SIV infection. Four gut compartments were analysed in each animal model (ileum, jejunum, colon and rectum) for quantification of DPP4, RORC and TBX21 gene expression in sorted [CD4.sup.+] cells. To analyse if sDPP4 levels increase when Th17 cells were restored, we quantified sDPP4 in plasma from SIV-infected macaques treated with IL-21. Results: We showed that sDPP4 levels were strongly decreased in primary HIV-1 infection. Strikingly, sDPP4 levels in primary HIV-1 infection predicted time to AIDS. They were not increased by cART in chronic HIV-1 infection (median 36 months on cART). In the gut of SIV-infected non-human primates, DPP4 mRNA was higher in [CD4.sup.+] than [CD4.sup.-] leucocytes. DPP4 specifically correlated with RORC expression, a Th17 marker, in [CD4.sup.+] cells from the intestine. We further demonstrated that sDPP4 activity levels were increased in animals treated with IL-21 and that this increase was associated with restoration of the Th17 compartment and reduced inflammation. Furthermore, DPP4 mRNA levels in small intestine [CD4.sup.+] cells positively correlated with circulating DPP4 activity. Conclusion: These data provide evidence that blood sDPP4 levels could be useful as a correlate for HIV-induced intestinal damage. Keywords: HIV; SIV; inflammation; intestine; dipeptidylpeptidase; biomarker; Th17, 1 | INTRODUCTION Combined anti-retroviral treatment (cART) drastically improves life expectancy and quality of life of HIV-infected individuals [1,2] but does not result in viral cure. Despite sustained undetectable viraemia [...]

Chronic infection with hepatitis C virus (HCV) is a major public health problem, with nearly 170 million infected individuals worldwide. Current treatment for chronic infection is a combination of pegylated IFN-[α.sub.2] and ribavirin (RBV); however, this treatment is effective in fewer than 50% of patients infected with HCV genotype 1 or 4. Recent studies identified the chemokine CXCL10 (also known as IP-10) as an important negative prognostic biomarker. Given that CXCL10 mediates chemoattraction of activated lymphocytes, it is counterintuitive that this chemokine correlates with therapeutic nonresponsiveness. Herein, we offer new insight into this paradox and provide evidence that CXCL10 in the plasma of patients chronically infected with HCV exists in an antagonist form, due to in situ amino-terminal truncation of the protein. We further demonstrated that dipeptidyl peptidase IV (DPP4; also known as CD26), possibly in combination with other proteases, mediates the generation of the antagonist form(s) of CXCL10. These data offer what we believe to be the first evidence for CXCL10 antagonism in human disease and identify a possible factor contributing to the inability of patients to clear HCV., Introduction There are nearly 170 million HCV-infected individuals worldwide (1). Many studies have explored the mechanisms by which the immune system is capable of mediating viral clearance (2). Although an [...]

A method for analyzing the T-cell receptor (TCR) repertoire was developed. The procedure used polymerase chain reaction amplification and primer extension analysis to determine the size spectrum of the CDR3-like region of all possible V-beta-J-beta combinations. The results showed that the number of rearranged TCR beta chains number at least 2,000. The segment size of the CDR3 region was dependent on the amino acid sequence of the V-beta and J-beta segments.

Generation and maintenance of an effective repertoire of T cell antigen receptors are essential to the immune system, yet the number of distinct T cell receptors (TCRs) expressed by the estimated [10.sup.12] T cells in the human body is not known. In this study, TCR gene amplification and sequencing showed that there are about [10.sup.6] different Β chains in the blood, each pairing, on the average, with at [east 25 different a chains. In the memory subset, the diversity decreased to 1 x [10.sup.5] to 2 x [10.sup.5] different Β chains, each pairing with only a single a chain. Thus, the naive repertoire is highly diverse, whereas the memory compartment, here one-third of the T cell population, contributes less than 1 percent of the total diversity., Adaptive immunity is dependent on a genetic recombination machinery that assembles a diverse set of functional immunoglobulin or TCR genes from a pool of discontinuous gene segments. The available pool, [...]

Abstract: Introduction: Combined anti‐retroviral therapy (cART) transformed HIV‐1 from a deadly disease into a chronic infection, but does not cure HIV infection. It also does not fully restore HIV‐induced gut damage unless administered extremely early after infection. Additional biomarkers are needed to evaluate the capacity of therapies aimed at HIV remission/cure to restore HIV‐induced intestinal immune damage and limit chronic inflammation. Herein, we aimed to identify a systemic surrogate marker whose levels would reflect gut immune damage such as intestinal Th17 cell loss starting from primary HIV‐1 infection. Methods: Biomarker discovery approaches were performed in four independent cohorts, covering HIV‐1 primary and chronic infection in 496 naïve or cART‐treated patients (Amsterdam cohort (ACS), ANRS PRIMO, COPANA and CODEX cohorts). The concentration and activity of soluble Dipeptidylpeptidase 4 (sDPP4) were quantified in the blood from these patients, including pre‐ and post‐infection samples in the ACS cohort. For quantification of DPP4 in the gut, we utilized two non‐human primate models, representing pathogenic (macaque) and non‐pathogenic (African green monkey) SIV infection. Four gut compartments were analysed in each animal model (ileum, jejunum, colon and rectum) for quantification of DPP4, RORC and TBX21 gene expression in sorted CD4+ cells. To analyse if sDPP4 levels increase when Th17 cells were restored, we quantified sDPP4 in plasma from SIV‐infected macaques treated with IL‐21. Results: We showed that sDPP4 levels were strongly decreased in primary HIV‐1 infection. Strikingly, sDPP4 levels in primary HIV‐1 infection predicted time to AIDS. They were not increased by cART in chronic HIV‐1 infection (median 36 months on cART). In the gut of SIV‐infected non‐human primates, DPP4 mRNA was higher in CD4+ than CD4− leucocytes. DPP4 specifically correlated with RORC expression, a Th17 marker, in CD4+ cells from the intestine. We further demonstrated that sDPP4 activity levels were increased in animals treated with IL‐21 and that this increase was associated with restoration of the Th17 compartment and reduced inflammation. Furthermore, DPP4 mRNA levels in small intestine CD4+ cells positively correlated with circulating DPP4 activity. Conclusion: These data provide evidence that blood sDPP4 levels could be useful as a correlate for HIV‐induced intestinal damage. [ABSTRACT FROM AUTHOR]

Background & Aims Chronic infection with HCV remains a public health problem with approximately 150 million people infected worldwide. HCV intersects with lipid metabolism for replication and entry; and plasma concentrations of apolipoproteins have been identified as predictors for response to therapy. Herein, we conducted a screen of plasma proteins, including all apolipoproteins, to identify correlates of response to pegylated-interferon/ribavirin ( PR) and HCV non-structural protein 3 ( NS3) inhibitors (i.e., telaprevir/boceprevir) therapy in treatment-experienced cirrhotic patients from the ANRS CUPIC cohort. Methods We analysed 220 baseline plasma protein concentrations in 189 patients using Luminex technology and analyzed results. Results We identified baseline levels of apolipoprotein H (apoH) as a surrogate marker for sustained virological response (SVR). Notably, increased plasma concentration of apoH, used in combination with known clinical parameters, established a robust model with improved classification of patients as likely to achieve SVR ( AUC = 0.77, Se = 66%, Sp = 72%, NRI = 39%). Moreover, we provide mechanistic information that indicates a previously unidentified role for apoH during viral entry. Using a human liver slices HCV infection model, we demonstrate that apoH limits replication. Conclusion These data support testing of new biomarker strategies for the management of cirrhotic HCV patients and expand our understanding of how apoH may intersect with HCV infection. [ABSTRACT FROM AUTHOR]

Presents a study in which T cell receptors (TCR) gene amplification and sequencing showed that there are about ten... different beta chains in the blood. Experiment done to determine the diversity of the TCR beta chain; Analysis of the amino acid rearrangement in two samples of 10... T cells.

Some Toll and Toll-like receptors (TLRs) provide immunity to experimental infections in animal models, but their contribution to host defense in natural ecosystems is unknown. We report a dominant-negative TLR3 allele in otherwise healthy children with herpes simplex virus 1 (HSV-1) encephalitis. TLR3 is expressed in the central nervous system (CNS), where it is required to control HSV-1, which spreads from the epithelium to the CNS via cranial nerves. TLR3 is also expressed in epithelial and dendritic cells, which apparently use TLR3-independent pathways to prevent further dissemination of HSV-1 and to provide resistance to other pathogens in TLR3-deficient patients. Human TLR3 appears to be redundant in host defense to most microbes but is vital for natural immunity to HSV-1 in the CNS, which suggests that neurotropic viruses have contributed to the evolutionary maintenance of TLR3. [ABSTRACT FROM AUTHOR]