Toll-like receptor 9 polymorphisms and Hepatitis B virus clearance in Moroccan chronic carriers.

OBJECTIVES: Toll-like receptor 9 (TLR9) plays a crucial role in the innate immune response against viral infections. The failure of this system may result, in an attenuated immune response against HBV. Recent research has focused on the possibility of targeting the defects in TLR9 pathway as a novel approach for anti-HBV treatment. Our study aimed to assess the impact of both TLR9 rs5743836 and rs187084 polymorphisms on spontaneous HBV clearance in Moroccan chronic HBV carriers. METHODS: In this study, 239 individuals chronically infected with HBV (CHB) and 133 subjects who spontaneously resolved the infection (SRB) were genotyped using a Taqman allelic discrimination assay. RESULTS/CONCLUSION: Remarkably, we observed a dosage effect of both SNPs on viral loads; with a significant increase of circulating HBV DNA within AA, AG to GG rs5743836 genotypes, whereas the inverse phenomenon was noticed within rs187084 genotypes. There were no consistent association between TLR9 polymorphisms and spontaneous clearance of HBV, however, a significant association was observed between rs187084 AA genotype and HBV progression to advanced liver disease. Further studies on larger populations might be necessary to understand the modulating effect of TLR9 polymorphisms on HBV loads that remain a viral factor of paramount importance to predict HCC development.

Effect of MBOAT7 variant on hepatitis B and C infections in Moroccan patients.

The outcomes of HBV and HCV infections are associated both with viral and host genetic factors. Here, we explore the role of a genetic variation located in membrane-bound O-acyltransferase domain-containing protein 7 (MBOAT7) gene on spontaneous clearance of HBV and HCV infections and on liver fibrosis. We genotyped MBOAT7 rs641738 polymorphism in 971 consecutive Moroccan subjects, including 288 patients with chronic hepatitis C (CHC), 98 cases with spontaneous clearance of HCV, 268 patients with chronic hepatitis B (CHB), 126 spontaneously cleared HBV infections and 191 healthy controls. MBOAT7 rs641738 variant is not associated with spontaneous clearance of HBV (OR = 0.67, 95% CI: 0.39-1.14; p = 0.131) and HCV infections (OR = 1.33, 95% CI: 0.79-2.23; p = 0.278). Furthermore, multivariable logistic regression analysis adjusted for biologically relevant covariates and potential confounders associated with the risk of liver disease progression revealed that MBOAT7 rs641738 is not associated either with fibrosis progression in CHC group (OR = 1.12; 95% CI: 0.55-2.28; p = 0.761) or with chronic progressive state in CHB patients (OR = 0.81; 95% CI: 0.41-1.61; p = 0.547). We conclude that the variant MBOAT7 rs641738 genotype is not associated with spontaneous clearance of HBV and HCV infections or with the progression of liver disease in chronic hepatitis B or C in a genetic context of Mediterranean patients.

Programmed cell death-1 3'-untranslated region polymorphism is associated with spontaneous clearance of hepatitis B virus infection.

Hepatitis B virus (HBV)-specific CD8+ T cells play an important role in the clearance of HBV infection. Programmed cell death-1 (PD-1), an immunosuppressive molecule that regulates T-cell activation and peripheral immune tolerance, is increasingly shown to influence the outcome of HBV infection. rs10204525, a single-nucleotide polymorphism in the 3'-untranslated region (3'-UTR) of PD-1, has been associated with susceptibility and disease progression of chronic HBV infection in far-eastern patients. The aim of our study was to assess the impact of rs10204525 variation on HBV infection in Moroccan patients. A total of 236 patients with chronic HBV infection and 134 individuals with spontaneous HBV resolution were genotyped using a Taqman assay. In addition, PD-1 mRNA expression in peripheral blood nuclear cells was determined by quantitative reverse-transcription polymerase chain reaction. We found that the AA genotype is protective (odds ratio, 0.43; 95% confidence interval, 0.19 to 0.97; P = 0.038) against HBV infection. Interestingly, PD-1 messenger RNA (mRNA) expression analysis has revealed that chronic HBV carriers with GG and GA displayed higher levels of PD-1 mRNA compared with corresponding genotypes in resolved subjects (P = 0.031 and 0.014, respectively). Our data suggest that Mediterranean HBV-infected patients carrying PD-1 GG and GA genotypes at rs10204525 have high PD-1 mRNA expression and may be more prone to installation of chronicity.

Lack of Ser267Phe variant of sodium taurocholate cotransporting polypeptide among Moroccans regardless of hepatitis B virus infection status.

BACKGROUND: The sodium taurocholate co-transporting polypeptide, encoded by SLC10A1, was identified as a functional receptor for hepatitis B virus (HBV). The objective of this study was to determine if there was an association of the Ser267Phe variant (rs2296651) with HBV infection status in Moroccan patients. METHODS: Using a TaqMan 5' allelic discrimination assay, the Ser267Phe variant was genotyped in 286 chronic hepatitis B patients, 135 individuals with spontaneous clearance from HBV infection and 109 healthy controls negative for hepatitis B serological markers. RESULTS: In this cohort, we detected only wild-type genotype (S267S) in all groups. This polymorphism was not associated with the HBV infection status in Moroccan patients. CONCLUSIONS: The S267F variant is absent among Moroccans regardless of chronic HBV infection status.

Structural bases for CRMP function in plexin-dependent semaphorin3A signaling.

Collapsin response mediator proteins (CRMPs) are cytosolic phosphoproteins involved in neuronal differentiation and axonal guidance. CRMP2 was previously shown to mediate the repulsive effect of Sema3A on axons and to participate in axonal specification. The X-ray crystal structure of murine CRMP1 was determined at 2.1 A resolution and demonstrates that CRMP1 is a bilobed 'lung-shaped' protein forming a tetrameric assembly. Structure-based mutagenesis of surface-exposed residues was employed to map functional domains. As a rapid assay for CRMP, we exploited a reconstituted Sema3A signaling system in COS-7 cells expressing the receptor components Neuropilin1 and PlexinA1 (NP1/PlexA1). In these cells, CRMP and PlexA1 form a physical complex that is reduced in amount by NP1 but enhanced by Sema3A/NP1. Furthermore, CRMP accelerates Sema3A-induced cell contraction. Alanine substitutions in one domain of CRMP1 produce a constitutively active protein that causes Sema3A-independent COS-7 contraction. This mutant CRMP mimics the DRG neurite outgrowth-inhibiting effects of Sema3A and reduces Sema3A-induced axonal repulsion. These data provide a structural view of CRMP function in Plex-dependent Sema3A signaling.

Structure and function of the immune semaphorin CD100/SEMA4D.

Semaphorins are a large family of membrane-bound and secreted molecules involved in numerous functions, including axon guidance, morphogenesis, carcinogenesis, and immunomodulation. A growing number of semaphorins--namely, human CD100/SEMA4D, CD108/SEMA7A, and SEMA3A; viral semaphorins, SemaVA and SemaVB; and, very recently, mouse Sema4A--were reported to regulate immune cell responses. Among them, the role of CD100 has been well documented in both humans and mice. CD100, in particular, has been shown to influence monocyte migration, T-cell activation, B-cell survival as well as T/B and T/dendritic cell cooperation. In contrast to other semaphorins, CD100 is the only semaphorin for which membrane and soluble forms are endowed with functional properties, and for which bidirectional signaling has been suggested. The human membrane-bound CD100 engagement triggers costimulatory signals to T cells through its interaction with membrane protein tyrosine phosphatase CD45 and an intracellular serine kinase. Its soluble extracellular region acts most likely through its receptors, human PlexinB1 and mouse CD72, to promote T-cell priming, B-cell survival and antibody production in response to T-dependent antigens. Human soluble CD100 also induces monocyte paralysis and the arrest of its spontaneous and chemokine-induced migration by signaling through an as yet unknown receptor that is different from PlexinB1 and CD72. In this review, we discuss recent advances in research studies on human and murine CD100, and we describe the relationship of CD100 function to its expression and structure. The signaling events that support CD100 function are also discussed.