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Hepatitis B Virus (HBV) is the most common cause of chronic liver disease worldwide. The mechanisms that regulate HBV viral replication remain poorly defined. Here, we show that blocking of the neddylation elicits antiviral effect against HBV replication, indicating that NEDD8 supports viral production. To explore role of neddylation, HBV-replicating HepG2.2.15.7 cells and HBV-infected HepG2-hNTCP-30 cells were treated with siNEDD8 and MLN4924, a potent and selective NEDD8-activating enzyme inhibitor. Cell viability, intracellular and extracellular HBV DNA, covalently closed circular DNA (cccDNA), HBsAg, HBeAg, and HBcrAg were measured to assess the consequences of the various treatments on viral replication. Our data showed that HBV infection increased NEDD8 expression in human liver cell lines. Symmetrically, NEDD8 knockdown by siRNA or MLN4924 treatments decreased HBV replication in HepG2.2.15.7 and HepG2-hNTCP-30 cells. Notably, HBsAg, and HBeAg secretions were strongly suppressed in the culture supernatants, but not the HBcrAg. These results indicate that the suppression of NEDD8 decreases HBV replication. However, cccDNA steady level confirms once again its persistence and longevity in chronic infection. The manipulation of the neddylation pathway can thus provide new tools interfering with HBV persistence as well as novel therapeutic strategies against chronic hepatitis B.

Background:Globally, the recent outbreak of Zika virus (ZIKV) in Brazil, Asia Pacific, and other countries highlighted the unmet medical needs. Currently, there are neither effective vaccines nor therapeutics available to prevent or treat ZIKV infection.Objective:In this study, we aimed to design an epitope-based vaccine for ZIKV using an in silico approach to predict and analyze B- and T-cell epitopes.Methods:The prediction of the most antigenic epitopes has targeted the capsid and envelope proteins as well as non-structural proteins NS5 and NS3 using immune-informatics tools PROTPARAM, CFSSP, PSIPRED, and Vaxijen v2.0. B and T-cell epitopes were predicted using ABCpred, IEDB, TepiTool, and their toxicity was evaluated using ToxinPred. The 3-dimensional epitope structures were generated by PEP-FOLD. Energy minimization was performed using Swiss- Pdb Viewer, and molecular docking was conducted using PatchDock and FireDock server.Results:As a result, we predicted 307 epitopes of MHCI (major histocompatibility complex class I) and 102 epitopes of MHCII (major histocompatibility complex class II). Based on immunogenicity and antigenicity scores, we identified the four most antigenic MHC I epitopes: MVLAILAFLR (HLA-A*68:01), ETLHGTVTV (HLA-A*68:02), DENHPYRTW (HLA-B*44:02), QEGVFH TMW (HLA-B*44:03) and TASGRVIEEW (HLA-B*58:01), and MHC II epitopes: IIKKFKKDLAAMLRI (HLA-DRB3*02:02), ENSKMMLELDPPFGD (HLA-DRB3*01:01), HAET WFFDENHPYRT (HLA-DRB3*01:01), TDGVYRVMTRRLLGS (HLA-DRB1*11:01), and DGCW YGMEIRPRKEP (HLA-DRB5*01:01).Conclusion :This study provides novel potential B cell and T cell epitopes to fight against Zika virus infections and may prompt further development of vaccines against ZIKV and other emerging infectious diseases. However, further investigations for protective immune response by in vitro and in vivo studies to ratify immunogenicity, the safety of the predicted structure, and ultimately for the vaccine properties to prevent ZIKV infections are warranted.

The ongoing coronavirus disease 19 caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has become fatal for the world with affected population crossing over 25 million in more than 217 countries, consequently declared a global pandemic by the World Health Organization. Unfortunately, neither specific prophylactic or therapeutic drugs nor vaccines are available. To address the unmet medical needs, we explored a strategy identifying new compounds targeting the main protease (Mpro) of SARS-CoV-2. Targeting the SARS-CoV-2 Mpro crystal structure (PDB ID: 6LU7) a combination of in silico screening, molecular docking, and dynamic approaches, a set of 5000 compounds of the ZINC database were screened. As a result, we identified and ranked the top 20 compounds based on the scores of ligand-interaction, their drug-likeness properties, and their predicted antiviral efficacies. The prominent drug-like and potent inhibitory compounds are 2-[2-(2-aminoacetyl) aminoacetyl] amino-3-(4-hydroxyphenyl)-propanamide (ZINC000004762511), 6'-fluoroaristeromycin (ZINC000001483267) and cyclo (L-histidyl-L-histidyl) (ZINC000005116916) scaffolds. Further in vitro and in vivo validations are required to demonstrate anti-SARS-CoV-2 activities.

Zika virus (ZIKV), an RNA virus, rapidly spreads

The genome feature of SARS-CoV-2 leads the virus to mutate and creates new variants of concern. Tackling viral mutations is also an important challenge for the development of a new vaccine. Accordingly, in the present study, we undertook to identify B- and T-cell epitopes with immunogenic potential for eliciting responses to SARS-CoV-2, using computational approaches and its tailoring to coronavirus variants. A total of 47 novel epitopes were identified as immunogenic triggering immune responses and no toxic after investigation with in silico tools. Furthermore, we found these peptide vaccine candidates showed a significant binding affinity for MHC I and MHC II alleles in molecular docking investigations. We consider them to be promising targets for developing peptide-based vaccines against SARS-CoV-2. Subsequently, we designed two efficient multi-epitopes vaccines against the SARS-CoV-2, the first one based on potent MHC class I and class II T-cell epitopes of S (FPNITNLCPF–NYNYLYRLFR–MFVFLVLLPLVSSQC), M (MWLSYFIASF–GLMWLSYFIASFRLF), E (LTALRLCAY–LLFLAFVVFLLVTLA), and N (SPRWYFYYL–AQFAPSASAFFGMSR). The second candidate is the result of the tailoring of the first designed vaccine according to three classes of SARS-CoV-2 variants. Molecular docking showed that the protein-protein binding interactions between the vaccines construct and TLR2–TLR4 immune receptors are stable complexes. These findings confirmed that the final multi-epitope vaccine could be easily adapted to new viral variants. Our study offers a shortlist of promising epitopes that can accelerate the development of an effective and safe vaccine against the virus and its adaptation to new variants. Communicated by Ramaswamy H. Sarma

Coronavirus disease 2019 (COVID-19) is a highly contagious disease caused by severe acute respiratory coronavirus 2 (SARS-CoV-2). This virus is capable of human-to-human transmission, and is spreading rapidly round the globe, with markedly high fatality rates. Unfortunately, there are neither vaccines nor specific therapies available to combat it, and the developments of such approaches depend on pursuing multiple avenues in biomedical science. Accordingly, in this paper we highlight one such avenue—nanobodies—for potential utility in therapeutic and diagnostic interventions to combat COVID-19. Communicated by Ramaswamy H. Sarma

Background: It has been reported that interferon-λ3 (IFNL3)might influence the pathogenesis and clearance of human papillomavirus (HPV) infection. The impact of IFNL3 single-nucleotide polymorphism (SNP) on HPV infection is currently unknown. The aim of this study was to investigate the association between variants in the IFNL3 region and HPV infection in women with human immunodeficiency virus (HIV) infection. Methods: A total of 236 HIV patients, including 65 HPV-negative and 171 HPV DNA-positive women, were enrolled into this study. The IFNL3 rs12979860 polymorphism was genotyped using a predesigned TaqMan SNP genotyping assay. Results: Data showed no significant differences in genotypes or allele frequencies between the HPV DNA-positive and the HPV-negative women (p > 0.05). After dividing the HPV-positive women according to cytology results into patients with abnormal and normal lesions, the genotype and allele distribution of the SNP did not significantly differ between the 2 groups (p > 0.05). Conclusions: Our results showed that the IFNL3 rs12979860 polymorphism is not a major determinant of the susceptibility to HPV infection and their progression to abnormal cervical lesions in women living with HIV.

Hepatitis B Virus (HBV) is the most common cause of chronic liver disease worldwide. The mechanisms that regulate HBV viral replication remain poorly defined. Here, we show that blocking of the neddylation elicits antiviral effect against HBV replication, indicating that NEDD8 supports viral production.To explore role of neddylation, HBV-replicating HepG2.2.15.7 cells and HBV-infected HepG2-hNTCP-30 cells were treated with siNEDD8 and MLN4924, a potent and selective NEDD8-activating enzyme inhibitor. Cell viability, intracellular and extracellular HBV DNA, covalently closed circular DNA (cccDNA), HBsAg, HBeAg, and HBcrAg were measured to assess the consequences of the various treatments on viral replication. Our data showed that HBV infection increased NEDD8 expression in human liver cell lines. Symmetrically, NEDD8 knockdown by siRNA or MLN4924 treatments decreased HBV replication in HepG2.2.15.7 and HepG2-hNTCP-30 cells. Notably, HBsAg, and HBeAg secretions were strongly suppressed in the culture supernatants, but not the HBcrAg. These results indicate that the suppression of NEDD8 decreases HBV replication. However, cccDNA steady level confirms once again its persistence and longevity in chronic infection.The manipulation of the neddylation pathway can thus provide new tools interfering with HBV persistence as well as novel therapeutic strategies against chronic hepatitis B.

PurposeSevere acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the causative agent of the ongoing pandemic of coronavirus disease 2019 (COVID-19). One year has passed since the first COVID-19 case, and concerns have emerged regarding new variants, meaning that characterizing antibody-mediated immune response dynamics is of paramount importance. Here, we evaluated the humoral immune response against SARS-CoV-2 in subjects during the first and second waves of the pandemic in Morocco. MethodsWe assessed humoral immune response in samples from 94 seropositive individuals in the first wave (February to August 2020) and 596 seropositive individuals in the second wave (December 2020 to January 2021). Plasma samples were collected from volunteer blood donors and their levels of serum IgG to SARS-CoV-2 nucleoprotein (NP) were determined using architect SARS-CoV-2 IgG chemiluminescence microparticle immunoassay.ResultsOur results revealed an increase of humoral immunity during the second wave than first wave (3.897 ± 0.079 vs. 2.842 ± 0.153, respectively, p

International audience; West Nile virus (WNV) was recently detected in Culex pipiens mosquitoes in Morocco. The aim of this study was to evaluate the seroprevalence of WNV in humans and in domestic birds in two regions of Morocco by the detection of IgG antibodies. Blood samples were obtained from 91 human patients and 92 domestic birds from September to December 2019. All study samples were tested using competitive enzyme-linked immunosorbent assay (cELISA) and WNV neutralization tests (VNT) were performed on positive sera. Of all samples, 4 (4.39 %) humans and 4 (4.34 %) birds were found to be seropositive for flaviviruses by the cELISA test. The VNT revealed that three of the four human samples detected positive by cELISA contained neutralizing antibodies against WNV. Two bird samples were confirmed positive by VNT. These results show a significant seroprevalence of anti-WNV antibodies and therefore suggest the active circulation and exposure of human and bird populations in the northwest of Morocco.

>Hepatitis B virus (HBV) is a global health concern. Viral and host factors orchestrate the natural history of HBV infection, but the impact of host factors that influence the clinical course of the disease remains poorly understood. The aim of this study was to identify host factors crucial to the HBV life cycle by conducting a meta-analysis utilizing public microarray datasets. Methods: An integrative meta-analysis of expression data from two microarray datasets of HBVinfected liver tissues and healthy uninfected livers was conducted to identify gene expression signatures and overlapping biological processes modulating infection/disease. Results: Using integrative meta-analysis of expression data (INMEX), we identified across two datasets a total of 841 genes differentially expressed during HBV infection, including 473 upregulated and 368 downregulated genes. In addition, through functional enrichment and pathway analysis, we observed that Jak-STAT, TLR, and NF-κB are the most relevant signaling pathways in chronic HBV infection. The network-based meta-analysis identified NEDD8, SKP2, JUN, and HIF1A as the most highly ranked hub genes. Conclusion: Thus, these results may provide valuable information about novel potential host factors modulating chronic HBV infection. Such factors may serve as potential targets for the development of novel therapeutics such as activin receptor-like kinase inhibitors.

Human Immunodeficiency Virus (HIV-1) infections are characterized by dysfunctional cellular and humoral antiviral immune responses. The progressive loss of effector functions in chronic viral infection has been associated with the up-regulation of programmed death-1 (PD-1), a negative regulator of activated T cells and Natural Killer cells. In HIV-1 infection, increased levels of PD-1 expression correlate with CD8 + T-cell exhaustion. In vitro, PD-1 blockade using PD-1 antibodies led to an increase in HIV-1 specific CD8 + T and memory B cell proliferation. We aimed to investigate the impact of PDCD1 rs10204525 polymorphism on HIV-1 susceptibility, AIDS development, and treatment response outcomes in HIV-1 infection in a Moroccan population. A total of 214 HIV-1 seropositive and 250 seronegative subjects were enrolled to investigate the association between the between the single-nucleotide polymorphism (SNP) rs10204525 of PDCD1 gene and HIV-1 pathogenesis using a predesigned TaqMan SNP genotyping assay. No significant association was found between rs10204525 and susceptibility to HIV-1 infection and AIDS development (p 0.05). Genotype frequencies were significantly associated with the viral load before ART (p = 0.0105). HIV-1 viral load was significantly higher among subjects with the CC compared to TT genotype (p = 0.0043). In treated subjects, the median of viral load levels was significantly higher in CC and CT groups than TT subjects (p 0.005). However, analysis of the correlation between CD4 + T-cell levels and PDCD1 polymorphism before and after ART showed no significant difference (p 0.05). Our results demonstrated that rs10204525 polymorphism does not affect HIV-1 infection. However, this polymorphism may affect the response to treatment as measured by RNA viral load levels.

The current Coronavirus Disease 2019 (COVID-19) pandemic is causing great alarm around the world. The pathogen for COVID-19 - severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) - is the seventh known coronavirus to cause pneumonia in humans. While much remains unknown about SARS-CoV-2, physicians and researchers have begun to publish relevant findings, and much evidence is available on coronaviruses previously circulating in human and animal populations. In this review, we situate COVID-19 in its context as a transboundary viral disease, and provide a comprehensive discussion focused on the discovery, spread, virology, pathogenesis, and clinical features of this disease, its causative coronaviral pathogen, and approaches to combating the disease through immunotherapies and other treatments and vaccine development. An epidemiological survey revealed a potentially large number of asymptomatic SARS-CoV-2 carriers within the population, which may hamper efforts against COVID-19. Finally, we emphasize that vaccines against SARS-CoV-2, which may be developed by 2021, will be essential for prevention of COVID-19.

Objectives The interferon (IFN) is known to bridge innate and adaptive immune responses, and to play a critical role particularly against hepatitis B virus (HBV) infection. Defects in IFN signals may result, therefore, in attenuated responses against HBV. Accordingly, polymorphisms in genes coding for immune response effectors may affect the clinical outcome of HBV infection. We analyzed the putative association between IFNL4 rs12979860 polymorphism and the outcome of HBV infection in Moroccan patients. Methods In this study, 237 chronic HBV (CHB) patients and 129 spontaneously resolved HBV (SRB) individuals were enrolled and genotyped using a predesigned Taqman allelic discrimination assay. Results Our data show a significant increase of HBV DNA loads in patients with IFNL4 rs12979860 CC genotype compared to patients with CT and TT genotypes (p = 0.0008). However, there was no consistent association between IFNL4 rs12979860 polymorphism and the outcome of HBV infection. Conclusions Although IFNL4 rs12979860 polymorphism seems to modulate circulating HBV DNA levels, it is disconnected from chronic disease progression. This observation suggests that the role of rs12979860 in liver disease is restricted to viral control and inactive in the deleterious immune pathology that affects liver tissue. Taken together, our data suggest that rs12979860 CC genotypes could be useful as a predictor of success or failure of IFN-based therapy in chronic HBV-infected patients.

Toll-like receptors (TLRs) play an important role in activating the innate immune response, inducing inflammation and initiating the adaptive immune response. In this study, we assess the influence of TLR7 and TLR8 gene polymorphisms on HIV-1 susceptibility, AIDS development, and treatment outcomes. The TLR7 and TLR8 single nucleotide polymorphisms (SNPs) were genotyped through real-time PCR in 222 patients living with HIV-1 and 141 healthy controls. Frequencies of the TLR7-IVS2-151 G/A and TLR7-IVS1 + 1817 G/T genotypes and alleles were not significantly increased in patients with HIV-1 infection compared to healthy controls both in males and females. Whereas, males carrying TLR8 Met allele were twice susceptible to HIV-1 infection compared to subjects with A allele (OR = 2.04, 95 % CI 1.10-3.76; p = 0.021). Interestingly, for TLR8-129 G/C, both males and females carrying G allele and GG genotype, respectively were significantly associated with HIV-1 infection (p0.0001). Moreover, the TLR7 IVS1 + 1817 G/T and the TLR8 rs3764880 were associated with protection to progress the AIDS stage in male and female, respectively (p0.05). Males carrying TLR7 IVS2-151-A allele showed a significant increased level of HIV-1 viral load pre-treatment, in comparison with individuals carrying the G allele (p-value = 0.036). Additionally, males carrying TLR8 Met allele showed statistically higher HIV viral load at baseline (p-value = 0.04) and after treatment (p-value = 0.013). Regarding CD4 + T cell counts, no significant association was found with TLR7 and TLR8 SNPs before and after antiretroviral treatment. This data demonstrates that TLR8 polymorphisms could affect HIV-1 infection. Moreover, an association between TLR7 IVS2-151-A and TLR8 Met alleles and plasma HIV viral load level was found.

The ongoing coronavirus disease 19 caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has become fatal for the world with affected population crossing over 25 million in more than 217 countries, consequently declared a global pandemic by the World Health Organization. Unfortunately, neither specific prophylactic or therapeutic drugs nor vaccines are available. To address the unmet medical needs, we explored a strategy identifying new compounds targeting the main protease (Mpro) of SARS-CoV-2. Targeting the SARS-CoV-2 Mpro crystal structure (PDB ID: 6LU7) a combination of in silico screening, molecular docking, and dynamic approaches, a set of 5000 compounds of the ZINC database were screened. As a result, we identified and ranked the top 20 compounds based on the scores of ligand-interaction, their drug-likeness properties, and their predicted antiviral efficacies. The prominent drug-like and potent inhibitory compounds are 2-[2-(2-aminoacetyl) aminoacetyl] amino-3-(4-hydroxyphenyl)-propanamide (ZINC000004762511), 6′-fluoroaristeromycin (ZINC000001483267) and cyclo (L-histidyl-L-histidyl) (ZINC000005116916) scaffolds. Further in vitro and in vivo validations are required to demonstrate anti-SARS-CoV-2 activities. Electronic supplementary material The online version of this article (10.1007/s13337-020-00627-6) contains supplementary material, which is available to authorized users.

International audience; Hepatitis C virus (HCV) is still one of the main causes of liver disease worldwide. Metabolic disorders, including non-alcoholic fatty liver disease (NAFLD), induced by HCV have been shown to accelerate the progression of fibrosis to cirrhosis and to increase the risk of hepatocellular carcinoma. An optimal peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PPARGC1A) activity is crucial to prevent NAFLD installation. The present study aims to investigate the associations between two common PPARGC1A polymorphisms (rs8192678 and rs12640088) and the outcomes of HCV infection in a North African context. A series of 592 consecutive Moroccan subjects, including 292 patients with chronic hepatitis C (CHC), 100 resolvers and 200 healthy controls were genotyped using a TaqMan allelic discrimination assay. PPARGC1A variations at rs8192678 and rs12640088 were not associated with spontaneous clearance of HCV infection (adjusted ORs = 0.76 and 0.79 respectively, P > 0.05, for both). Furthermore, multivariable logistic regression analysis showed that both SNPs were not associated with fibrosis progression (OR = 0.71; 95% CI 0.20-2.49; P = 0.739; OR = 1.28; 95% CI 0.25-6.54; P = 0.512, respectively). We conclude that, in the genetic context of South Mediterranean patients, rs8192678 and rs12640088 polymorphisms of PPARGC1A are neither associated with spontaneous clearance nor with disease progression in individuals infected with HCV.

Introduction: Women infected with human immunodeficiency virus (HIV) have a higher risk of contracting human papillomavirus (HPV) infections and are more prone to develop cervical cancer. The objective of this study was to determine the prevalence of HPV and its association with risk factors among Moroccan women living with HIV/AIDS. Methodology: We enrolled 251 HIV-infected non-pregnant women in Morocco from February 2013 to September 2016. Sociodemographic, lifestyles, behavioral and clinical data were collected. Polymerase chain reaction followed by sequencing were performed for molecular detection and HPV genotyping in cervical samples, respectively. Results: Abnormal cervical smears were found in 34/246 patients (13.82%). The overall prevalence of HPV was 74.50%. HPV 58 was the most prevalent (39.29%) followed by HPV 18 (10.71%), HPV 70 (8.93%), HPV 33 (7.14%), HPV 6 (6.25%) and other genotypes (< 3%). Overall, high-risk HPV (HR-HPV) types were present in 75% (84/112) of patients and the prevalence of HR-HPV types in samples with abnormal Pap was higher than in normal Pap (55/83, 66.27% vs. 28/83, 33.33%, p < 0.0001). Univariate analyses showed that none of the socio-demographic and behaviors factors was associated with HPV infection. Moreover, Pap results were not affected by HPV status (p = 0.532). Whereas, CD4 T-cell counts above 200/mm3 at enrolment were apparently not protective to HPV infection. We found a high prevalence of HPV infection and HR-HPV types among HIV-positive women that significantly associated with abnormal Pap. Conclusion: Our findings suggest a high prevalence of HPV infection with high-risk types was observed among HIV-positive women warrant to implement a regular screening by Pap smear.

Human Immunodeficiency Virus type 1 (HIV-1) infection and progression varies widely among individuals. Interferon-λ3 exerts anti-HIV function by activating JAK/STAT pathway-mediated innate immunity. Therefore, we aimed to investigate the association between single nucleotide polymorphisms of the interleukin 28B (IL28B) gene, and the risk of acquisition, AIDS development and therapeutic outcome of HIV-1 in a Moroccan population. A total of 266 HIV-1 seropositive and 158 HIV-1 seronegative subjects were enrolled. Genotyping of rs12979860 of the IL28B was performed using a predesigned TaqMan SNP genotyping assay. No significant association was found between IL28B rs12979860 polymorphism and susceptibility to HIV-1 infection and AIDS development (p > .05). However, in HIV-1 treated patients carrying CC genotype had a more pronounced high levels of CD4 + T-cell compared to subjects with TT genotype (p = .0004). Interestingly, regarding HIV-1 viral load no significant differences between IL28B genotypes in treated and untreated patients were observed (p IL28B rs12979860 polymorphism not influences the susceptibility to HIV-1 and the AIDS development. However, this polymorphism may affect the response to treatment as measured by CD4+ T cell counts.

Background & Aims The natural outcomes of hepatitis C virus (HCV) as well as the progression of the liver disease are highly variable and depend primarily on an efficient immune response. As Toll-like receptors 7 (TLR7) and 8 (TLR8) are important effectors of the innate immunity, the present study aims to evaluate the association between TLR7 and TLR8 polymorphisms and the HCV infection outcomes in Moroccan subjects. Methods In this case-control study, 643 subjects including 293 mild chronic hepatitis patients, 119 with advanced liver disease (AdLD), 93 with HCV spontaneous clearance and 138 healthy controls were genotyped using TaqMan SNPs assays. Results Patients carrying TLR7 rs179008-A allele were more likely to clear the virus spontaneously (P=0.0001 for women, and P

Eight human viruses have been classified by the International Agency for Research on Cancer as carcinogenic or probably carcinogenic for humans. Infection with high risk human papillomaviruses, hepatitis B and C viruses, Epstein-Barr virus (EBV), human T-Cell Lymphotropic Virus Type 1 (HTLV-1), Human herpesvirus 8 (HHV-8), Merkel cell polyomavirus and human immunodeficiency virus-1 (HIV1) alone or in combination with other agents are the main etiologic factors of many cancers. This review highlights some aspects of virus-associated human cancers, potentially responsible for >14,000 malignancies per year in Morocco. Given that not all individuals infected with these viruses develop cancer, somatic alterations, genetic predisposition, and lifestyle or environmental factors obviously play potentializing roles modulating viral activity. These viral, host genetic signatures and lifestyle interactions may represent a reservoir of biomarkers for early detection, prevention of cancer and rationale-based therapy.

International audience; Non-primate hepacivirus (NPHV) is a homolog of hepatitis C virus and has been isolated from dogs and horses. Data on NPHV prevalence and distribution are not complete, and there is a particular lack of reports from the African continent. The present study represents the first investigation of NPHV prevalence in horses and dogs in North Africa.Blood was collected from 172 horses and 36 dogs at different locations in Morocco, and screened for NPHV RNA using nested PCR targeting 5’UTR and NS3 regions and analyzed for anti-NPHV NS3 antibody using a Gaussia luciferase immunoprecipitation system—to determine seroprevalence. Eight sequences of the NS3 region isolated from positive serum samples were targeted for phylogenetic analysis.Horses and dogs showed respective NPHV RNA positivity rates of 10.5% and 5.5%, and seroprevalences of 65.7% and 8.33%. Juvenile horses appeared more susceptible to infection, with a 23.5% NHPV RNA positivity rate. Seropositivity was more extensive in mares than stallions (77.14% vs. 46.27%, p < 0.0001). Phylogenetically, that NPHV NS3 genes isolated from horses and dog are clustered together. The NPHV strains we detected showed no correlation with geographic location within Morocco.In conclusion, Moroccan horses showed much evidence of previous and/or current NPHV infection, with young age and female sex as noted potential risk factors. Interestingly, NPHV is circulating in dogs as well as horses, suggesting that it has crossed species barriers and that horses and dogs are potential vectors by which an ancestor to hepatitis C virus was transmitted into human populations.

Despite the effectiveness of nucleotide analogs (NAs), drug resistance and cccDNA inaccessibility are still significant obstacles to long-term efficacy of antiviral therapy in chronic hepatitis B infection (CHB). Mutations pre-exist spontaneously in Hepatitis B Virus (HBV) reverse transcriptase (RT) gene in minor viral populations and can emerge to confer drug resistance and treatment failure. This study aimed to analyze mutations within the HBV polymerase gene in treatment-naive Moroccan patients with CHB. The HBV polymerase gene was analyzed by nested-PCR and direct sequencing in 123 subjects. A computational analysis was performed to confirm the effect of detected mutations on targeted NAs, using homology and docking tools. Sixty samples were successfully amplified by PCR. Analyses revealed an intermediate rate (13%) of pre-treatment NA resistance mutations and a high frequency of putative resistance mutations (65%). Among these, 56% were lamivudine resistance mutations and 44% adefovir resistance mutations. Two pretreatment resistance mutations, “Y124N” and “N139D/K/H/Q” were detected in 8/60 patients, and 11 putative resistance mutations (N53S/T/D, L91I, H126Y, T128I, V207I, V214A, Q215P/S, L217R, F221Y, L229V, N238H/T) in 39/60 patients, where two have a combination of F221Y and A194T “a classical NA drug resistance mutation.” The computational analysis demonstrated that the combination of A194T + F221Y mutations on HBV RT sequence does not affect its susceptibility to ADV. These results confirm that HBV mutations conferring resistance against currently available anti-HBV NA predate treatment in naive Moroccan patients. The high rate of non-classical NA resistance mutations needs further in vitro phenotype analysis.

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.

Defective interfering (DI) RNAs have been detected in several human viruses. HCV in-frame deletions mutants (IFDMs), missing mainly the envelope proteins, have been found in patient sera and liver tissues. IFDMs replicate independently and can be trans-packaged into infectious virions in the presence of full length viral genome. So far, their biological role is unclear. In this study, we have isolated and cloned IFDMs from sera samples and liver tissues of patients infected with HCV genotypes 1b, 2a, and 3a. IFDMs were present in up to 26% of samples tested. Using the in vitro HCV cell culture system, co-expression of the wild type (wt) HCV replicon with HCV IFDMs RNA resulted in increased HCV replication. Additionally, co-transfection of the HCV full length genome RNA and a defective mutant missing the envelope region led to increased viral release, collectively suggesting an important biological role for IFDMs in the virus life cycle. Recently, exosomes, masters of intercellular communication, have been implicated in the transport of HCV viral genomes. We report for the first time that exosomal RNA isolated from HCV sera samples contains HCV defective genomes. We also demonstrate that inhibition of exosomal biogenesis and release influences HCV viral replication. Overall, we provide evidence that the presence of HCV IFDMs affects both viral replication and release. IFDMs exploit exosomes as means of transport, a way to evade the immune system, to spread more efficiently and possibly maintain persistent infection.

Chronic Hepatitis C is one of the most important risk factors of liver cirrhosis and hepatocellular carcinoma. Before reaching these ultimate steps, insulin resistance triggered by hepatitis C virus infection is known to participate in the progression of liver disease. The present study aims to investigate the influence of two functional polymorphisms on SOCS3 mRNA expression and on the outcomes of CHC progression in a North African context.In this case-control study, 601 Moroccan subjects composed of 200 healthy controls, 101 resolvers and 300 patients with persistent HCV infection including 95 mild chronic hepatitis, 131 Advanced Liver Diseases and 74 HCC were enrolled. They were genotyped for the 4874 A/G (rs4969170) and A + 930- G (rs4969168) SOCS3 variants using TaqMan SNPs assays. SOCS3 mRNA expression was assessed using Real Time PCR technique.Logistic regression analysis showed that variation at rs4969168 was associated with spontaneous clearance of HCV (P 0.05). In addition, minor allele frequencies were significantly higher in AdLD patients when compared to the mCHC group both for rs4969168 (P = 7.0 E-04) and rs4969170 (P = 4.0 E-05). A significant association between haplotype and liver disease progression was also found. Moreover, SOCS3 mRNA was significantly more expressed in peripheral leukocytes from patients with HCC than in those from mCHC. Finally, rs4969170 was significantly associated with LDL-lipoprotein (P = 0.04), total cholesterol (P = 5.0 E-04), and higher fasting glucose levels (P = 0.005) in patients with persistent HCV infection.Our results underline the importance of the functional SOCS3 polymorphisms in the modulation of CHC progression and suggest their contribution to HCC development by affecting its mRNA expression and perturbing key metabolic parameters.

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.

International audience; 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.

Viral clearance during acute hepatitis C virus (HCV) infection is associated with the induction of potent antiviral T-cell responses. Since dendritic cells (DC) are essential in the activation of primary T-cell responses, gene expression was analyzed in DC from patients during acute HCV infection. By using microarrays, gene expression was compared in resting and activated peripheral blood plasmacytoid (pDC) and myeloid (mDC) DC from acute HCV resolving patients (AR) and from patients who become chronically infected (ANR), as well as in healthy individuals (CTRL) and chronically-infected patients (CHR). For pDC, a high number of upregulated genes was found in AR patients, irrespective of DC stimulation. However, for mDC, most evident differences were detected after DC stimulation, again corresponding to upregulated genes in AR patients. Divergent behavior of ANR was also observed when analyzing DC from CTRL and CHR, with ANR patients clustering again apart from these groups. These differences corresponded to metabolism-associated genes and genes belonging to pathways relevant for DC activation and cytokine responses. Thus, upregulation of relevant genes in DC during acute HCV infection may determine viral clearance, suggesting that dysfunctional DC may be responsible for the lack of efficient T-cell responses which lead to chronic HCV infection.

Hepatitis B Virus (HBV) is a major global health burden. Interferon alpha and nucleos(t)ide analogues are currently the standard-of-care for chronic HBV infection. However, these antiviral agents have limited efficacy and do not result in a sustained virological response in the majority of infected patients. Virtual Screening (VS) strategies have now a strong impact on drug discovery, the strength of this research field has been corroborated by recent contributions in the development of novel drug candidates which are in clinical trials or which are already available in the clinics. In this context, different VS strategies have been applied to HBV in order to discover novel inhibitors. In this review, we summarize the VS efforts to identify and design novel HBV interventions. We believe that the combination of in silico and in vitro tools can lead to faster validation of novel drug targets which could accelerate the HBV drug discovery and development efforts.

Background & Aims Morocco is one of low to intermediate endemic areas for hepatitis B virus (HBV) infection, but no reports have been published on Occult HBV infection (OBI). To determine the prevalence of OBI and its clinical impact among patients with cryptogenic and HCV-related chronic liver disease in Morocco. Methods A total of 152 HBsAg-negative patients (60 patients with cryptogenic hepatitis and 92 HCV carriers) were enrolled in this study. Sera collected from all patients were tested for anti-HBc and anti-HBs antibodies. OBI was assessed in serum and liver tissue samples using highly sensitive PCR assays targeting Surface, X and core regions of the HBV genome and confirmed by Southern blot hybridization. Results A high rate of anti-HBc positivity was found among patients with HCV infection (57/92, 61.95%) compared to those with cryptogenic hepatitis (24/60, 40%) (P = 0.034). A high prevalence of OBI was found among patients with HCV infection (42/92, 45.65%) compared to those with cryptogenic hepatitis (17/60, 28.3%) (P = 0.013). In both groups, the prevalence of OBI increased in parallel with advancing stage of liver disease (χ2 = 6.73; P = 0.0095). The highest proportion of OBI was reached among HCV-related HCC cases (62.5%). Multivariate Cox regression analysis revealed that older age (≥56 years), positivity for anti-HBc and presence of OBI were independent risk factors for the development of HCC in HCV-infected patients. Conclusion This study helps to understand the current status of OBI and its impact on the severity of liver disease in Moroccan patients.

Hepatitis B virus (HBV) poses a threat to global public health mainly because of complications of HBV-related chronic liver disease. HBV exhibits a narrow host range, replicating primarily in hepatocytes by a still poorly understood mechanism. For the generation of progeny virions, HBV depends on interactions with specific host factors through its life cycle. Revealing and characterizing these interactions are keys to identifying novel antiviral targets, and to developing specific treatment strategies for HBV patients. In this review, recent insights into the HBV-host interactions, especially on virus entry, intracellular trafficking, genome transcription and replication, budding and release, and even cellular restriction factors were reviewed.

In this study, we describe the synthesis of 1,4-disustituted-1,2,3-triazolo-quinazoline ribonucleosides or acyclonucleosides by means of 1,3-dipolar cycloaddition between various O or N-alkylated propargyl-quinazoline and 1'-azido-2',3',5'-tri-O-benzoylribose or activated alkylating agents under microwave conditions. None of the compounds selected showed significant anti-HCV activity in vitro.

Recent reports revealed an association between variation in the PNPLA3 gene and alcohol-induced hepatocellular carcinoma among Europeans. We have assessed whether the PNPLA3 rs738409 (I148M) polymorphism may also affect the resolution and/or the progression of hepatitis C in a Moroccan cohort. Genotype and allele frequencies at rs738409 were determined using a TaqMan 5' allelic discrimination assay in 437 individuals. Among them, 230 patients had a persistent infection with hepatitis C virus (HCV) with 129 patients affected by a chronic hepatitis and 101 patients by a hepatocellular carcinoma (HCC). In addition, we analyzed 75 individuals who naturally cleared HCV and 132 healthy subjects. Variation at rs738409 was not associated with significant changes in resolution rate of hepatitis C. By contrast, M/M genotype, present at higher frequencies (22.8%) in HCC patients than in patients with chronic hepatitis C (8.5%, P = 0.004) or control individuals (9.1%, P = 0.005) was associated with a 3-fold increase of liver cancer risk. In North African subjects, the PNPLA3 I148M variant apparently stimulates liver cancer development without interfering on the HCV clearance process. This polymorphism may, therefore, represent a valuable genetic marker to monitor liver cancer risk in populations from the Southern bank of the Mediterranean.

Human immunodeficiency virus (HIV), hepatitis B virus (HBV) and hepatitis Cvirus (HCV) are major public health concerns. We aimed to determine the prevalence of HBV and HCV infections among HIV-infected patients, and to identify the main circulating hepatitis strains in Morocco. The study was carried out in 503 HIV-infected patients. Our survey indicated that the prevalence of HIV/hepatitis co-infection was 10.6%; 5.2% of patients were HBV surface antigen positive, and 5.4% of patients were anti-HCV positive. Among the HBV surface antigen-positive group, HBV DNA sequencing identified exclusively genotype D (D1: 26.7%; D7: 73.3%) in accordance with what is found in the general population. In contrast, sequencing of HCV isolates produced an unusual subtype distribution with a decreasing order of prevalence: 1a, 3a (both 23.5%), 1b, 4a (both 17.6%), 1c (11.8%) and 6h (6%).

Hepatitis C is a global health problem with a worldwide prevalence of about 3% (around 170 million people). Hepatitis C virus (HCV) is major concern in the Maghreb countries, Algeria, Libya, Mauritania, Morocco, and Tunisia, but no detailed description of its epidemiology in the region is available. In the present review, a systematic search was undertaken covering HCV data available in peer-reviewed databases as well as institutional reports and regional conference meeting abstracts from the Maghreb countries. Reports written in English and French were included in this analysis. Estimates of national and regional prevalence of HCV infection (based on anti-HCV antibody) and of the size of patient populations were performed. In addition, the molecular features of the circulating viral strains in the region are discussed. A substantial proportion, 1.2-1.9% of the Maghreb inhabitants, have anti-HCV antibodies. Genotype 1b predominates among viral strains in all countries except in Libya, where genotype 4 is dominant as in neighboring Egypt. This epidemiological situation is of significant concern, and requires urgent, broad, and active intervention for the prevention and control of HCV. More specifically, the application of state-of-the-art hygiene procedures and rigorous controls in medical disciplines such as hemodialysis, transfusion, endoscopic procedures, and dentistry is necessary to reduce significantly the number of new infections in the region.

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.

Hepatitis C virus (HCV) infection and type 2 diabetes mellitus (T2DM) present a significant health burden, with increasing complications and mortality rates worldwide. Pycnogenol® (PYC), a natural product, possesses antidiabetic and antiviral properties that may improve HCV-associated T2DM. In this review, we present previously published data on the effectiveness of PYC against HCV replication and T2DM. We believe that supplementing conventional treatment with PYC may improve the current HCV therapy, attenuate HCV-associated T2DM, and reduce the risk of complications such as cirrhosis or hepatocellular carcinoma and cardiovascular disease.

Host genetic factors may influence the establishment of chronicity or spontaneous clearance in viral hepatitis B and C infections. More light was shed on the role played by interferon-stimulated genes in the innate immunity. Myxovirus resistance 1 (MX1) is one of those key genes that have reported to inhibit several viruses. The present study aims to explore the possible association of -88G/T and -123C/A promoter variants of MX1 with susceptibility to chronic hepatitis B and C and/or with spontaneous clearance in a Moroccan population. The -88G/T and -123C/A SNPs were genotyped by PCR-RFLP in 538 individuals stratified into HBV chronically infected patients (n = 120), HCV-chronically infected patients (n = 115), HBV spontaneously resolved subjects (n = 114), HCV spontaneously resolved group (n = 52), and healthy controls (n = 137). A significant association of -123C allele with HBV spontaneous clearance has been found (P = 0.002, OR = 2.34; 95%CI [1.36-4]). In addition, a significant correlation between the MX1-GC haplotype and HBV spontaneous clearance (P

Infection with Hepatitis C Virus (HCV) is one of the most important risk factor of hepatocellular carcinoma (HCC). HCV is suspected to induce HCC primarily through chronic inflammation and promotion of cirrhosis, a well-known pre-neoplastic condition. The NF-κB pathway is a key regulator of immune and inflammatory processes and plays a pivotal role in oncogenesis. Genetic variations affecting the pathway may alter NF-κB activity in response to HCV infection and contribute to liver tumorigenesis. The present study aims to evaluate the association between -94Ins/DelATTG (rs28362491) polymorphism in NF-κB1 gene promoter region and 2758G>A (rs696) single nucleotide polymorphism in the 3'UTR region of NFκBIA and the outcomes of HCV infection. In this case-control study, 559 subjects (343 patients with HCV infection including 237 mild chronic hepatitis patients and 106 patients with Advanced Liver Disease (AdLD), 78 individuals who naturally cleared HCV and 138 healthy subjects) were genotyped for the NFκB1 and NFκBIA SNPs using PCR-RFLP. Logistic regression was used to assess the association between polymorphisms and the outcome and progression of the infection. Variation at rs696 was not associated with HCV resolution or progression (P>0.05). By contrast, the Ins/Ins genotype was associated with a 4-fold increase of AdLD risk when compared to mild chronic hepatitis C (OR=4.69; 95% CI, 2.15-10.19; P=0.0001) and the risk was more pronounced when compared to healthy controls (OR=5.02; 95% CI, 2.30-10.98; P=0.00005). Furthermore, carriage of Ins allele at rs28362491 was significantly associated with higher viral loads (P=0.003). Our results suggest that variation in NFκB1 gene promoter modulates the progression of chronic hepatitis C toward advanced liver disease.

The implication of hemochromatosis (HFE) gene mutations in chronic viral hepatitis remains controversial. The aim of the present study was to measure the frequencies of the common HFE gene mutations in Moroccan subjects with chronic viral hepatitis B and C and to assess their influence on the progression of liver disease. H63D and C282Y mutations were screened by the polymerase chain reaction followed by restriction fragment length polymorphism analysis in 170 chronic hepatitis B patients, 168 chronic hepatitis C patients, and 200 healthy controls. A very small proportion of patients infected with hepatitis B virus (HBV) or hepatitis C virus (HCV; 1.8% and none, respectively) were heterozygous for the C282Y mutation, that is, rates not statistically different from those observed in healthy control (2%, P > 0.05). Similarly, the frequency of the H63D allele was not significantly different between HBV (13.8%) or HCV (14.3%) patients and controls (13.5%, P > 0.05). Multivariate analysis showed that carriers of the H63D mutation infected with HBV are at higher risk to progress towards an advanced liver disease when compared with patients infected with HBV with wild-type (OR = 2.45, 95% CI = 1.07–5.58). In contrast, no association between HFE mutated HCV-infected patients and an increased risk of disease progression was found (OR = 1.24, 95% CI = 0.61–2.50, P = 0.547). In conclusion, in Morocco the frequency of the HFE C282Y allele is very low and H63D mutation carriage occurs in almost 14% of the patients, a rate similar in chronic hepatitis patients and healthy controls. In the case of chronic hepatitis B, the carriage of the H63D variant represents a risk factor of evolution towards a more active disease. J. Med. Virol. 83:2096–2102, 2011. © 2011 Wiley Periodicals, Inc.

International audience; Hepatocellular carcinoma is a major malignant tumor characterized in all areas by the disparity of risk between genders. The molecular bases of such disparity are still poorly understood. DNA-methyltransferase-3B (DNMT3B) may play an oncogenic role during tumorigenesis, and its genetic variants have been consistently associated with risk of several cancers, but a single study has investigated their roles in hepatocellular carcinoma (HCC). Polymorphisms of the DNMT3B gene may influence its activity on DNA methylation in several cancers, thereby modulating susceptibility to tumorigenesis. To test this hypothesis, we investigated the association between single nucleotide polymorphism -149C>T (rs2424913) in the promoter region DNMT3B and risk of HCC in a Moroccan population. In this case-control study, the DNMT3B SNP was genotyped by polymerase chain reaction-restriction fragment length polymorphism in 96 HCCs patients and 222 healthy controls that matched for age, sex and ethnicity. Overall, we found that, the DNMT3B 149 TT genotype was not significantly associated with increased risk of HCC (adjusted odds ratio (OR), 0.86, 95% CI, 0.41-1.80, P=0.697). Stratification analysis detected, however, a trend towards a profound risk in the female subset of patients (OR=2.04, 95% CI, 0.77-5.42) and a lesser risk for HCV-infected patients (OR=1.33, 95% CI, 0.43-4.17). Our findings contrast with those of previous studies performed in various cancers, which showed that individuals carrying at least one T allele have a significantly increased risk of developing cancer. In addition, we provide genetic evidence for the major difference of HCC risk between men and women. Further mechanistic studies are needed to unravel the underlying molecular mechanisms.

International audience; Background: The Murine double minute 2 (MDM2) gene encodes a negative regulator of the p53 tumor suppressor protein. A single nucleotide polymorphism (SNP) in the MDM2 promoter (a T to G exchange at nucleotide 309) has been reported to produce accelerated tumor formation. The aim of this study was to investigate whether this functional SNP is associated with an enhanced risk of liver tumorigenesis in Moroccan patients. Methods: The study consisted in the comparison of 96 hepatocellular carcinomas (HCC) cases and 222 controls without HCC matched for age, gender and ethnicity. PCR–RFLP and sequencing methods were used to determine the genotype at the MDM2 SNP309T>G locus. Results: Overall, our results indicate that the GG genotype of SNP309 is significantly associated with an increased risk of HCC (odds ratio, OR = 2.60, 95% CI, 1.08–6.28). Interestingly, despite a wide range of confidence interval, there is a trend associating the GG genotype with a high risk of HCC in males (OR = 3.31; 95% CI, 0.93–11.82) and in HCV-infected patients (OR = 3.7; 95% CI, 0.82–16.45). By contrast, no association between age at diagnosis and MDM2 SNP309 genotypes was observed in HCC patients (P = 0.610). Conclusion: Our findings suggest that the MDM2 309T>G polymorphism is an important modulator of hepatocellular carcinoma development in Moroccan patients.