Activation-induced pyroptosis contributes to the loss of MAIT cells in chronic HIV-1 infected patients

Background: Mucosal-associated invariant T(MAIT) cells are systemically depleted in human immunodeficiency virus type 1(HIV-1) infected patients and are not replenished even after successful combined antiretroviral therapy(cART).This study aimed to identify the mechanism underlying MAIT cell depletion.Methods: In the present study, we applied flow cytometry, single-cell RNA sequencing and immunohistochemical staining to evaluate the characteristics of pyroptotic MAIT cells in a total of 127 HIV-1 infected individuals, including 69 treatment-naive patients, 28 complete responders, 15 immunological non-responders, and 15 elite controllers, at the Fifth Medical Center of Chinese PLA General Hospital, Beijing, China.Results: Single-cell transcriptomic profiles revealed that circulating MAIT cells from HIV-1 infected subjects were highly activated, with upregulation of pyroptosis-related genes. Further analysis revealed that increased frequencies of pyroptotic MAIT cells correlated with markers of systemic T-cell activation, microbial translocation, and intestinal damage in cART-naive patients and poor CD4+ T-cell recovery in long-term cART patients. Immunohistochemical staining revealed that MAIT cells in the gut mucosa of HIV-1 infected patients exhibited a strong active gasdermin-D(GSDMD, marker of pyroptosis) signal near the cavity side, suggesting that these MAIT cells underwent active pyroptosis in the colorectal mucosa. Increased levels of the proinflammatory cytokines interleukin-12(IL-12) and IL-18 were observed in HIV-1 infected patients. In addition, activated MAIT cells exhibited an increased pyroptotic phenotype after being triggered by HIV-1 virions, T-cell receptor signals, IL-12 plus IL-18, and combinations of these factors, in vitro.Conclusions: Activation-induced MAIT cell pyroptosis contributes to the loss of MAIT cells in HIV-1 infected patients,which could potentiate disease progression and poor immune reconstitution.

Sofosbuvir and ABT-450: Terminator of hepatitis C virus?

Combination therapy with peginterferon (pegIFN)-α and ribavirin (RBV) has been the standard of care (SOC) for chronic hepatitis C. Unfortunately, not all patients can achieve a sustained virologic response (SVR) with this regimen. SVR rates are approximately 80% in patients with hepatitis C virus (HCV) genotype 2, 3, 5 and 6 and 40%-50% in patients with genotype 1 and 4. Therefore, strategies to improve SVR rates have been an important issue for clinical physicians. Several direct acting antiviral agents (DAAs) have significantly higher SVR rates when combined with pegIFN-α and RBV than pegIFN-α and RBV alone. Treatments containing DAAs have several advantages over the previous SOC, including higher specificity and efficacy, shorter treatment durations, fewer side effects, and oral administration. Based on these advantages, treatment with pegIFN-α and RBV plus telaprevir or boceprevir has become the current SOC for patients with genotype 1 HCV infection. However, many patients are either not eligible for therapy or decline treatment due to coexisting relative or absolute contraindications as well as an inability to tolerate the hematological side effects and adverse events caused by the new SOC. These factors have contributed to the advent of pegIFN-α-free regimens. The newest therapeutic regimens containing sofosbuvir and ABT-450 have shown promising results. In this review, we summarize the development of anti-HCV agents and the clinical efficacy of sofosbuvir and ABT-450-based therapies as well as the potential for future HCV studies.

Primary biliary cirrhosis-associated hepatocellular carcinoma in Chinese patients:Incidence and risk factors

AIM: To investigate the incidence, characteristics, and risk factors for hepatocellular carcinoma(HCC) in Chinese patients with primary biliary cirrhosis(PBC).METHODS: We reviewed the data of 52 PB Cassociated HCC patients treated at Beijing 302 Hospital from January 2002 to December 2013 and analyzed its incidence and characteristics between the two genders. The risk factors for PBC-associated HCC were analyzed via a case-control study comprising 20 PBC patients with HCC and 77 matched controls without HCC. The matched factors included gender, age, follow-up period and Child-Pugh scores. Conditional logistic regression was used to evaluate the odds ratios of potential risk factors for HCC development. A P < 0.05 was considered statistically significant. RESULTS: The incidence of HCC in Chinese PBC patients was 4.13%(52/1255) and was significantly higher in the males(9.52%) than in the females(3.31%). Among the 52 PBC patients with HCC, 55.76%(29/52) were diagnosed with HCC and PBC simultaneously, and 5.76%(3/52) were diagnosed with HCC before PBC. The males with PBC-associated HCCwere more likely than the females to have undergone blood transfusion(18.75% vs 8.33%, P = 0.043), consumed alcohol(31.25% vs 8.33%, P = 0.010), smoked(31.25% vs 8.33%, P = 0.010), had a family history of malignancy(25% vs 5.56%, P = 0.012), and had serious liver inflammation, as indicated by the elevated levels of alanine aminotransferase, aspartate aminotransferase, alkaline phosphatase, and γ-glutamyl transpeptidase(P < 0.05). Conditional logistic regression analysis revealed that body mass index(BMI) ≥ 25 [adjusted odds ratio(AOR) = 1.116, 95%CI: 1.002-1.244, P = 0.045] and history of alcohol intake(AOR = 10.294, 95%CI: 1.108-95.680, P = 0.040) were significantly associated with increased odds of HCC development in PBC patients. CONCLUSION: HCC is not rare in Chinese PBC patients. Risk factors for PBC-associated HCC include BMI ≥ 25 and a history of alcohol intake. In addition to regular monitoring, PBC patients may benefit from abstinence from alcohol and body weight control.

Risk factors for liver-related mortality in chronic hepatitis C patients:A deceased case-living control study

AIM: To investigate the risk factors for liver-related mortality in chronic hepatitis C (CHC) patients.

HBsAg Loss Due to Tenofovir Treatment for HBV Reactivation Following DAAs Therapy in One Patient with HBV-HCV Coinfection

Hepatitis B virus(HBV)reactivation induced by administration of direct-acting antiviral agents(DAAs)to treat hepatitis C virus(HCV)infection has been reported in previous studies,the subsequent clinical outcomes varied from no symptom to liver failure or death,however,the timing of anti-HBV treatment is controversial.We report the clinical HBV reactivation in a 51 years old female fibrotic patient with chronic HBV-HCV infection during the paritaprevir/ritonavir/ombitasvir and dasabuvir(PrOD)therapy.Her baseline HCV RNA,HBV DNA,alanine aminotransferase(ALT),and liver stiffness measurement levels were 5,560,000IU/mL,<15IU/mL,48U/L,and 11.8 kPa,respectively.At 8weeks of PrOD treatment,her HCV RNA,HBV DNA,and ALT levels were<15IU/mL,2,880,000 IU/mL,and 837U/L,respectively,and clinical reactivation was diagnosed.Meanwhile,tenofovir was immediately used for anti-HBV treatment.Fortunately,HBV DNA and ALT were undetectable and normalized after 16weeks of anti-HBV therapy,and unexpectedly,hepatitis B surface antigen loss occurred at 80weeks of anti-HBV treatment.This study may extend our understanding of the timing of anti-HBV therapy to prevent potential HBV reactivation during DAAs treatment in HBVHCV coinfected patients,and proper initiation timing may lead to functional cure of chronic HBV infection.