The role of sex hormones and receptors in HBV infection and development of HBV-related HCC.

Gender disparity in hepatitis B virus (HBV)-related diseases has been extensively documented. Epidemiological studies consistently reported that males have a higher prevalence of HBV infection and incidence of hepatocellular carcinoma (HCC). Further investigations have revealed that sex hormone-related signal transductions play a significant role in gender disparity. Sex hormone axes showed significantly different responses to virus entry and replication. The sex hormones axes change the HBV-specific immune responses and antitumor immunity. Additionally, Sex hormone axes showed different effects on the development of HBV-related disease. But the role of sex hormones remains controversial, and researchers have not reached a consensus on the role of sex hormones and the use of hormone therapies in HCC treatment. In this review, we aim to summarize the experimental findings on sex hormones and provide a comprehensive understanding of their roles in the development of HCC and their implications for hormone-related HCC treatment.

Posttranslational modifications of ACE2 protein: Implications for SARS-CoV-2 infection and beyond.

The present worldwide pandemic of coronavirus disease 2019 (COVID-19) has highlighted the important function of angiotensin-converting enzyme 2 (ACE2) as a receptor for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) entry. A deeper understanding of ACE2 could offer insights into the mechanisms of SARS-CoV-2 infection. While ACE2 is subject to regulation by various factors in vivo, current research in this area is insufficient to fully elucidate the corresponding pathways of control. Posttranslational modification (PTM) is a powerful tool for broadening the variety of proteins. The PTM study of ACE2 will help us to make up for the deficiency in the regulation of protein synthesis and translation. However, research on PTM-related aspects of ACE2 remains limited, mostly focused on glycosylation. Accordingly, a comprehensive review of ACE2 PTMs could help us better understand the infection process and provide a basis for the treatment of COVID-19 and beyond.

CDK4/6 inhibitor palbociclib promotes SARS-CoV-2 cell entry by down-regulating SKP2 dependent ACE2 degradation.

Coronavirus disease 2019 (COVID-19) outbreak has become a global pandemic. CDK4/6 inhibitor palbociclib was reported to be one of the top-scored repurposed drugs to treat COVID-19. As the receptor for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) entry, expression level of angiotensin-converting enzyme 2 (ACE2) is closely related to SARS-CoV-2 infection. In this study, we demonstrated that palbociclib and other methods could arrest cells in G0/G1 phase and up-regulate ACE2 mRNA and protein levels without altering its subcellular localization. Palbociclib inhibited ubiquitin-proteasome and lysosomal degradation of ACE2 through down-regulating S-phase kinase-associated protein 2 (SKP2). In addition, increased ACE2 expression induced by palbociclib and other cell cycle arresting compounds facilitated pseudotyped SARS-CoV-2 infection. This study suggested that ACE2 expression was down-regulated in proliferating cells. Cell cycle arresting compounds could increase ACE2 expression and facilitate SARS-CoV-2 cell entry, which may not be suitable therapeutic agents for the treatment of SARS-CoV-2 infection.

Acceptance of COVID-19 boosters among hypertensive patients in China: A multicenter cross-sectional study.

Hypertension, a prevalent chronic disease, has been associated with increased COVID-19 severity. To promote the COVID-19 booster vaccination of hypertensive patients, this study investigated the willingness to receive boosters and the related influencing factors based on the health belief model (HBM model). Between June and October 2022, 453 valid questionnaires were collected across three Chinese cities. The willingness to receive a booster vaccination was 72.2%. The main factors that influenced the willingness of patients with hypertension to receive a booster shot were male (χ2 = 7.008, p = .008), residence in rural (χ2 = 4.778, p = .029), being in employment (χ2 = 7.232, p = .007), taking no or less antihypertensive medication (χ2 = 9.372, p = .025), with less hypertension-related comorbidities (χ2 = 35.888, p < .0001), and did not have any other chronic diseases (χ2 = 28.476, p < .0001). Amid the evolving COVID-19 landscape, the willingness to receive annual booster vaccination was 59.4%, and employment status (χ2 = 10.058, p = .002), and presence of other chronic diseases (χ2 = 14.256, p < .0001) are associated with the willingness of annual booster vaccination. Respondents with higher perceived severity, perceived benefits, perceived self-efficacy, and lower perceived barriers were more willing to receive booster shots. The mean and median value of willingness to pay (WTP) for a dose of booster were 53.17 CNY and 28.31 CNY. Concerns regarding booster safety and the need for professional advice were prevalent. Our findings highlight the importance of promoting booster safety knowledge and health-related management among hypertensive individuals through professional organizations and medical specialists.

Circulating immune complexes and mutations of HBsAg are associated with the undetectable HBsAg in anti-HBs and HBeAg positive occult hepatitis B virus infection.

Introduction: Occult hepatitis B virus infection (OBI) is an HBsAg negative state in HBV infection with usually inactive HBV replication. However, there were a minority of individuals with positive HBeAg and anti-HBs among OBI blood donors and few studies have focused on this unusual serological pattern. Methods: 2022 plasma of blood donors that preliminary screened reactive for HBV DNA and non-reactive for HBsAg were collected from 16 provinces in China from 2015 to 2018. HBV DNA and HBsAg in these samples were retested using the Cobas TaqScreen MPX test and ARCHITECT HBsAg Quantitative II assay. Lumipulse HBsAg-HQ assay and polyethylene glycol (PEG)-double precipitation following HCl and trypsin digestion were performed to detect HBsAg from HBsAg-anti-HBs circulating immune complexes (CICs). Results: 1487 of 2022 samples were positive for Cobas HBV DNA test and non-reactive for ARCHITECT HBsAg assay, while 404 of them were positive using Lumipulse HBsAg-HQ assay. 10 HBsAg-/anti-HBs+/HBeAg+ OBI blood donor samples were further dissociated and HBsAg-CICs were detected in 7 samples. Sequencing analysis showed that D44N, N98T, G73S, Del 56-116, and I161T occurred in the pre-S region, and immune escape mutations such as P127T, F134L, G145R, V168A, and I126T/S in the S region were found. Discussion: In conclusion, there were a minority of HBsAg-/anti-HBs+/HBeAg+ individuals in OBI blood donors. The undetectable HBsAg in these individuals was mainly due to HBsAg-CICs. Immune escape-associated mutations also happened under the host's selective pressure. HBsAg dissociation methods or Lumipulse HBsAg-HQ assay is recommended to distinguish these individuals.

Naturally occurring pre-S mutations promote occult HBV infection by affecting pre-S2/S promoter activity.

Occult hepatitis B virus (HBV) infection (OBI) has non-negligible clinical significance, but the mechanism of its occurrence remains unclear. Growing evidence suggests that mutations in the pre-S region of HBV genome may be associated with the occurrence of OBI. However, the role of pre-S mutations in OBI and its molecular mechanism was not fully understand. Here, the pre-S sequences from 307 OBI blood donors and 293 hepatitis B surface protein (HBsAg)-positive blood donors were obtained, and we observed a higher frequency of naturally occurring pre-S mutations in OBI donors infected with genotype B/C HBV than in HBsAg-positive donors, suggesting their potential positive role in OBI. In both genotype B and C, several pre-S mutants resulted in markedly reduced HBsAg production in vitro. In particular, the T68I, S78N and N98T mutants of genotype B were proven to significantly decrease the HBsAg synthesis by affecting the pre-S2/S promoter activity, and thereby promoting the occurrence of OBI.

Role of S protein transmembrane domain mutations in the development of occult hepatitis B virus infection.

Occult HBV infection (OBI) is a special infection status during Hepatitis B virus (HBV) infection. The underlying mechanism of its occurrence remains unclear. This study conducted sequencing analysis on 104 OBI plasma samples and 524 HBsAg positive samples from 29 blood centres, and searched for high-frequency mutations in transmembrane domain (TMD) of S protein in the OBI population. Plasmids with TMD high-frequency mutations were constructed, in vivo and in vitro functional experiments were performed to investigate possible molecular mechanisms of OBI occurrence. We found 22 high-frequency TMD mutations in genotype B OBI strains. Among them, five mutations can lead to impairment of HBsAg secretion; seven mutations had accumulated intracellular HBsAg while extracellular HBsAg didn't decrease compared to wildtype. This study chose C85R from TMD2, F220C, and F220Y from TMD4 for further exploration. Protein structure predication showed these three mutant HBsAg displayed changed hydrophilic properties and tended to accumulate in the phospholipid bilayer of cell membrane. Mutant HBsAg's secretion disorder may induce OBI. On the other hand, V168A + V177A from TMD3 expressed increased HBsAg both in intracellular and extracellular levels. This mutation had most unstable natural conformation and may be inclined to transition into V177A or V168A + S174N + V177A. These three mutations were more prone to mixed infection, presenting a state of coexistence, thus approaching the impaired secretion pattern of OBI. This study demonstrated TMD mutations could contribute to the occurrence of OBI and provided a theoretical basis for OBI study and the functional cure of chronic hepatitis B virus infection.