Sexually transmitted infections (STIs) are a major global public health concern, with human papillomavirus (HPV) being one of the most common STIs affecting both men and women worldwide [1]. It is estimated that about 75% of sexually active people will contract HPV at some point in their lives [1]. The impact of HPV on health can be severe, causing various health problems such as genital warts, cervical, anal, penile, and oropharyngeal cancers [2].Several studies conducted in Africa have shown significant HPV prevalence rates among men who have sex with men (MSM). In sub-Saharan Africa, HPV was detected in a range of 19.1% to 100% of men, with a pooled prevalence of 78.2% among HIV-positive men and 49.4% among HIV-negative men [3]. Another study in South Africa found that HPV genotypes were detected in 72.8% of anal, 11.5% of oro-pharyngeal, and 15.3% of urine specimens of MSM, with multiple HPV types being more common in the anal canal [4]. Additionally, a study in Nigeria reported a higher prevalence of anal high-risk HPV (HR-HPV) among HIV-positive MSM compared to HIV-negative MSM [5], while another study in Mali found that a significant percentage of MSM had anal HPV infection of any genotypes, with a large portion being HR-HPV positive [6]. The increasing prevalence of anal HR-HPV among MSM in Africa highlights the urgent need for increased HPV screening and prevention measures targeted at this population, particularly HIV-positive MSM.HPV vaccination programs are highly effective in reducing the burden of HPV and associated diseases in both men and women [3]. The vaccine offers long-lasting protection against HPV infections that are most commonly associated with cancer [7]. Although the vaccine is primarily known for preventing cervical cancer in women, it can also prevent HPV-related cancers in men, such as anal, penile, and oropharyngeal cancers [7]. Moreover, vaccinating men can lead to herd immunity, which can protect women from HPV-related diseases [2]. Therefore, it is essential to prioritize the HPV vaccine for MSM who engage in anal sex to prevent HPV-related cancers and reduce the overall burden of HPV in Africa.However, the low uptake of the HPV vaccine in Africa, especially among high-risk individuals, is concerning despite the vaccine’s effectiveness in preventing HPV-related diseases. Only 14 of the 54 African nations have included the HPV vaccine in their national immunization programs for girls as of 2021, and no countries in western and central Africa have included widespread HPV vaccination in their national immunization programs [8 10]. Furthermore, currently, no countries in Africa offer HPV vaccination to men [8]. This means that individuals engaging in anal sex, who are at a higher risk of developing anal cancer, are not receiving the protection they need, despite the high prevalence of HPV infection among MSM. This underscores the urgent need to prioritize the inclusion of the HPV vaccine in national immunization programs in Africa, and to ensure equitable access to the vaccine for all persons, including MSM.To improve access to healthcare services and HPV vaccination for MSM in Africa, it is crucial to address both the structural and social barriers that hinder their access to these services. Some of the barriers that HPV-infected MSM face include a lack of information, general vaccine hesitancy, a lack of advice from healthcare professionals, expense and logistics, and the perception that HPV vaccination may encourage promiscuity [9]. Furthermore, discrimination and the criminalization of same-sex behavior can further prevent MSM from accessing healthcare programs [10].A comprehensive approach is necessary to overcome these barriers and improve access to healthcare services and HPV vaccination for MSM in Africa. This includes community-based interventions [11], and healthcare professional training to increase awareness about HPV, the benefits of vaccination, and to reduce vaccine hesitancy among MSM [12]. Healthcare professionals should also receive training to provide culturally competent care to meet the unique healthcare needs of MSM in a non-judgmental manner [12]. Policy changes are also necessary to eliminate discrimination and criminalization of same-sex behavior and enable MSM to access healthcare services without fear of stigma or persecution [10]. Moreover, to increase vaccine coverage in Africa, the HPV vaccine should be made affordable and accessible to all individuals, regardless of their socioeconomic status [10]. This can be achieved by implementing community-based vaccination programs, mobile clinics, and school-based vaccination programs. Overall, these interventions can help to improve vaccination rates and increase access to healthcare services for MSM in Africa, ultimately leading to better health outcomes and reducing health disparities.

Background: It is unknown whether Torque Teno virus (TTV) DNA load monitoring could anticipate the development of infectious events in hematological patients undergoing treatment with small molecular targeting agents. We characterized the kinetics of plasma TTV DNA in patients treated with ibrutinib or ruxolitinib and assessed whether TTV DNA load monitoring could predict the occurrence of Cytomegalovirus (CMV) DNAemia or the magnitude of CMV-specific T-cell responses. Methods: Multicenter, retrospective, observational study, recruiting 20 patients treated with ibrutinib and 21 with ruxolitinib. Plasma TTV and CMV DNA loads were quantified by real-time PCR at baseline and days +15, +30, +45, +60, +75, +90, +120, +150, and +180 after treatment inception. Enumeration of CMV-specific IFN-γ-producing CD8 + and CD4 + T cells in whole blood was performed by flow cytometry. Results: Median TTV DNA load in ibrutinib-treated patients increased significantly ( P=0.025) from baseline (median, 5.76 log 10 copies/ml) to day +120 (median, 7.83 log 10 copies/ml). A moderate inverse correlation (Rho=-0.46; P<0.001) was found between TTV DNA load and absolute lymphocyte count (ALC). In ruxolitinib-treated patients, TTV DNA load quantified at baseline was not significantly different from that measured after treatment inception ( P ≥0.12). TTV DNA loads were not predictive of the subsequent occurrence of CMV DNAemia in either patient group. No correlation was observed between TTV DNA loads and CMV-specific IFN-γ-producing CD8 + and CD4 + T cell counts in either patient group. Conclusion: The data did not support the hypothesis that TTV DNA load monitoring in hematological patients treated with ibrutinib or ruxolitinib could be useful to predict either the occurrence of CMV DNAemia or the level of CMV-specific reconstitution.

COVID-19 bivalent ancestral/Omicron mRNA booster vaccinations became available to boost and expand the immunity against SARS-CoV-2 Omicron infections. In a prospective cohort study including 59 healthcare workers, we assessed SARS-CoV-2 ancestral and Omicron BA.5-specific neutralizing antibody and T cell responses in previously infected and infection-naive individuals. Also, we assessed the effect of an ancestral/Omicron BA.1 bivalent mRNA booster vaccination on these immune responses. 10 months after previous monovalent mRNA vaccinations, ancestral SARS-CoV-2 S1-specific T cell and anti-RBD IgG responses remained detectable in most individuals and a previous SARS-CoV-2 infection was associated with increased T cell responses. T cell responses, anti-RBD IgG, and Omicron BA.5 neutralization activity increased after receiving an ancestral/Omicron BA.1 bivalent booster mRNA vaccination. An Omicron BA.5 infection in addition to bivalent vaccination led to a higher ratio of Omicron BA.5 to ancestral strain neutralization activity compared to bivalent vaccination without a recent SARS-CoV-2 infection. In conclusion, SARS-CoV-2 T cell and antibody responses persist for up to 10 months after a monovalent booster mRNA vaccination. An ancestral/Omicron BA.1 bivalent booster mRNA vaccination increases these immune responses and also induces Omicron BA.5 cross-neutralization antibody activity. Finally, our data indicate that hybrid immunity is associated with improved preservation of T cell immunity.

Clinical and histopathological evidence suggest that the male reproductive system may be negatively impacted in patients with coronavirus disease (COVID-19). The objective of this study is to investigate the effect of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) on semen parameters by comparing semen analyses before and after COVID-19 diagnosis in the same patient. We retrospectively analyzed 342 semen analyses by reviewing medical records. The study included two groups of patients: (i) those who underwent two consecutive semen analyses within 6 months, one before (n=114) and one after (n=114) COVID-19 diagnosis, and (ii) a control group (n=114) that was age-matched and did not receive a diagnosis of COVID-19. The study results indicated a significant decrease in semen volume, total sperm count per ejaculate, progressive motile sperm count, total motile sperm count, and normal sperm morphology after SARS-CoV-2 infection in comparison to their respective values before the infection. Subgroup analyses showed that the duration of COVID-19 diagnosis (short-term vs long-term) did not impact the changes in semen parameters. However, fever during the COVID-19 process had a negative effect on semen parameters, particularly sperm concentration, unlike in patients without fever. In conclusion, our findings suggest that SARS-CoV-2 infection is associated with a decline in semen quality, which may potentially impact male fertility. Furthermore, it’s important to note that the negative effects on semen parameters may persist in the long-term. Our results also indicate that fever during active infection could be a significant risk factor that negatively affects spermatogenesis.

Chikungunya virus (CHIKV) is an arbovirus ( Togaviridae family, Alphavirus genus), first identified in 1953 in Tanzania. In 2005, CHIKV emerged in India, and later caused outbreaks in Southeast Asia, Oceania and the Americas. Some Clinical signs are associated with CHIKV infection include fever and/or concomitant arthralgia, neurological manifestations and death. However, in infections caused by other arboviruses, such as the Dengue virus and West Nile virus, its often observed changes in liver enzymes. This study aims to evaluate the profile of the biochemical markers for kidney and liver injury patients infected with CHIKV in acute phase of infection. We found a significant elevation on the levels of creatinine in CHIKV-infected people, possibly associated with myalgia and indicative of muscle damage. The novelty was the elevated levels of creatinine found during a long period.

Abstract: Background: Cytidine/uridine monophosphate kinase 2 (UMP-CMP kinase 2, CMPK2) has been reported as an antiviral interferon-stimulated gene (ISG). We previously observed that the expression of CMPK2 was significantly upregulated after Zika Virus (ZIKV) infection in A549 cells. However, the role of CMPK2 in ZIKV replication remains to be determined. Methods: CMPK2 or retinoic acid inducible gene I (RIG-I) was overexpressed by plasmid transfection or knocked down by siRNA, respectively in A549 cells before the cells were infected with ZIKV. ZIKV RNA and NS1 protein were detected by RT-qPCR and Western Blot, respectively. The activation status of Jak-STAT signaling pathway was determined by the evaluation of the phosphorylation level of STAT1 (p-STAT1, by Western Blot), interferon stimulated response element (ISRE) activity (by dual luciferase assay) and interferon stimulated gene (ISG) expression (by RT-qPCR). Results: We found that ZIKV infection induced CMPK2 expression dependent on RIG-I. Overexpression of CMPK2 inhibited while CMPK2 knockdown promoted ZIKV replication. Mechanically, we found that CMPK2 inhibited ZIKV replication probably through the activation of Jak/STAT signaling pathway as shown by the increased level of p-STAT1, enhanced activity of ISRE, and the up-regulated expression of some downstream ISGs. Conclusion: ZIKV infection induced CMPK2 expression, which activated the Jak/STAT signaling pathway to inhibit ZIKV replication. Keywords: CMPK2; ZIKV; Jak/STAT signaling pathway

In May 2022, several countries reported mpox cases from patients without history of traveling to endemic areas. France was one of the most affected European countries. In this study, we described the clinical characteristics of mpox cases in France, and studied the genetic diversity of the virus. Patients diagnosed with mpox infection (qPCR ct<28) between 21 th May and 4 th July 2022 and between 16 th August and 10 th September 2022 were included to this study. Twelve amplicons corresponding to the most polymorphic regions of the mpox genome and covering ~30,000 nucleotides were generated and sequenced using the S5 XL Ion Torrent technology to evaluate the genetic diversity of mpox sequences. One hundred and fourty-eight patients were diagnosed with mpox-infection. 95% were men, 5% transgender (M-to-F), 50% were taking HIV pre-exposure prophylaxis, and 25% were HIV seropositive. One hundred and sixty-two samples were sequenced and compared to GenBank sequences. Thirty-two distinct mutational patterns were identified. Overall, low genetic diversity of mpox sequences was found compared with pre-epidemic Western-African sequences, with 32 distinct mutational patterns. Our results provide a first glance at the mutational landscape of early mpox 2022 circulating strains in Paris (France).

Since 1999, Vaccinia virus (VACV) has been described as a causative agent of bovine vaccinia (BV), a zoonotic disease that occurs mainly in rural areas of Brazil. However, the circulation of VACV in urban environments and its associated burden has been poorly explored. Moreover, the current Mpox outbreak has raised questions regarding the immune status of the worldwide population previous vaccinated against smallpox. Hence, we conducted a cross-sectional study to better understand the prevalence of anti-OPV neutralizing antibodies (NA) in a susceptible urban population of Brazil. A total of 372 individuals were sampled, yielding an overall seroprevalence of 16.9% (CI95%=13.4–21.1), and antibodies titers ranging from 100 to 800 NU/ml. The prevalence of NA among vaccinated individuals (≥36yo) was 24.9% (IC 95%=19.5–31.2), and among those unvaccinated (<36yo) was 6.7% (IC 95%=3.7–11.8). Multivariate logistic regression analysis indicated that age ≥36yo and the presence of vaccine take were independently associated with the presence of anti-OPV NA. Our findings suggest that vulnerable populations could be subclinically exposed to VACV in urban areas, drawing attention to alternative routes of zoonotic VACV exposure. Our data is also important for better strategies in order to mitigate zoonotic OPV infections mainly among vulnerable populations.

Omicron BF.7 became the predominant SARS-CoV-2 variant in Beijing after the adjustment of COVID-19 response strategies in December 2022. The ability of antibodies elicited by BF.7 infection to cross-react with SARS-CoV-2-like viruses is unknown. This study aimed to investigate the cross-reactive neutralizing antibodies against SARS-CoV-2-related pangolin coronavirus GX_P2V in sera from vaccinated and/or SARS-CoV-2 infected individuals. All vaccinated individuals who recovered from Omicron BF.7 breakthrough infections exhibited substantially higher levels of neutralizing antibodies against GX_P2V among collected subject populations (geometric mean titer [GMT] = 362). Uninfected individuals who received four-mixed-dose vaccines also demonstrated higher levels of neutralizing antibodies (GMT = 44) against GX_P2V than those who received two- or three-dose vaccines and those who recovered from wild type SARS-CoV-2. This finding highlights the significance of prior and hybrid booster vaccinations with wild-type SARS-CoV-2 vaccines in generating potent cross-protective immunity against future spillovers of SARS-CoV-2-like viruses.

Severe fever with thrombocytopaenia syndrome virus (SFTSV) and Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) can cause the hyperproduction of inflammatory cytokines, which have pathological effects in patient including severe or fatal cytokine storms. To characterize the effect of SFTSV and SARS-CoV-2 infection on the production of cytokines in SFTS and COVID-19 patients, we performed an analysis of cytokines in SFTS and COVID-19 patients and also investigated the role of IL-10 in vitro studies: LPS-induced THP-1-derived macrophages, SFTSV infection of THP-1 cells, and SARS-CoV-2 infection of THP-1 cells. In this study, we found that levels of both IL-10 and IL-6 were significantly elevated, the level of TGF-β was significantly decreased and IL-10 was elevated earlier than IL-6 in severe and critical COVID-19 and fatal SFTS patients, and inhibition of IL-10 signalling decreased the production of IL-6 and elevated that of TGF-β. Therefore, the hyperproduction of IL-10 and IL-6 and the low production of TGF-β have been linked to cytokine storm-induced mortality in fatal SFTS and severe and critically ill COVID-19 patients and that IL-10 can play an important role in the host immune response to severe and critical SARS-CoV-2 and fatal SFTSV infection.

Rotavirus molecular surveillance remains important in the post vaccine era in order to monitor the changes in transmission patterns, identify vaccine induced antigenic changes and discover potentially pathogenic vaccine related strains. The Canadian province of Alberta introduced rotavirus vaccination into its provincial vaccination schedule June 2015. To evaluate the impact of this program on stool rotavirus positivity rate, strain diversity and seasonal trends, we analyzed a prospective cohort of children with acute gastroenteritis recruited between December 2014 and August 2018. We identified dynamic changes in rotavirus positivity and genotype trends during pre- and post- rotavirus vaccine introduction periods. Genotypes G9P[8], G1P[8], G2P[4] and G12P[8] predominated consecutively each season with overall lower rotavirus incidence rates in 2016 and 2017. The demographic and clinical features of rotavirus gastroenteritis were comparable among wild type rotaviruses; however, children with G12P[8] infections were older (P<0.001). Continued efforts to monitor changes in the molecular epidemiology of rotavirus using whole genome sequence characterization is needed to further understand the impact of the selection pressure of vaccination on rotavirus evolution.

In somatic cells, microRNAs (miRNAs) bind to the genomes of RNA viruses and influence their translation and replication. Here we demonstrate that a significant number of miRNA binding sites locate in the NSP4 region of the SARS-CoV-2 genome, and the intestinal human miRNAs exert evolutionary pressure on this region. Notably, in infected cells, NSP4 promotes the formation of double-membrane vesicles, which serve as the scaffolds for replication-transcriptional complexes and protect viral RNA from intracellular destruction. In three years of selection, the loss of many miRNA binding sites, in particular, those within the NSP4, has shaped the SARS-CoV-2 genomes to promote the descendants of the BA.2 variants as the dominant strains that define current momentum of the pandemics. Findings highlight the possibility that intestinal tissue may significantly impact evolution of the SARS-CoV-2 genome and may play a pivotal role in the long COVID.

At present, the horse or human rabies immunoglobulin (RIG) used for post-exposure prevention of human rabies (PEP) has high cost and limited availability. It is strongly encouraged to replace RIG with equivalent or more effective and safer products. Mouse and human monoclonal antibodies have been shown to protect rodents from lethal rabies virus (RABV) attacks. In this study, we reported a human-mouse chimeric monoclonal antibody, 12-2A12, which showed a strong neutralization potency and a wide breadth against multiple street viruses of RABV in vitro. The antibody binds the viral glycoprotein (G) with nanomolar affinity. The complex structure of 12-2A12 bound to RABV G reveals that the antibody recognizes an epitope that partially overlaps with the recognition region for the nicotinic acetylcholine receptor (nAChR). The antibody therefore would interfere with the nAChR/G interaction to block the viral receptor binding. In addition, comparison of our complex structure with the G structure in the acidic state reveals a clear steric clash, highlighting that the antibody would further prevent the conformational changes of the viral glycoprotein that are essential for membrane fusion. In light of these functional and structural data, we believe that 12-2A12 might be developed to be included in an antibody cocktail for potential use in human rabies PEP.

Despite recent advances in prophylactic vaccination, SARS-CoV-2 infections continue to cause significant morbidity. A better understanding of immune response differences between vaccinated individuals with and without later SARS-CoV-2 breakthrough infection is urgently needed. CoV-ADAPT is a prospective long-term study comparing humoral (anti-spike-RBD-IgG, neutralization capacity, avidity) and cellular (spike-induced T-cell interferon-γ release) immune responses in individuals vaccinated against SARS-CoV-2 at four different time points (three before and one after third vaccination). In this cohort study, 62 fully vaccinated individuals presented with SARS‑CoV-2 breakthrough infections vs 151 without infection 3-7 months following third vaccination. Breakthrough infections significantly increased anti-spike-RBD-IgG (p<0.01), but not spike-directed T-cell interferon-γ release (TC), antibody neutralization capacity or avidity. Anti-spike-RBD-IgG and antibody avidity decreased with age (p<0.01) and females showed higher anti-spike-RBD-IgG (p<0.01), and a tendency towards higher antibody avidity (p=0.051). The association between humoral and cellular immune responses previously reported at various time points was lost in subjects after breakthrough infections (p=0.807). Finally, a machine-learning approach based on our large immunological data set (a total of 49 variables) from different time points was unable to predict breakthrough infections (AUC: 0.55). In conclusion, distinct differences in humoral vs cellular immune responses in fully vaccinated individuals with or without breakthrough infection could be demonstrated. Breakthrough infections predominantly drive the humoral response without boosting the cellular component. Breakthrough infections could not be predicted based on immunological data, which indicates a superior role of environmental factors (e.g. virus exposure) in individualized risk assessment.

Introduction: In this paper we examine the relationship between vaccination against COVID-19 and both the death rate from COVID-19 and the rate of COVID-19 spread. Our goal is determine if vaccination is associated with reduced death and/or spread of disease at the local level. Methods: This analysis was conducted at the county level in the state of Pennsylvania, United States of America, with data that were collected during the first half of 2022 from the state of Pennsylvania’s Covid Dashboard ([COVID-19 Data for Pennsylvania (pa.gov)](https://www.health.pa.gov/topics/disease/coronavirus/pages/cases.aspx) . Result s: Given that, during this time period, the vaccines being used were not geared specifically toward the common variants at that time, we found no statistically significant relationship between disease spread and vaccination rate at the county level. That said, we did find a highly statistically significant relationship between death rate and vaccination rate (p-value = 0.006). Specifically, a 1% increase in vaccination rate was found to correspond to a 0.751% decrease in death rate (95% confidence interval (0.236%, 1.266%)). Conclusions: These results support previous findings from across the world that Covid vaccination is highly efficacious in preventing death from the disease. Even during a time when vaccine design was not optimally matched with the prevailing strains, vaccination was found to reduce death rate. Hence, improving global vaccine availability is vitally important, in order to achieve necessary outcomes.

Objectives In a COVID-19 sero-surveillance cohort study with predominantly healthy and vaccinated individuals, the objectives were (i) to investigate longitudinally the factors associated with the quantitative dynamics of anti-spike IgG antibody levels, (ii) to evaluate whether the antibody levels were associated with protection from SARS-CoV-2 infection and (iii) to assess whether the association was different in the pre-Omicron compared with the Omicron period. Methods The QuantiVac Euroimmun ELISA test was used to quantify anti-S1 IgG levels. The entire study period (16 months), the 11-month pre-Omicron period and the cross-sectional analysis prior to the Omicron surge included 3219, 2310 and 895 reactive serum samples from 949, 919 and 895 study participants, respectively. Mixed-effect linear, mixed-effect time-to-event and logistic regression models were used to achieve the objectives. Results Age and time since infection or vaccination were the only factors associated with a decline of anti-S1 IgG levels. Antibody levels were significantly associated with protection from SARS-CoV-2 infection, and the association was higher for the Omicron than for the Alpha and Delta variants. In a prediction model, it was estimated that >8000 BAU/mL anti-S1 IgG was required to reduce the risk of infection with Omicron variants by 20% to 30% for 90 days. Conclusions Anti-S1 IgG antibody levels are associated with protection from infection. The levels in the pre-Omicron periods were less significant than during the Omicron surge, which in turn required very high levels for protection in a statistical model.

Objectives: Circulating nucleocapsid (NCP) antigen of SARS-CoV-2 is increased in severely ill COVID-19 patients. However, clinical deterioration of COVID-19 often happens about one week after benign initial presentation. The role of NCP antigenemia as a biomarker in those cases remains unclear. We investigated NCP clearance kinetics in hospitalized patients as a risk assessment tool for predicting necessity of intensive care treatment of COVID-19 patients. Methods: Serum NCP was quantified using a commercial NCP-specific ELISA in hospitalized COVID-19 patients (n=63) during their hospital stay. Results were correlated to COVID-19 disease severity, inflammation parameters, antibody response and results of SARS-CoV-2 PCR from nasopharyngeal swabs.   Results: We demonstrate that NCP antigen levels in serum remained elevated in 45.6% of patients requiring treatment on intensive care units (ICU) after >8 days post positive SARS-CoV-2 PCR, compared to complete clearance in all non-ICU patients. This was in contrast to mucosal clearance of virus as measured by PCR. Antigen clearance was associated with higher IgG against S1 but not NCP.   Conclusions: Detection of NCP antigenemia after 8 days post COVID-19 diagnosis identifies patients who will require intensive care. Lack of NCP clearance after one week can thus help to assess the risk to develop severe COVID-19.

Chronic hepatitis B virus (HBV) infection causes hepatitis, liver cirrhosis and hepatocellular carcinoma. Covalently closed circular DNA (cccDNA) is the transcription template for HBV RNAs and not affected by current treatment options. Effective therapeutics with ability to remove cccDNA need to be developed. Previously, we established an HBV persistence mouse model via hydrodynamic injection of a clinical isolate (BPS) and identified IL-21 as a potent inducer of viral clearance. Here, we aimed to explore the anti-HBV effects of IL-21 messenger RNA (mRNA) delivered by lipid nanoparticle (LNP-IL-21) system. First, LNP-IL-21 was prepared and analyzed for its safety, expression, biodistribution and stability in vitro and in vivo. Next, LNP-IL-21 was injected into two HBV persistence mouse models based on BPS and recombinant cccDNA (rcccDNA) respectively. LNP-IL-21 administration successfully cleared HBV serum markers, and more importantly, BPS replicons and rcccDNA in livers, which was associated with activation of viral specific immune responses. Notably, transfer of peripheral blood mononuclear cells from BPS persistence mice stimulated ex vivo with LNP-IL-21 and viral antigen could induce HBV clearance in recipient mice. These findings suggested that both LNP-IL-21-based gene and cellular therapies provided novel therapeutic strategies against chronic HBV infection.