Impact of integrated viral DNA on the goal to clear hepatitis B surface antigen with different therapeutic strategies

Lindh, Magnus; Rydell, Gustaf E.; Larsson, Sofia

doi:10.1016/j.coviro.2018.01.011

Cited by 22 publications

(26 citation statements)

References 50 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…The unanswered question is whether the modifications of both HBsAg-specific and total B cells are caused only by circulating HBsAg, other viral products, or by mechanisms not linked to virological products, such as an altered intrahepatic environment present in CHB patients, as suggested by Burton et al (50). The full understanding of the contribution of these mechanisms on B cell functionality in CHB infection will be important for selecting the new therapeutic strategies that aim to recover the faulted HBV-specific immunity present in CHB patients and that are now entering clinical trials (23,29,56). Agents designed to reduce secretion or synthesis of HBsAg might indeed restore HBV immune function, since, to our knowledge, our observation that full HBsAg-specific B cell functionality is recovered only at the time of complete negativity of serological HBsAg represents what we believe is the first clear observation that circulating HBsAg acts, in HBV-infected patients, not only as a decoy of anti-HBs Abs (28), but also as a modulator of HBsAgspecific B cell function.…”

Section: Discussionmentioning

confidence: 99%

“…One attractive hypothesis is that HBsAg functions as a decoy to saturate anti-HBs Abs and so prevents virus neutralization (28). It has also been proposed that HBsAg can suppress innate, humoral, or cellular immunity (29). In this study, we developed a method to directly detect HBsAg-specific B cells ex vivo, which allows us to analyze the impact that HBsAg has on the quantity, phenotype, and function of virus-specific B cells and on potential strategies that can boost their functionality.…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

PD-1 blockade partially recovers dysfunctional virus–specific B cells in chronic hepatitis B infection

Salimzadeh¹,

Bert²,

Dutertre³

et al. 2018

Journal of Clinical Investigation

195

234

View full text Add to dashboard Cite

Chronic HBV (CHB) infection suppresses virus-specific T cells, but its impact on humoral immunity has been poorly analyzed. Here, we developed a dual-staining method that utilizes hepatitis B virus (HBV) surface antigens (HBsAg) labeled with fluorochromes as "baits" for specific ex vivo detection of HBsAg-specific B cells and analysis of their quantity, function, and phenotype. We studied healthy vaccinated subjects (n = 18) and patients with resolved (n = 21), acute (n = 11), or chronic (n = 96) HBV infection and observed that frequencies of circulating HBsAg-specific B cells were independent of HBV infection status. In contrast, the presence of serum HBsAg affected function and phenotype of HBsAg-specific B cells that were unable to mature in vitro into Ab-secreting cells and displayed an increased expression of markers linked to hyperactivation (CD21lo) and exhaustion (PD-1). Importantly, B cell alterations were not limited to HBsAg-specific B cells, but affected the global B cell population. HBsAg-specific B cell maturation could be partially restored by a method involving the combination of the cytokines IL-2 and IL-21 and CD40L-expressing feeder cells and was further boosted by the addition of anti-PD-1 Abs. In conclusion, HBV infection has a marked impact on global and HBV-specific humoral immunity, yet HBsAg-specific B cells are amenable to a partial rescue by B cell-maturing cytokines and PD-1 blockade.

show abstract

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

PD-1 blockade partially recovers dysfunctional virus–specific B cells in chronic hepatitis B infection

Salimzadeh¹,

Bert²,

Dutertre³

et al. 2018

Journal of Clinical Investigation

195

234

View full text Add to dashboard Cite

show abstract

“…In clinical definition, complete cure of HBV infection is defined as the clearance of HBsAg and HBV DNA. Compared with the reduction of HBV DNA load, the level of HBsAg works as a more accurate indicator to evaluate the drug efficacy and disease prognosis [4][5][6][7] . HBsAg seroconversion represents achievement of a strong suppression of viral replication and a low risk of off-treatment virological relapse, and data from the REVEAL study suggest that higher HB-sAg in low viremic patients is associated with an increased risk for HCC [8][9][10] .…”

Section: Introductionmentioning

confidence: 99%

Niacin analogue, 6-Aminonicotinamide, a novel inhibitor of hepatitis B virus replication and HBsAg production

Ren

Yang

et al. 2019

eBioMedicine

View full text Add to dashboard Cite

Background: Hepatitis B surface antigen (HBsAg) is one of the important clinical indexes for hepatitis B virus (HBV) infection diagnosis and sustained seroconversion of HBsAg is an indicator for functional cure. However, the level of HBsAg could not be reduced by interferons and nucleoside analogs effectively. Therefore, identification of a new drug targeting HBsAg is urgently needed. Methods: In this study, 6-AN was screened out from 1500 compounds due to its low cytotoxicity and high antiviral activity. The effect of 6-AN on HBV was examined in HepAD38, HepG2-NTCP and PHHs cells. In addition, the antivirus effect of 6-AN was also identified in mouse model. Findings: 6-AN treatment resulted in a significant decrease of HBsAg and other viral markers both in vitro and in vivo. Furthermore, we found that 6-AN inhibited the activities of HBV SpI, SpII and core promoter by decreasing transcription factor PPAR α, subsequently reduced HBV RNAs transcription and HBsAg production. Interpretation: We have identified a novel small molecule to inhibit HBV core DNA, HBV RNAs, HBsAg production, as well as cccDNA to a minor degree both in vitro and in vivo. This study may shed light on the development of a novel class of anti-HBV agent.

show abstract

“…Despite this, a decline in serum HBV DNA or HBsAg does not correlate well with a reduction in intrahepatic cccDNA for those receiving antiviral therapy, as hepatocytes with HBV DNA integrated into their chromosomes persist and continue to produce large amounts of HBsAg. As new markers, serum levels of HBV core related antigen (HBcrAg) and HBV RNA might be more accurate for quantifying treatment induced impact on cccDNA because these markers are expected to be expressed only from cccDNA and not from integrated HBV DNA . HBV pgRNA concentration in both intrahepatic and serum correlates equally well with intrahepatic cccDNA in HBeAg‐positive patients .…”

Section: Association Of Pgrna With Existing and New Markersmentioning

confidence: 99%

Pregenomic RNA: How to assist the management of chronic hepatitis B?

Wen

Xiao

et al. 2019

Reviews in Medical Virology

View full text Add to dashboard Cite

Pregenomic RNA (pgRNA) is an emerging serological marker for chronic hepatitis B virus (HBV) infection. While pgRNA is principally the template for viral proteins and viral DNAs, additional novel functions for the serum pgRNA have recently been described. These results extend for pgRNA a regulatory function in the viral life cycle and potentially a role in pathogenesis. Here, we review the diverse roles of pgRNA in HBV replication and pathogenesis, emphasizing how the unique structure of this RNA is key to its various functions. We focus in particular on the role of HBV pgRNA in guiding antiviral therapy including nucleot(s)ide analog interruption and role as a marker of cure with new curative therapies. We also briefly allude to the emerging niche for new direct-acting or indirect-acting antivirals targeting pgRNA.

show abstract

Impact of integrated viral DNA on the goal to clear hepatitis B surface antigen with different therapeutic strategies

Cited by 22 publications

References 50 publications

PD-1 blockade partially recovers dysfunctional virus–specific B cells in chronic hepatitis B infection

PD-1 blockade partially recovers dysfunctional virus–specific B cells in chronic hepatitis B infection

Niacin analogue, 6-Aminonicotinamide, a novel inhibitor of hepatitis B virus replication and HBsAg production

Pregenomic RNA: How to assist the management of chronic hepatitis B?

Contact Info

Product

Resources

About