An OX40/OX40L interaction directs successful immunity to hepatitis B virus

Publicover, Jean; Gaggar, Anuj; Jespersen, Jillian M.; Halac, Ugur; Johnson, A. J.; Goodsell, Amanda; Avanesyan, Lia; Nishimura, Stephen L.; Holdorf, Meghan; Mansfield, Keith G.; Judge, Joyce; Koshti, Arya; Croft, Michael; Wakil, Adil E.; Rosenthal, Philip; Pai, Eric; Cooper, Stewart; Baron, Jody L.

doi:10.1126/scitranslmed.aah5766

Cited by 30 publications

(38 citation statements)

References 39 publications

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“…In addition, an in-depth analysis of HBV-specific T helper cells and especially Tfh cells, which provide help for B cell maturation via CD40L and IL-21 in the germinal center, in association with B cells will be important for better understanding the causes of HBsAg-specific B cell defects. Recent data in mouse models have shown the importance of boosting the T helper and Tfh cell responses for HBsAg seroconversion (51,52), but data on Tfh cells in humans remain limited (53).…”

Section: Discussionmentioning

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

218

250

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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.

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Section: Discussionmentioning

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

218

250

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“…Higher intrahepatic expression of the costimulatory T cell receptor OX40 (TNFRSF4) in C R vs. U but not C NR vs. U (Supplementary Table Accepted Article © 2020 The Authors. Hepatology published by Wiley Periodicals LLC on behalf of American Association for the Study of Liver Diseases 6) is also notable because hepatic OX40 + CD4 + T cells play a key role in IL-21 production by T FH and the development of an effective immune response to HBV in an adoptive transfer mouse model (18).…”

Section: Baseline Intrahepatic Transcriptional Profile Differentiatesmentioning

confidence: 99%

Toll‐Like Receptor 8 Agonist GS‐9688 Induces Sustained Efficacy in the Woodchuck Model of Chronic Hepatitis B

et al. 2020

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GS-9688 (selgantolimod) is an oral selective small molecule agonist of toll-like receptor 8 (TLR8) in clinical development for the treatment of chronic hepatitis B (CHB). In this study, we evaluated the antiviral efficacy of GS-9688 in woodchucks chronically infected with woodchuck hepatitis virus (WHV), a hepadnavirus closely related to hepatitis B virus (HBV). WHV-infected woodchucks received eight weekly oral doses of vehicle, 1 mg/kg GS-9688 or 3 mg/kg GS-9688. Vehicle and 1 mg/kg GS-9688 had no antiviral effect, whereas 3 mg/kg GS-9688 induced a >5 log 10 reduction in serum viral load and reduced WHV surface antigen (WHsAg) levels to below the limit of detection in half of the treated woodchucks. In these animals, the antiviral response was maintained until the end of the study (>5 months after the end of treatment). GS-9688 treatment reduced intrahepatic WHV RNA and DNA levels by >95% in animals in which the antiviral response was sustained after treatment cessation, and these woodchucks also developed detectable anti-WHsAg antibodies. The antiviral efficacy of weekly oral dosing with 3 mg/kg GS-9688 was confirmed in a second woodchuck study. The antiviral response to GS-9688 did not correlate with systemic GS-9688 or cytokine levels but was associated with transient elevation of liver injury biomarkers and enhanced proliferative response of peripheral blood mononuclear cells (PBMC) to WHV peptides. Transcriptomic analysis of liver biopsies taken prior to treatment suggested that T follicular helper cells (T FH) and various other immune cell subsets may play a role in the antiviral response to GS-9688. Conclusion: Finite, short-duration treatment with a clinically relevant dose of GS-9688 is well tolerated and can induce a sustained antiviral response in WHV-infected woodchucks. The identification of a baseline intrahepatic transcriptional signature associated with response to GS-9688 treatment provides insights into the immune mechanisms that mediate this antiviral effect. Approximately 260 million individuals are chronically infected with hepatitis B virus (HBV), and over half a million people are estimated to die each year due to liver diseases associated with chronic hepatitis B (CHB), such as cirrhosis and hepatocellular carcinoma (HCC). Immunological control of CHB ("functional cure") is defined as sustained loss of HBV surface antigen (HBsAg) off treatment, with or without seroconversion to anti-HBs antibody. Several nucleos(t)ide analogs, as well as interferon-alpha (IFN-α), are approved for the treatment of CHB. These therapies reduce viremia and

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“…If this is the case, additional CD4 + T cell help might be necessary to promote adequate antibody responses. This may be achieved through inclusion of additional HBV antigens, such as core and/or polymerase, combination with antibodies to stimulate immune checkpoint blockade [ 37 , 38 , 39 ] or to agonize other immunostimulatory receptors such as 4-1BB or OX40 [ 40 , 41 , 42 ].…”

Section: Discussionmentioning

confidence: 99%

Modified Alphavirus-Vesiculovirus Hybrid Vaccine Vectors for Homologous Prime-Boost Immunotherapy of Chronic Hepatitis B

Chiale

Yarovinsky

Mason³

et al. 2020

Vaccines

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Virus-like vesicles (VLV) are hybrid vectors based on an evolved Semliki Forest virus (SFV) RNA replicon and the envelope glycoprotein (G) from vesicular stomatitis virus (VSV). Previously, we showed that VLV can be used to express protein antigens and generate protective antigen-specific CD8+ T cells. This report describes VLV vectors designed for enhanced protein expression and immunogenicity. Expressing hepatitis B virus (HBV) middle S antigen (MHBs) from VLV using a dual subgenomic promoter significantly increased MHBs-specific CD8+ T cell and antibody production in mice. Furthermore, envelope glycoprotein switch from VSV Indiana to the glycoprotein of Chandipura virus enabled prime-boost immunization and further increased responses to MHBs. Therapeutic efficacy was evaluated in a mouse model of chronic HBV infection initiated by HBV delivery with adeno-associated virus. Mice with lower or intermediate HBV antigen levels demonstrated a significant and sustained reduction of HBV replication following VLV prime-boost immunization. However, mice with higher HBV antigen levels showed no changes in HBV replication, emphasizing the importance of HBV antigenemia for implementing immunotherapies. This report highlights the potential of VLV dual promoter vectors to induce effective antigen-specific immune responses and informs the further development and evaluation of hybrid viral vaccine platforms for preventative and therapeutic purposes.

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An OX40/OX40L interaction directs successful immunity to hepatitis B virus

Cited by 30 publications

References 39 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

Toll‐Like Receptor 8 Agonist GS‐9688 Induces Sustained Efficacy in the Woodchuck Model of Chronic Hepatitis B

Modified Alphavirus-Vesiculovirus Hybrid Vaccine Vectors for Homologous Prime-Boost Immunotherapy of Chronic Hepatitis B

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