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Journal articles recommended by our Emerging Scholars Scientific and Medical Advisors

Each month, one of our emerging scholars in the field of hepatitis B basic and clinical research recommends one or two current scholarly article(s) in the field.

PICKS OF THE MONTH - January 2023

For January our presenting emerging scholars are Julie Dang, PhD, MPH and Mohsin Khan, MSc, PhD.

Julie Dang3Julie Dang, PhD, MPH

Pham TN, Le DH, Dao DV, Phan LT, Pham TT, Nguyen TB, Mize GW, Gish RG, Lee WM, Trang A, Le AN. Establishing baseline framework for hepatitis B virus micro-elimination in Ho Chi Minh City, Vietnam–A community-based seroprevalence study. The Lancet Regional Health-Western Pacific. 2023 Jan 1;30:100620.

https://www.thelancet.com/journals/lanwpc/article/PIIS2666-6065(22)00235-8/fulltext

Impact: This is the first population-based community HBV study to estimate the prevalence of HBV statuses in Vietnam. Use of three sero-marker screening for HBV enabled researchers to distinguish among those who were: HBV susceptible population (negative all three seromarkers), chronic carriers (HBsAg(+)), HBV exposure with immune control (anti-HBc total (+), with or without anti-HBs), and HBV vaccination (anti-HBs(+) without HBsAg). Researchers also found wide variations in HBsAg (+) and HBV vaccination rates between districts, risk factors, and socio-economic statuses. This study demonstrated the feasibility of conducting a large-scale comprehensive HBV screening and access to care program in an HBV endemic country that involved collaboration among diverse stakeholders including government, health care institutions, community organizations, and private sector.

moshin khan3

Mohsin Khan, MSc, PhD

Chu JYK, Chuang YC, Tsai KN, et al. Autophagic membranes participate in hepatitis B virus nucleocapsid assembly, precore and core protein trafficking, and viral release. Proc Natl Acad Sci U S A. 2022;119(30):e2201927119.

https://www.pnas.org/doi/10.1073/pnas.2201927119

It is widely known that Hepatitis B virus (HBV) replication is regulated by autophagy. This investigation, led by Prof. Jing-hsiung James Ou at UCLA, has precisely examined and characterized how autophagic membranes participate in the HBV life cycle. Autophagy is a process in which the cells eliminate their organelles and macromolecules. Under normal circumstances, autophagy ensures homeostasis and proper recycling of cellular biomaterials. However, the signaling events of autophagy are often altered during stress, inflammation, and infection. Interestingly many pathogens, especially viruses, have evolved with successful strategies to hijack this cellular process to support their replication. HBV is one among those viruses that are successful invaders and play with autophagic machinery efficiently.

Autophagy, at the cellular level, starts with the formation of isolation membranes that are called phagophores (PP). PP are crescent structures that subsequently expand to form complete double-membrane vesicles called autophagosomes (APS). The APS can fuse with either lysosome or MVBs (multivesicular bodies) to form autolysosomes or amphisomes respectively.

In this investigation, it was observed that the PP and APS, purified from the cells that contained replicating HBV, are highly enriched with core particles. These PP- and APS-associated core particles contain hypo-phosphorylated core protein. The PP-associated core particles have mostly double-stranded HBV DNA, while APS-associated core particles are rich in both, single- and double-stranded DNA. With some additional experiments, it was further confirmed that APS-associated core particles are nucleocapsids that contain viral pgRNA (progenome RNA) and/or DNA. It was also observed that the association of HBV core with PP and APS is independent of pre-core protein. Interestingly, the ectopically expressed core protein did not localize to APS. These observations suggest that the cellular trafficking of individually expressed core protein does not entirely mimic the trafficking of core protein originating from active HBV replication. Possibly, the packaging of pgRNA is a cooperative event that is required for the association of core to APS.

Additionally, it was noted that HBV could induce the formation of amphisome, and disruption of this event suppresses HBV release from the cells. It signifies that although HBV induces autophagy via PP and APS formation, it does not promote autolysosome formation. In other words, HBV induces only early events of autophagy and utilizes PP and APS for packaging and replication purposes. However, it directs a major pool of APS towards amphisome formation and does not promote the degradative stage of autophagy to ensure the successful release of mature HBV.

In summary, this report provided detailed information about the intracellular trafficking of HBV proteins and the relation between autophagy and HBV replication. This will be very helpful for the development of novel anti-HBV drugs that target the autophagic pathway.

PICK OF THE MONTH - December 2022

Peter block3For December, our presenting emerging scholar is Peter Block, MD, MSc. 

Yuen M-F, Lim S-G, Plesniak R, et al. Efficacy and safety of bepirovirsen in chronic hepatitis B infection. N Engl J Med 2022; 387:1957-68.

https://pubmed.ncbi.nlm.nih.gov/36346079/

The search for an HBV cure has been an area of active investigation for decades. While the backbone of our current treatment – nucleotide/nucleoside analogues (NAs) – can suppress the virus, they rarely eradicate it. The scientific community has therefore sought to develop novel therapeutics with curative effects. The article highlighted here describes the clinical efficacy of bepirovirsen, a new antiviral agent that may bring us closer to this goal.

Bepirovirsen is an antisense RNA-based drug delivered that impairs HBV replication by targeting viral messenger RNA in the infected hepatocyte.  This study evaluated its antiviral activity through a phase 2b clinical trial in patients with CHB either receiving (or not receiving) NA therapy. Study participants were randomized into different treatment arms, where they received varying durations of therapy with bepirovirsen and then were followed for 24 weeks after completion of treatment.

The major takeaway is that a significant minority of study participants treated with bepirovirsen achieved a functional cure from CHB, defined by the sustained clearance of both HBV DNA and HBV surface antigen (HBsAg). While this primary endpoint was achieved in only 6% of the total study population, rates of response were higher in certain subgroups. Specifically, upwards of 16-25% of patients with low pre-treatment levels of HBsAg attained clearance of both HBV and HBsAg after receiving bepirovirsen. These rates of functional cure are much higher than what is typically seen in those receiving conventional monotherapy with NAs.

Overall, the study reports promising clinical data on an emerging treatment option for chronic hepatitis B. Future studies on bepirovirsen will be monitored closely by the HBV community, as such studies should clarify the durability of bepirovirsen’s antiviral activity, safety profile, and long-term outcomes.

PICKS OF THE MONTH - November 2022

ESMAB photos 150 188 px 3For November, our presenting emerging scholar is Lena Allweiss, PhD.  She has selected two articles. 

Smc5/6 silences episomal transcription by a three-step function. Abdul F, Diman A, Baechler B, Ramakrishnan D, Kornyeyev D, Beran RK, Fletcher SP, Strubin M. Nat Struct Mol Biol. 2022 Sep;29(9):922-931. doi: 10.1038/s41594-022-00829-0

https://pubmed.ncbi.nlm.nih.gov/36097294/

The chromosomal maintenance complex SMC5/6 is a restriction factor against HBV because it blocks transcription from its episomal viral genome. For an active infection to be established, HBV relies on its regulatory protein HBx to specifically degrade this complex and relieve its transcriptional suppression. This publication describes the mechanism by which SMC5/6 silences viral transcription from the HBV genome - a mechanism that might hold true for the restriction of other DNA virus such as HIV and HPV. Elucidating this process will not only generate basic knowledge about the interaction of viruses with their hosts but might also assist with the design of antiviral drugs targeting HBx.

 

Conversion of hepatitis B virus relaxed circular to covalently closed circular DNA is supported in murine cells. Wei L, Cafiero TR, Tseng A, Gertje HP, Berneshawi A, Crossland NA, Ploss A. JHEP Rep. 2022 Jul 9;4(9):100534. doi: 10.1016/j.jhepr.2022.100534.

https://pubmed.ncbi.nlm.nih.gov/36035363/

Mice are often used to study viral infections and test novel antiviral treatments. In the case of HBV, however, mice cannot simply be used for these purposes since HBV does not naturally infect mice. Scientists are currently trying to develop a genetically modified mouse model that is engineered to express missing factors or eliminate inhibitory factors necessary to establish an HBV infection in these mice. In this publication, the authors show that a crucial step in HBV infection, the conversion of incoming viral relaxed circular DNA to covalently closed circular DNA, does take place in mouse hepatocytes, thus ruling out this step as a potential block for infection establishment. This knowledge is important because it will help create such a mouse model for HBV research, a model in which this step does not need to be modified.