# The Structural Biology of HBV

> **NIH NIH R01** · TRUSTEES OF INDIANA UNIVERSITY · 2020 · $372,968

## Abstract

Summary
240 million people suffer from chronic Hepatitis B Virus infection (HBV). In vivo, assembly of new
virions begins with a complex of the viral polymerase with a stem loop on the viral RNA. This complex
nucleates assembly of a T=4 capsid resulting in the RNA-filled core. Within the RNA-filled core the
polymerase becomes active and reverse transcribes the linear single stranded RNA pregenome to the
relaxed circular double strand DNA of mature HBV cores. Mature cores and empty cores, but not
immature cores, display signals that allow their transport to the nucleus or the ER. These directions
respectively maintain chronic infection or result in envelopment and secretion from the cell. Our
preliminary studies show that viral RNA lines the interior surface of the capsid and supports the
hypothesis that in RNA-filled cores the nucleating polymerase complex occupies a specific site (or a
small number of sites) with respect to the capsid. We further propose that that the polymerase travels
on the RNA during reverse transcription. We propose that owing to its stiffness, the dsDNA genome of
mature capsids must adopt a completely different organization. We will investigate the structure and
biochemistry of empty, RNA-filled, and mature DNA-filled capsid. Our overarching goals are to
describe the mechanism of reverse transcription and the structural basis for signaling maturation of
the HBV genome. Towards this end we will develop purification strategies for purifying different
classes of core, examine their dynamic properties using biophysical techniques, use single molecule
techniques to determine variability of core mass, and investigate the reverse transcription reaction
itself. In a second set of aims we will determine structures of RNA-filled and DNA-filled cores to
investigate the disposition of the nucleic acid, its effects on capsid symmetry, and the availability of
capsid binding sites for host proteins, such as the importins responsible for nuclear import.
Treatment of chronic HBV with reverse transcriptase inhibitors, the standard of care, decreases viral
load and improves liver condition but it rarely leads to a “cure”, even after years of treatment.
Remarkably, there is no real understanding of the structural basis of reverse transcription and how a
signal for nucleic acid state is transduced to allow the virus lifecycle to progress. Addressing these
deficits is the goal of this proposal.

## Key facts

- **NIH application ID:** 9899197
- **Project number:** 5R01AI144022-02
- **Recipient organization:** TRUSTEES OF INDIANA UNIVERSITY
- **Principal Investigator:** Adam Zlotnick
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $372,968
- **Award type:** 5
- **Project period:** 2019-04-01 → 2023-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9899197

## Citation

> US National Institutes of Health, RePORTER application 9899197, The Structural Biology of HBV (5R01AI144022-02). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9899197. Licensed CC0.

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