Pursue Epigenetic Treatment Strategies Against HBV in HBV/HIV Co-Infection

NIAID invites applications for innovative basic, translational, and clinical research to identify and address epigenetic treatment strategies for achieving a hepatitis B virus (HBV) cure in people living with HIV (PLWH) through Notice of Special Interest (NOSI): Epigenetic Modulation of HBV cccDNA and integrated HBV DNA (iDNA): Implications for Epigenetic Treatment Strategies Against HBV in HIV/HBV Co-Infection. 

The main barriers to cure HBV include the persistence of covalently closed-circular DNA (cccDNA), integrated HBV DNA (iDNA), and HBV surface antigen (HBsAg). The current HBV cure pipeline focuses on silencing cccDNA but does not directly target iDNA-derived HBsAg. An HIV infection poses additional challenges for people living with HBV and may reduce an individual’s ability to mount an effective, sustained immune response as well as increase the risk of adverse events and drug-drug interactions with HBV cure interventions. 

This NOSI will support studies on the epigenetic mechanisms regulating HBV cccDNA and iDNA in the presence of HIV and research targeting epigenetic pathways for achieving an HBV cure.  

The objective of this NOSI is to fill scientific gaps needed to:  

1. Shed more light on cccDNA and iDNA epigenetics, and provide novel antiviral targets for development of therapeutics that epigenetically silence cccDNA and iDNA to achieve a functional cure for chronic HBV (CHB). 
2. Understand mechanisms regulating the epigenetic transcriptional activity of cccDNA and iDNA and epigenetic strategies to silence their activity. 
3. Develop approaches for complete silencing of cccDNA and iDNA for achieving a cure for CHB. 
4. Elucidate the mechanisms underlying epigenetic regulation of cccDNA and iDNA transcription in hepatocytes. 

To achieve those ends, example research topics of interest include: 

• Developing therapeutic strategies to silence or eliminate cccDNA and iDNA by targeting epigenetic pathways. 
• Determining the viral and host epigenetic factors regulating HBV pathogenesis. 
• Determining the epigenetic gene regulatory mechanisms impacting viral and host genomes in establishing HBV pathogenesis. 
• Determining how chromosomal positioning and epigenetic features affect the transcriptional activity of cccDNA and iDNA. 
• Identifying molecular functions of HBx that prevent permanent silencing of cccDNA and iDNA. 
• Determining the role of non-coding RNA (e.g., sncRNAs, lncRNAs) in modulating HBV pathogenesis. 
• Defining the molecular mechanisms for epigenetic factors that favor HBV rebound. 
• Expanding existing knowledge on the role of HBx as a factor underlying the epigenetic regulation of cccDNA and iDNA. 
• Developing molecular tools to directly silence or eliminate the cccDNA and iDNA such as designer nucleases and nickases, zinc finger (ZF) nucleases, transcription activator-like effector nucleases (TALENs), and CRISPR.

This NOSI will not support applications that focus on hepatitis viruses other than HBV, nor those that focus solely on either HIV or HBV. While clinical trials are not allowed, use of samples from clinical trials is allowed. Animal research is allowed, to include nonhuman primates. 

Submission Details 

For standard due dates on or after September 7, 2024, and through May 7, 2027, you may apply using the following parent notices of funding opportunities (NOFOs) or their subsequent reissues:  

• NIH Research Project Grant (Parent R01, Clinical Trial Not Allowed) 
• NIH Exploratory/Developmental Research Grant Program (Parent R21, Clinical Trial Not Allowed) 
• PHS 2024-2 Omnibus Solicitation of the NIH for Small Business Technology Transfer Grant Applications (Parent STTR [R41/R42], Clinical Trial Not Allowed) 
• PHS 2024-2 Omnibus Solicitation of the NIH, CDC, and FDA for Small Business Innovation Research Grant Applications (Parent SBIR [R43/R44], Clinical Trial Not Allowed) 

Direct questions about the NOSI to our scientific/research contact Dr. Chris Lambros at clambros@niaid.nih.gov or 240-627-3093.