Key Dates

Related Announcements

• July 12, 2023 - PHS 2023-2 Omnibus Solicitation of the NIH, CDC and FDA for Small Business Innovation Research Grant Applications (Parent SBIR R43/R44] Clinical Trial Not Allowed). See NOFO PA-23-230
• July 12, 2023 - PHS 2023-2 Omnibus Solicitation of the NIH for Small Business Technology Transfer Grant Applications (Parent STTR [R41/R42] Clinical Trial Not Allowed). See NOFO PA-23-232
• May 7, 2020 - NIH Exploratory/Developmental Research Grant Program (Parent R21 Clinical Trial Not Allowed). See NOFO PA-20-195
• May 5, 2020 - NIH Research Project Grant (Parent R01 Clinical Trial Not Allowed). See NOFO PA-20-185

Issued by

National Institute of Allergy and Infectious Diseases (NIAID)

Purpose

Background

Viral hepatitis is a leading cause of morbidity and mortality among people living with HIV (PLWH). The World Health Organization (WHO) estimates nearly 10% of PLWH are also living with hepatitis B, though this number is likely underestimated given testing for viral hepatitis globally is extremely low. Rates of chronic HBV are higher in PLWH, who also have higher rates of liver-related morbidity, mortality, and hospitalizations compared to people living with HBV alone. The progression of HBV-induced liver disease is accelerated in PLWH, resulting from the combined action of HBV replication, immune-mediated hepatocytolysis, and HIV-induced immunosuppression and immunosenescence. Even when receiving suppressive antiretroviral therapy, the incidence of hepatocellular carcinoma (HCC) is much higher in PLWH than in people with HBV alone.

The main barriers to cure HBV include the persistence of covalently closed-circular DNA (cccDNA), integrated HBV DNA (iDNA), and HBsAg. Currently available treatments for chronic HBV infection (1) do not eradicate cccDNA or iDNA; (2) do not lower the rate of HBsAg loss; (3) require a long duration of treatment; and (4) do not eliminate the risk of HCC. Although suppression of plasma HBV DNA leads to decreased levels of fibrosis, cirrhosis and HCC, levels of HBsAg still remain elevated, which may be related to the persistence of cccDNA and iDNA. HBsAg loss is complex because it derives from both cccDNA and iDNA. The current HBV cure pipeline focuses on silencing cccDNA but does not directly target iDNA-derived HBsAg. Achieving HBsAg loss requires a greater understanding of how both cccDNA and iDNA contribute to HBsAg production, which will inform on approaches to suppress and silence these reservoirs. Since HBV persists within the nucleus of hepatocytes in the form of cccDNA and iDNA despite immune control, HBV has the potential to be reactivated spontaneously following cessation of nucleos(t)ide analogs. HIV infection poses additional challenges for people living with HBV and may reduce the host’s ability to mount an effective, sustained immune response as well as increase risks for adverse events and drug-drug interactions with HBV cure interventions.

Epigenetics refers to modifications of chromosomal DNA that do not alter the underlying nucleotide sequence but affect the downstream transcription and translation of the genetic code. Three major forms of epigenetic modifications include  DNA methylation, histone modification, and chromatin conformation, all of which alter the three-dimensional structure of DNA leading to changes in how genes are expressed and regulated. Examples of modifications include methylation, acetylation, ubiquitination, and phosphorylation of DNA; changes in histone protein composition and structure that impact access of transcription factors to gene regulatory elements; and non-coding RNAs that interact directly with histones, DNA or DNA binding proteins to alter gene expression. These changes in gene expression are a natural and highly regulated cellular mechanism that drive complex biological processes such as organ tissue specificity and cell types (e.g., immune, muscle, epithelial); however, improper regulation of epigenetic mechanisms driven by intrinsic or extrinsic influences may lead to malignancies and other human diseases. In the case of HIV, epigenetic changes are driven both by the integration of the HIV provirus and the host inflammatory response, resulting in chronic inflammation and immune activation. HIV integration establishes a latent reservoir of infected cells that serves as the source of new viral particles. Therapeutic approaches that target epigenetic modifications for HIV cure include “block and lock”, which permanently silences HIV pro-viral expression by locking it within heterochromatin, or “kick and kill”, which reverses HIV latency using drugs that target epigenetic mechanisms to activate pro-viral expression in combination with ART treatment to eliminate the reservoir. While these mechanisms are being developed for HIV treatment, there is a significant gap in our knowledge of how epigenetic modifications impact the natural history of HBV infection and influence HBV gene expression, and our understanding of the therapeutic potential of targeting epigenetic modifications on cccDNA and iDNA for HBV cure in the context of PLWH.

Purpose and Research Objectives

The purpose of this Notice of Special Interest (NOSI) is to invite applications for innovative basic, translational, and clinical research to identify and address epigenetic treatment strategies for achieving HBV cure in PLWH. This NOSI will support studies on (1) the epigenetic mechanisms regulating HBV cccDNA and iDNA in the presence of HIV; and (2) targeting epigenetic pathways for achieving 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 of chronic HBV (CHB); (2) Understand mechanisms regulating the epigenetic transcriptional activity of cccDNA and iDNA and epigenetic strategies to silence their activity, which will be applicable towards a cure for CHB; (3) Develop approaches for complete silencing of cccDNA and iDNA for achieving a cure for CHB; and (4) Elucidate the mechanisms underlying epigenetic regulation of cccDNA and iDNA transcription in hepatocytes.

Research topics of interest in the context of epigenetic regulation in PLWH include, but are not limited to:

• Develop therapeutic strategies to silence/eliminate cccDNA and iDNA by targeting epigenetic pathways
• Determine the viral and host epigenetic factors regulating HBV pathogenesis
• Determine the epigenetic gene regulatory mechanisms impacting viral and host genomes in establishing HBV pathogenesis
• Determine how chromosomal positioning and epigenetic features affect the transcriptional activity of cccDNA and iDNA
• Identify molecular functions of HBx that prevent permanent silencing of cccDNA and iDNA
• Determine the role of non-coding RNA (e.g., sncRNAs, lncRNAs) in modulating HBV pathogenesis
• Define the molecular mechanisms for epigenetic factors that favor HBV rebound
• Expand existing knowledge on the role of HBx as a factor underlying the epigenetic regulation of cccDNA and iDNA
• Develop 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

Although clinical trials are not allowed, use of samples from clinical trials is allowed. Animal research is allowed, to include non-human primates.

The areas below will NOT be supported through this NOSI:

• Applications that propose clinical trials (all phases), the establishment of patient cohorts or adding patients to existing cohorts.
• Applications that focus solely on HIV or solely on HBV.
• Applications that focus on hepatitis viruses other than HBV. 

Application and Submission Information

This notice applies to due dates on or after September 7, 2024 and subsequent receipt dates through May 7, 2027.

Submit applications for this initiative using one of the following NOFOs or any reissues of these announcements through the expiration date of this notice.

• PA-20-185 - NIH Research Project Grant (Parent R01 Clinical Trial Not Allowed).
• PA-20-195 - NIH Exploratory/Developmental Research Grant Program (Parent R21 Clinical Trial Not Allowed).
• PA-23-230 - PHS 2023-2 Omnibus Solicitation of the NIH, CDC and FDA for Small Business Innovation Research Grant Applications (Parent SBIR R43/R44] Clinical Trial Not Allowed).
• PA-23-232 - PHS 2023-2 Omnibus Solicitation of the NIH for Small Business Technology Transfer Grant Applications (Parent STTR [R41/R42] Clinical Trial Not Allowed).

All instructions in the SF424 (R&R) Application Guide and the funding opportunity announcement used for submission must be followed, with the following additions:

• For funding consideration, applicants must include “NOT-AI-24-050” (without quotation marks) in the Agency Routing Identifier field (box 4B) of the SF424 R&R form. Applications without this information in box 4B will not be considered for this initiative.

Applications nonresponsive to terms of this NOSI will not be considered for the NOSI initiative.

Inquiries

Please direct all inquiries to the contacts in Section VII of the listed notice of funding opportunity with the following additions/substitutions:

Scientific/Research Contact(s)

Josh Radke, PhD
National Institute of Allergy and Infectious Disease (NIAID)
Telephone: 301-761-6525
Email: [email protected]

Financial/Grants Management Contact(s)

Robert Kirker
National Institute of Allergy and Infectious Diseases (NIAID)
Telephone: 301-451-3176
Email: [email protected]