Investigating Transposable Elements and Mobile DNA as Targets of Integration for Establishing HIV Reservoirs in the Brain (R61/R33 - Clinical Trial Optional) | RFA DA 23 003

Opportunity Information: Apply for RFA DA 23 003

This funding opportunity, RFA-DA-23-003 from the National Institutes of Health, supports research on how transposable elements and other forms of mobile DNA in the brain may shape where HIV integrates and how long-lasting HIV reservoirs become established, particularly in microglia. The core idea is that many substances of abuse, including cocaine, methamphetamine, and several opioids, can act as strong environmental stressors to genomic DNA in the brain. Those insults may trigger the activation of transposable elements and mobile DNA, which together make up nearly half of the human genome. Under typical conditions, these elements are kept silent by epigenetic mechanisms, but drug-induced changes in the brain may loosen that control and increase their activity.

The opportunity is focused on a possible mechanism linking substance use to HIV persistence and neurological disease. If mobile DNA becomes more active in people who use drugs, it may create additional or altered genomic “landing zones” where HIV can integrate within microglia, the brain’s resident immune cells and an important suspected reservoir site. Integration in these unstable or highly active regions could contribute to chromosomal rearrangements and widespread disruption of gene expression. Over time, that kind of genomic instability and transcriptional dysregulation could play a role in HIV-associated Neurocognitive Disorder (HAND). The announcement also emphasizes a related concern: drug-driven activation of these genomic regions might increase the likelihood that latent HIV in microglia is later reactivated, helping explain why substance use can worsen neurological outcomes and complicate long-term HIV control even in the era of antiretroviral therapy.

From a scientific and public health standpoint, the goal is to push the field toward a clearer understanding of the factors that influence HIV integration and persistence in brain-based reservoirs, and how those factors interact with inflammation, substance exposure, and disease progression. By clarifying how HIV, mobile DNA activity, epigenetic regulation, and neuroinflammation intersect, funded studies are expected to generate insights that could inform next-generation HIV therapies and, longer term, cure strategies aimed at eliminating or permanently silencing difficult-to-reach reservoirs in the central nervous system. The clinical trial designation is “optional,” meaning applicants may propose studies with or without a clinical trial component, depending on what is scientifically justified.

The mechanism is an R61/R33 phased innovation award. In general terms, this structure is intended to support high-impact projects that begin with a defined, milestone-driven early stage (R61) and then transition to a second stage (R33) if the project meets predetermined objectives. That design encourages ambitious, potentially transformative work while still requiring clear go/no-go criteria and measurable progress before expanding into the later phase.

Eligibility is broad and includes many types of organizations and institutions. Domestic applicants can include state, county, city, township, and special district governments; public housing authorities; independent school districts; public and private institutions of higher education; federally recognized Native American tribal governments; other Native American tribal organizations; nonprofits with or without 501(c)(3) status (outside of higher education); for-profit organizations (other than small businesses); and small businesses. The announcement also highlights additional eligible applicants such as Historically Black Colleges and Universities, Hispanic-serving Institutions, Alaska Native and Native Hawaiian Serving Institutions, AANAPISIs, Tribally Controlled Colleges and Universities, faith-based or community-based organizations, eligible federal agencies, U.S. territories or possessions, and non-U.S. entities and regional organizations. The program is listed under CFDA 93.279 and falls within the education and health activity category, reflecting its emphasis on biomedical research with clear implications for treatment and prevention of HIV-related neurological complications.

Key administrative details included in the source information are that the opportunity is a discretionary grant from NIH, created on February 11, 2022, with an original closing date of August 3, 2022. The public-facing description does not specify an award ceiling or the expected number of awards in the excerpt provided, but the intent of the initiative is clear: stimulate rigorous, integrative research that explains how drug exposure may alter genomic regulation in the brain in ways that affect HIV integration, reservoir stability, neuroinflammation, and ultimately neurocognitive outcomes.

• The National Institutes of Health in the education, health sector is offering a public funding opportunity titled "Investigating Transposable Elements and Mobile DNA as Targets of Integration for Establishing HIV Reservoirs in the Brain (R61/R33 - Clinical Trial Optional)" and is now available to receive applicants.
• Interested and eligible applicants and submit their applications by referencing the CFDA number(s): 93.279.
• This funding opportunity was created on 2022-02-11.
• Applicants must submit their applications by 2022-08-03. (Agency may still review applications by suitable applicants for the remaining/unused allocated funding in 2026.)
• Eligible applicants include: State governments, County governments, City or township governments, Special district governments, Independent school districts, Public and State controlled institutions of higher education, Native American tribal governments (Federally recognized), Public housing authorities/Indian housing authorities, Native American tribal organizations (other than Federally recognized tribal governments), Nonprofits having a 501 (c) (3) status with the IRS, other than institutions of higher education, Nonprofits that do not have a 501 (c) (3) status with the IRS, other than institutions of higher education, Private institutions of higher education, For-profit organizations other than small businesses, Small businesses, Others.

Apply for RFA DA 23 003

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