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

Frequently Asked Questions (FAQs)

1) What is the funding opportunity number and sponsor?

The opportunity is RFA-DA-23-003 and it is offered by the National Institutes of Health (NIH).

2) What research topic is this opportunity focused on?

This opportunity 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, with particular attention to microglia.

3) What are transposable elements and mobile DNA in the context of this announcement?

In this announcement, transposable elements and mobile DNA refer to genomic sequences that can become active and move or copy themselves within the genome. The description notes that they collectively make up nearly half of the human genome and are typically kept silent by epigenetic mechanisms.

4) Why does the announcement connect substance use with mobile DNA activity?

The announcement frames substances of abuse (including cocaine, methamphetamine, and several opioids) as strong environmental stressors to genomic DNA in the brain. It suggests these insults may activate transposable elements/mobile DNA by loosening normal epigenetic control, potentially increasing their activity.

5) How could mobile DNA activity affect HIV integration?

The central hypothesis described is that increased mobile DNA activity may create additional or altered genomic "landing zones" that influence where HIV integrates, especially within microglia. Integration in unstable or highly active regions is described as a potential contributor to genomic disruption.

6) Why are microglia emphasized?

Microglia are described as the brain's resident immune cells and an important suspected HIV reservoir site. The opportunity particularly focuses on how HIV integrates and persists in microglia-based reservoirs in the brain.

7) What is the proposed link to HIV persistence and reservoirs?

The opportunity focuses on a possible mechanism linking substance use to HIV persistence: drug-driven activation of mobile DNA may affect HIV integration patterns and contribute to the establishment and stability of long-lasting reservoirs in the brain.

8) How could these mechanisms relate to neurological disease such as HAND?

The announcement describes a pathway where integration in unstable or highly active genomic regions could contribute to chromosomal rearrangements and widespread disruption of gene expression. Over time, this genomic instability and transcriptional dysregulation is described as potentially contributing to HIV-associated Neurocognitive Disorder (HAND).

9) What does the opportunity say about latent HIV reactivation in the brain?

A related concern highlighted is that drug-driven activation of these genomic regions may increase the likelihood that latent HIV in microglia is later reactivated. This is presented as a possible explanation for why substance use can worsen neurological outcomes and complicate long-term HIV control even in the era of antiretroviral therapy.

10) What are the main scientific goals of the funding opportunity?

The stated goal is to move the field toward a clearer understanding of factors that influence HIV integration and persistence in brain-based reservoirs, and how these factors interact with inflammation, substance exposure, and disease progression.

11) What intersecting areas of biology does the announcement encourage applicants to study?

Funded studies are expected to clarify how HIV, mobile DNA activity, epigenetic regulation, and neuroinflammation intersect, especially in the context of substance exposure and central nervous system reservoirs.

12) What kinds of long-term impacts are expected from the research?

The announcement indicates that insights from funded studies 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.

13) Are clinical trials required?

No. The clinical trial designation is listed as "optional," meaning applicants may propose studies with or without a clinical trial component, depending on what is scientifically justified.

14) What funding mechanism is used for this program?

The mechanism is an R61/R33 phased innovation award.

15) How does the R61/R33 phased innovation structure work (in general terms)?

As described, the project begins with a defined, milestone-driven early stage (R61) and transitions to a second stage (R33) if predetermined objectives are met. The structure is intended to support ambitious projects while requiring clear go/no-go criteria and measurable progress before expanding into the later phase.

16) Who is eligible to apply?

Eligibility is broad. Domestic applicants may include various government entities (state, county, city, township, special district), 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.

17) Are specific institution types explicitly encouraged or called out as eligible?

Yes. The opportunity highlights additional eligible applicants such as Historically Black Colleges and Universities (HBCUs), 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, and U.S. territories or possessions.

18) Are non-U.S. organizations eligible?

Yes. The description includes non-U.S. entities and regional organizations among eligible applicants.

19) What is the CFDA number associated with this opportunity?

The program is listed under CFDA 93.279.

20) How is this opportunity categorized in terms of activity area?

It falls within the education and health activity category, reflecting an emphasis on biomedical research with implications for treatment and prevention of HIV-related neurological complications.

21) What type of grant is it?

It is described as a discretionary grant from NIH.

22) When was the opportunity created and what was the original closing date?

The opportunity was created on February 11, 2022, and the original closing date listed is August 3, 2022.

23) Is an award ceiling or the expected number of awards provided in the description?

No. The public-facing excerpt provided does not specify an award ceiling or the expected number of awards.

24) What is the overall purpose or intent of the initiative?

The intent is to stimulate rigorous, integrative research explaining how drug exposure may alter genomic regulation in the brain in ways that affect HIV integration, reservoir stability, neuroinflammation, and neurocognitive outcomes.