Adapting Immunotherapy and Gene Editing Based Strategies for Targeting HIV Reservoirs in the CNS: Potential Benefits and Risks (R21 Clinical Trial Optional) | RFA MH 21 226

Opportunity Information: Apply for RFA MH 21 226

This NIH funding opportunity (RFA-MH-21-226) is an R21 grant designed to support early-stage, high-impact research on how newer HIV cure strategies, specifically immunotherapy and gene-editing approaches, might be adapted to reach and address HIV reservoirs in the central nervous system (CNS). It is explicitly positioned as a companion to a related, larger R01 opportunity (RFA-MH-21-225), and it reflects a growing consensus in the field that the traditional "shock and kill" approach, which relies on latency-reversing agents (LRAs) to reactivate dormant HIV in people on antiretroviral therapy (ART), is unlikely to be sufficient on its own. The core scientific motivation is that even if latent virus is reactivated, the immune system or other clearance mechanisms may still fail to recognize and eliminate infected cells effectively, particularly in immune-privileged or hard-to-access compartments like the brain.

A central theme of the announcement is the push beyond LRA-only strategies toward combination or next-generation approaches that improve the identification and destruction of reservoir cells. On the immunotherapy side, the opportunity highlights several lines of work that could strengthen HIV-specific immune clearance, including therapeutic vaccines intended to boost HIV-specific cytotoxic T-lymphocyte (CTL) responses, engineered cellular therapies such as CAR-T cells, broadly neutralizing antibodies, and dual-affinity retargeting antibodies that both bind HIV envelope targets and recruit or activate CTL activity. It also calls attention to immune modulators, such as checkpoint inhibitors (for example, targeting PD-1 or CTLA-4 pathways), which are being explored as ways to counteract immune exhaustion that can persist even in ART-treated individuals. On the gene-editing side, the focus is on targeted excision or disruption of the integrated proviral genome using technologies such as TALENs or CRISPR/Cas9, particularly designs that cut at highly conserved regions of HIV to reduce the chance of viral escape. The announcement frames these approaches as promising, but notes that much of the existing development has emphasized peripheral reservoirs rather than CNS sites.

The CNS is treated here as both a critical reservoir and a unique translational obstacle. The opportunity emphasizes that the brain is difficult to access due to the blood-brain barrier and other delivery constraints, so applicants are expected to think creatively about strategies that could overcome those barriers or otherwise meaningfully impact HIV persistence in the CNS. At the same time, the funding opportunity underscores risk: because immunotherapies and gene-editing systems can produce inflammatory effects, off-target activity, or immune-related adverse outcomes, there is a strong interest in understanding potential CNS-specific toxicities. In practice, that means projects can be oriented not only toward efficacy and delivery concepts, but also toward careful evaluation of neurologic safety concerns, including the possibility that interventions being tested or proposed for systemic cure could have unintended consequences in the brain.

Administratively, this is a discretionary NIH grant mechanism under the R21 exploratory/developmental format, with clinical trials listed as optional. The award ceiling is $200,000, and the original closing date listed is 2021-08-27. The opportunity falls under health-related funding activity categories and is associated with CFDA numbers 93.242 and 93.853. Eligibility is broad and includes many types of U.S. organizations and governments (state, local, tribal, public housing authorities), higher education institutions (public and private), nonprofits (with or without 501(c)(3) status), for-profit organizations (other than small businesses), and small businesses, along with additional specified groups such as HBCUs, Hispanic-serving institutions, AANAPISI institutions, tribally controlled colleges and universities, faith-based or community-based organizations, U.S. territories or possessions, and even non-U.S. (foreign) entities and regional organizations. Overall, the grant is aimed at accelerating practical, innovative, and safety-conscious research that helps the field understand how to bring immunotherapy and gene-editing HIV cure strategies into the CNS context, where both potential benefits and neurologic risks need to be clearly defined.

• The National Institutes of Health in the health sector is offering a public funding opportunity titled "Adapting Immunotherapy and Gene Editing Based Strategies for Targeting HIV Reservoirs in the CNS: Potential Benefits and Risks (R21 Clinical Trial Optional)" and is now available to receive applicants.
• Interested and eligible applicants and submit their applications by referencing the CFDA number(s): 93.242, 93.853.
• This funding opportunity was created on 2021-05-24.
• Applicants must submit their applications by 2021-08-27. (Agency may still review applications by suitable applicants for the remaining/unused allocated funding in 2026.)
• Each selected applicant is eligible to receive up to $200,000.00 in funding.
• 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 MH 21 226

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