Adapting Immunotherapy and Gene Editing Based Strategies for Targeting HIV Reservoirs in the CNS: Potential Benefits and Risks (R01 Clinical Trial Optional) | RFA MH 21 225

Opportunity Information: Apply for RFA MH 21 225

This NIH funding opportunity (RFA-MH-21-225) supports R01 research projects aimed at improving and adapting HIV cure strategies that use immunotherapy and/or gene editing to specifically address HIV reservoirs in the central nervous system (CNS). The program is rooted in the growing recognition that the classic "shock and kill" approach, which tries to wake up latent HIV using latency-reversing agents (LRAs) and then eliminate infected cells, has not been consistently effective on its own. The opportunity is looking for work that goes beyond reactivation and focuses on the harder part: reliably identifying and clearing reservoir cells, especially in the brain, where biology, drug delivery, and safety concerns are different from the rest of the body.

A major emphasis is on immunotherapy-based strategies that could strengthen or redirect immune responses to recognize and eliminate HIV-infected cells after reactivation or as a stand-alone reservoir-targeting approach. Examples specifically highlighted include therapeutic vaccines designed to boost HIV-specific cytotoxic T lymphocyte (CTL) activity, CAR-T cell approaches engineered to target HIV-infected cells, and antibody-based strategies such as broadly neutralizing antibodies. The notice also points to more specialized antibody formats like dual-affinity retargeting antibodies that can bind HIV envelope antigens while also engaging or activating CTLs, essentially bridging immune effector cells to infected targets. In addition, immune checkpoint or immune modulation strategies (for example anti-PD-1 or anti-CTLA-4 approaches) are named as ways to potentially reverse immune exhaustion that can persist even in people on antiretroviral therapy (ART), which may be one reason reservoir clearance remains difficult.

Alongside immunotherapy, the opportunity encourages gene editing and gene excision concepts intended to directly damage or remove proviral HIV DNA in latently infected cells. The announcement calls out platforms such as TALENs and CRISPR/Cas9, with an emphasis on designs that cut highly conserved regions of the integrated HIV genome to reduce viral escape and improve the odds of durable disruption. The overall message is that these technologies are advancing quickly, but much of the field has focused on peripheral reservoirs in blood and lymphoid tissues, leaving open questions about feasibility, delivery, and safety in the CNS.

The CNS focus is a core distinguishing feature. The brain is described as uniquely challenging due to limited access and the need to contend with the blood-brain barrier, which restricts many therapeutics and delivery systems. The opportunity is therefore centered on innovative ways to translate or re-engineer immunotherapy and gene-editing strategies so they can reach, act within, and be evaluated appropriately in the CNS environment. That includes not only efficacy-oriented questions (whether an intervention can meaningfully impact HIV persistence in the brain) but also practical and mechanistic issues like delivery approaches, targeting specificity in CNS cell populations, and how CNS reservoirs may differ from peripheral ones.

Safety and risk assessment in the CNS is also a clear priority. The notice explicitly raises the concern that immunotherapy and gene-editing approaches being explored in clinical trials may carry potential CNS toxicities, and it signals the need to understand those risks. In real terms, that could include neuroinflammation, off-target immune activation, unintended effects of immune checkpoint manipulation in the brain, or gene-editing related risks such as off-target cuts, delivery-vector toxicity, or other neurologic adverse outcomes. Because the CNS is highly sensitive and less forgiving than many peripheral tissues, the opportunity underscores that benefits must be weighed carefully against neurologic risk, and that rigorous CNS-relevant evaluation is important.

Mechanistically and strategically, the grant is positioned to support research that either adapts existing cure concepts for CNS application or generates new approaches specifically designed for the brain compartment. The "clinical trial optional" designation means applicants may propose projects that are strictly preclinical/mechanistic, translational, or that include a clinical trial component, depending on the maturity of the approach and the specific aims. In practice, this allows a wide range of proposals, from CNS-targeted delivery platform development and reservoir measurement approaches, to early-stage human studies assessing feasibility, biomarkers, and safety.

Administratively, this is a discretionary NIH grant mechanism using the R01 activity code, under health-related funding activity categories associated with CFDA numbers 93.242 and 93.853. Eligible applicants are broad and include many types of U.S. governmental entities (state, county, city/township, special districts), public and private institutions of higher education, independent school districts, tribal governments and tribal organizations, public housing authorities/Indian housing authorities, nonprofits with or without 501(c)(3) status, for-profit organizations other than small businesses, and small businesses. The announcement also highlights additional eligible applicant categories such as HBCUs, Hispanic-serving institutions, AANAPISIs, tribal colleges and universities, Alaska Native and Native Hawaiian-serving institutions, faith-based or community-based organizations, U.S. territories or possessions, and non-U.S. (foreign) organizations and regional organizations. The sponsoring agency is the National Institutes of Health, and the original closing date listed for this opportunity was 2021-08-27, with a creation date of 2021-05-24.

In short, the opportunity is about pushing HIV cure science into the CNS arena by adapting immunotherapies and gene-editing tools that are mostly being optimized for peripheral reservoirs, while directly confronting the two issues that tend to limit CNS progress: getting interventions across or around the blood-brain barrier and understanding, anticipating, and measuring neurologic toxicity and other CNS-specific risks.

• 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 (R01 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.)
• 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 21 225

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