NIAID will support research that investigates HIV-1 Envelope (Env) cell surface expression and develops approaches that enhance the recognition and elimination of Env-expressing, HIV-1 infected cells through the notice of funding opportunity (NOFO): Targeting Cell Surface HIV Envelope for Cell Elimination (R01, Clinical Trial Not Allowed).
The HIV-1 envelope glycoprotein (Env) is the only viral protein expressed on the surface of infected cells. Env-targeting biologics, such as engineered antibodies/antibody-like molecules, T/natural killer (NK) cell engagers, and chimeric antigen receptor (CAR) T/NK cells, are potential new therapeutics that eliminate HIV-infected cells. On the other hand, HIV-1 has evolved ways to prevent Env-expressing cells from being recognized by Env-specific antibodies and biologics, protecting them from immune clearance.
Recent technological advances open new possibilities to investigate the viral-host interactions that impact Env surface expression, as well as the structural basis for biologic-mediated cell killing. NIAID aims to capture these opportunities to advance HIV-1 Env biology and enhance the elimination of Env-expressing, HIV-infected cells.
Research Objective
The goals of this NOFO are to understand the regulation of Env cell surface expression, explore the structural mechanism of biologic-mediated cell killing, and develop novel approaches to enhance the recognition and elimination of HIV-infected cells with different levels of Env surface expression. This NOFO supports basic research on HIV-1 Env biology, and/or translational research that develops or optimizes biologics, including engineered antibodies/antibody-like molecules, T/NK cell engagers, and CAR design.
Research Areas of Interest
NIAID is interested in the following research areas:
Dynamics and regulation of cell surface Env expression
- Characterize Env density and spatial distribution on the surface of primary infected cells.
- Investigate changes in Env surface expression upon the stimulation of infected cells with antigens, cytokines, or latency reversal agents that reactivate viral gene expression.
- Investigate cellular pathways involved in Env post-translational modification and trafficking.
- Identify host factors that regulate Env surface expression, including target identification for small-molecule modulation of cell surface Env expression.
- Explore approaches to manipulate Env surface expression with small molecules.
Detection and elimination of Env-expressing, HIV-1-infected cells
- Characterize conformation states of cell surface Env.
- Design novel strategies to increase the accessibility of conserved Env epitopes on the cell surface.
- Develop Env-specific reagents or technology to detect or isolate Env expressing, HIV-infected cells from clinical samples.
- Determine the structural basis for biologic-mediated killing with the goal to improve their efficiency and inform structure-based de novo design of Env-targeting biologics.
- Design, optimize, and evaluate next-generation biologics that eliminate HIV-infected cells.
Applications Not Responsive to This NOFO
NIAID considers applications proposing the following research areas to be nonresponsive and will not review them:
- Investigation focused solely on transcriptional control of Env expression.
- Identification of novel latency reversal agents.
- Discovery of new broadly neutralizing antibodies (bnAbs).
- High throughput screening of small molecule inhibitors of virus-host interaction.
Review Criteria Specific to This NOFO
Reviewers will consider criteria specific to this NOFO as part of the three factors to determine scientific merit and provide an overall impact score.
Within Factor 1. Importance of the Research (Significance and Innovation)
- Evaluate the likelihood that the project will increase the fundamental understanding of HIV-1 Env surface expression and dynamics or advance the development of biologics capable of killing HIV-infected cells in vivo.
- As applicable, evaluate the extent to which the application addresses the challenge of killing infected cells with a low-level of Env expression.
Within Factor 2. Rigor and Feasibility (Approach)
- Evaluate the extent to which the complementary approaches have been used to test the hypothesis.
Submission and Award Information
Application budgets are not limited but need to reflect the actual needs of the proposed project. The scope of the proposed project should determine the project period. The maximum project period is 5 years.
Application deadlines follow NIH AIDS standard due dates, i.e., May 7, September 7, and January 7, by 5 p.m. local time of the applicant organization, through January 7, 2028.
Contact Information
Direct any inquiries to NIAID’s scientific/research contact, Dr. Yan Zhou, zhouy16@niaid.nih.gov or 240-485-9785.