INSPIRE: Innovative Strategies for Personalized Immunotherapies and Reservoir Eradication

/ABSTRACT Antiretroviral therapy (ART) is highly effective against HIV-1 and has saved millions of lives. However, ART is not curative, and people living with HIV (PWH) require life-long therapy because they harbor integrated replication-competent proviruses that quickly fuel rebound when ART is discontinued. This reservoir of infected cells represents the major barrier to long-term ART-free HIV-1 control, and interventions aimed at decreasing or eliminating them remains a priority. A growing body of evidence shows that the intact, rebound-competent HIV- 1 reservoirs evolve over time in response to ongoing immunologic pressure. Importantly, reservoir composition, integration landscapes and transcriptional activity are variable among PWH. These observations highlight the need for tools to carefully characterize bona fide reservoirs and identify key drivers of persistence to tailor approaches that are more likely to effectively perturb reservoirs, and prevent the return of viremia upon ART cessation. The object of the proposed program – “INSPIRE: Innovative Strategies for Personalized Immunotherapies and Reservoir Eradication” – is to tailor a combination of immunologic approaches that disrupt latency and enhance cellular and humoral responses to effectively control or eliminate rebound competent reservoirs in vivo. The program will leverage new methods our groups developed to generate engineered and authentic reservoir CD4+ T-cells clones and engineer B cells to produce broadly neutralizing anti-HIV-1 antibodies. We will use the newly available technologies to characterize reservoirs of PWH, to define the rules governing susceptibility of silent or transcriptionally active intact proviruses to latency reversal and cell-mediated killing, and perform proof of concept experiments to suppress SHIV-1 infection long-term in the absence of ART. These technologies will be applied to categorize ‘reservoir types’ and to select interventions most likely to eliminate reservoir clones in an individual or individuals with similar ‘reservoir types’. Our program is structured in three Research Focus Areas: (1) Apply and improve platforms to isolate authentic clones of CD4+ T-cells carrying latent HIV-1 proviruses and produce engineered reporter CD4+ T-cell clones representing varied responses to bNAb therapy and use these reagents to tailor therapeutic strategies, including the selection of new clinically viable latency reserving agents, (2) Assess elimination of reservoir clones by tailored cytotoxic T lymphocytes (CTL)- and natural killer (NK)-based approaches and link to in vivo impact of broadly neutralizing antibody (bNAb) treatment, and (3) Engineer long-lasting, high-level expression of bNAbs to control established simian-human immunodeficiency virus (SHIV) infections as proof of concept towards tailored HIV-1 control. Project Number: 1UM1AI191237-01 | Fiscal Year: 2025 | NIH Institute/Center: National Institute of Allergy and Infectious Diseases (NIAID) | Principal Investigator: R. Brad Jones (+2 co-PIs) | Institution: WEILL MEDICAL COLL OF CORNELL UNIV, NEW YORK, NY | Award Amount: $2,948,452 | Activity Code: UM1 | Study Section: Special Emphasis Panel[ZAI1 KSW-A (J1)] View on NIH RePORTER: https://reporter.nih.gov/project-details/1UM1AI19123701