Pursue a goal of eradication of HIV infection through an accessible, interactive and coordinated program that will advance HIV cure research.
- Deliver a robust pipeline for the development, testing, and validation of novel LRAs that are fully characterized with respect to HIV protein or antigen expression from diverse cell populations in vitro and in vivo, their use in combination, and their effect on immune function
- Develop reagents for the recruitment of an effective anti-HIV-1 immune response that can recognize HIV proteins in the context of the latency reversal
- Develop, optimize, and validate assays with a focus on HIV protein antigen detection to support in vitro and in vivo studies
- Execute a platform of studies in animal models and humans that comprehensively evaluates interventions to reverse latency and significantly deplete latent, persistent HIV-1 infection.
CARE Collaboratory is organized around three focuses critical to advance efforts toward HIV-1 eradication.
IRF 1: Detection of HIV Antigen-Positive Cells
IRF 1 will elucidate which LRAs are capable of inducing expression to the extent that viral protein is detected or presented to immune effector mechanisms for clearance. Work will be pursued in parallel, examining known latency reversing agents and comparing these to novel tool compounds emerging from the collaboratory. The LRAs will be tested alone and in combination in relevant in vitro and in vivo models to assess their effectiveness at reversing latency. To facilitate the examination of protein antigen expression, novel tools and reagents are being developed and tested.
IRF 2: Clearance of HIV Antigen-Positive Cells
The development and testing of reagents capable of clearing cells expressing a diversity of viruses from the reservoirs of latent infection. The development of first generation DARTs will be continued. The first generation DARTs effectively mediated CD8+ T-cell clearance of HIV from resting CD4+ T-cell cultures following induction of latent virus expression both with full mitogen activation, but also (critically) after a pharmacologically relevant exposure to the LRA. In addition, further bNAbs and HLA-E peptides suitable for DART construction will be identified, and optimized to create a highly potent 2nd generation DARTs. DARTs alone and in combination with LRA will be studied in relevant in vitro and in vivo systems.
IRF 3: Revealing and Clearing Unseen HIV
Complementary studies in animal model systems and human clinical trials to study latency reversal and clearance of persistent, unseen infection will seek to unify and leverage the insights of IRF 1 and IRF 2 by demonstrating that a combination of cellular effects, induced over time, can allow expression of HIV proteins by latently infected cells in model systems and human studies, and that a sufficient immune response can then clear persistent, latent infection. In parallel, IRF 3 will seek to further advance HIV Cure research by the discovery of the next generation of LRAs so that they can be fed back into IRF 1 to feed the development pipeline of advancing and improving HIV cure interventions.
Scientific Research Support
In addition, three Scientific Resource Supports (SRS) will assist the research of CARE by providing: clinical, translational, and regulatory support (SRS 1); expertise, infrastructure, reagents, and personnel for the conduct of complex in vivo studies in Rhesus Macaques (RM) (SRS 2); and state of the art assays of SIV and SHIV RNA expression, virion production, and viral sequences (SRS 3).
Clinical Sciences SRS 1
SRS 1 seeks to provide essential services to the Collaboratory by providing a reciprocal link between CARE’s translational and basic scientists and HIV-infected study participants, uninfected volunteers, specimens and data, and to support novel translational research in HIV eradication.
Primate Virology SRS 2
SRS 2 aims to support the Collaboratory by consolidating and focusing the preclinical evaluation of novel concepts and products. SRS 2 will provide all the expertise, infrastructure, reagents, and personnel for the conduct of complex in vivo studies in Rhesus Macaques (RM).
Human Virology SRS 3
SRS 3 will provide support toward the measurement of the inducible latent reservoir with state-of-the-art assays monitoring antigen production and induced expression. In addition, SRS 3 will explore complementary assays based on viral sequence complexity, and provide virologic reagents in support of the development of model systems.