This Funding Opportunity Announcement (FOA) invites research grant applications that propose studies for adapting immunotherapy and gene therapy-based strategies to target viral reservoirs in the central nervous system (CNS) and examine the potential risks of applying such technologies to the brain. Basic and translational research in domestic and international settings are of interest. Multidisciplinary research teams and collaborations are encouraged but not required. High risk/high payoff projects that lack preliminary data may be most appropriate for the companion R21 FOA, RFA-MH-21-226, while applicants with preliminary data may wish to apply using the R01 mechanism.
Eradication of latent reservoirs of HIV-1 within the body and achieving a sterilizing or functional cure is a high priority research area. Anti-retroviral therapy (ART) can effectively block HIV-1 viral replication and prevent or reverse immunodeficiency in infected individuals but does not eliminate the virus due to the presence of latent reservoirs. There is now a major push in the field of HIV research to target latent reservoirs to achieve sustained virologic remission.
The “shock and kill” strategy is one of the commonly used approaches for targeting latent reservoirs in hopes of curing HIV-1. It is based on reactivation of latent reservoirs in ART-treated individuals by using stimulatory agents and immune targeting for virus elimination. However, it has become increasingly evident that attempts at elimination of HIV-1 reservoirs through latency reactivating agents (LRA) alone may not be sufficient. Novel strategies such as immunotherapy and gene editing to optimize the elimination of latent HIV reservoirs are being developed as described below.
T-cell therapy products, including engineered products, are currently being explored for HIV cure approaches. Chimeric antigen receptor (CAR) T-cells, have shown remarkable clinical success in a number of cancers, such as B-cell lymphomas. CAR-T-cells are being developed to target HIV infected cells and there is the potential to endow these CARs with antigen-recognition domains that will be difficult, for HIV to escape through mutations. CAR T-cells have the potential to contribute to either functional or sterilizing cures for HIV.
Another unconventional population of T-cells, gamma delta (γδ) T-cells, which share features of both conventional aß CD8+ T cells and natural killer (NK) cells are a highly cytotoxic T-cell subset. The γδ T-cells do not appear to require antigen processing and MHC (major histocompatibility complex) presentation of HIV epitopes to recognize infected cells. Ex vivo, γδ T-cells have been demonstrated to clear autologous HIV-infected CD4+ T-cells following latency reversal with vorinostat. Although the exact mechanisms of γδ T-cell recognition of HIV-infected cells are not fully elucidated, immunotherapy with γδ T-cells is another strategy that is being considered for sterilizing or functional cure for HIV.
There is growing interest in cells considered part of the innate immune system, particularly NK cells. NK cells have the potential to destroy virus-infected cells by several mechanisms, including the identification of generic signs of cellular distress or infection, or via antibody-mediated recruitment to a target cell (antibody-dependent cellular cytotoxicity/ADCC). Moreover, these cells release cytokines leading to the activation of cytotoxic lymphocytes (CTLs) and dendritic cells (DCs), contributing to efficient viral elimination. In addition, CAR-NK (chimeric antigen receptor-natural killer) cell-based antiviral therapies with the ability of antigen recognition have emerged as novel approaches for targeting HIV reservoirs.
Anti-HIV-1 broadly neutralizing antibodies (bNAbs) are also being explored in cure strategies in addition to their direct antiviral activity and potential role in HIV-1 prevention and treatment,. Antibodies are among the key modulators of immunity and differ from ART in that they can recruit immune effector functions through their Fc domains. Antibodies accelerate clearance of viruses and infected cells, and antigen-antibody immune complexes are potent immunogens that can foster development of host immune responses. HIV-specific bNAbs can be administered via passive immunization, and single as well as repeated administrations are generally well tolerated. Another strategy is long-term vector-mediated delivery, such as through the use of recombinant adeno-associated virus (rAAV) vectors or other DNA-based delivery systems which may allow for durable control of viremia. In addition engineered eCD4-IgG, bispecific-antibodies (bsAbs) and tri-specific antibodies (tsAbs) provide promising alternative to bNAb combination therapy by targeting multiple epitopes on the Env protein. These approaches may provide increased breadth to overcome HIV’s diversity and to cover natural resistance.
Enhancing T-cell, NK cell function and antiviral immunity using immunomodulatory molecules is an option explored for targeting HIV infected cells. Another promising approach is the use of therapeutic vaccines since they can engage both cellular and humoral immunity, re-educating the host immune response to induce durable immune-mediated viral control potentially reducing HIV reservoirs.
In addition to immunotherapy strategies, in recent years, gene editing strategies have been used for targeting HIV reservoirs in latently infected cells. The three main nuclease-mediated gene editing tools such as transcription activator-like nucleases (TALENs), zinc finger nucleases (ZFNs), and clustered regularly interspaced short palindromic repeat (CRISPR)/CRISPR-associated nuclease 9 (Cas9) are examples of such strategies being used for targeting peripheral HIV reservoirs.
As described above, extensive research efforts involving immunotherapy and genetic editing approaches are ongoing to achieve remission of HIV from cellular and anatomic reservoirs. Current immunotherapy and gene-editing based HIV eradication strategies are focused on the periphery and it is important to target CNS reservoirs as well. The brain presents a unique challenge where access is difficult and innovative strategies are needed to overcome the blood brain barrier. It is also important to understand the potential CNS toxicity of immunotherapy-and gene-editing based approaches currently being tested in clinical trials.
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