Non-human Primate (NHP Core)

University Of Pennsylvania, Philadelphia PA

Investigators

Abstract

Abstract Core C provides the nonhuman primate (NHP) resources and related expertise in support of the P01 proposal, “Immunoengineering Durable Control of HIV replication”. Led by Drs. Paiardini at the Emory National Primate Research Center (EPC) and Kiem at the Washington National Primate Research Center (WaNPRC), the Core will utilize simian-human immunodeficiency virus (SHIV)-infected, antiretroviral therapy (ART)-treated rhesus macaques (RMs) as a pathogenic, immunocompetent model to characterize the utility of autologous chimeric antigen receptor (CAR) immune cells and hematopoietic stem cells (HSCs) as approaches to cure HIV. By performing an ART analytical therapy interruption (ATI), the proposed NHP studies will evaluate the efficacy of these CAR-based approaches to prevent viral rebound or facilitate long-term viral control in the absence of ART. In NHP studies performed at EPC, mRNA-LNP CAR therapy will be performed in combination with mRNAs encoding molecules to enhance the killing capacity of and redirect CAR T cells to immune-privileged anatomical sites to efficiently intercept viral recrudescence at ATI (Project 2); whereas, in Project 3 HIV-specific Dual CAR T cells with enhanced sensitivity, function and persistence will be infused. These studies will be done side by side utilizing the same control cohort so additional information will be obtained from comparing the ability of each of these strategies to reduce the reservoir and control viral rebound. Project 4 will perform its studies at WaNPRC where Dr. Kiem has considerable experience developing stem cell therapies. Here, the investigators will adapt a therapeutic approach to cure all blood related cancers to also curing HIV as well. The Gill lab has developed a base editing strategy that alters an epitope in CD45 that prevents CD45-specific CAR T cells from binding and alters the start codon of CCR5, preventing its translation. These edits are performed in stem cells and CD45-specific CAR T cells and infused into NHPs. The CD45 specific CAR T cells will remove the non- base edited immune system, providing an innovative and effective way of removing the reservoir. Together, Projects 2-4 provide insight into how CARs can be used to eliminate the reservoir and cure HIV. Core C will direct highly innovative and clinically relevant studies for HIV eradication and control in the absence of ART. Functions of Core C will include NHP assignment, per diem support, oversight, and clinical management of NHPs; processing and distribution of tissue specimens; and support of ex vivo immunologic and virologic assays. Implementation of the proposed NHP studies will be performed in close collaboration with the investigators of Projects 2, 3, and 4, and data from these studies will provide critical insights on therapeutic safety and efficacy per translating to clinical trials aimed at HIV cure.