Engineering HIV-Specific Immunity with Chimeric Antigen Receptors

Abstract

HIV remains a highly important public health and clinical issue despite many recent advances in attempting to develop a cure, which has remained elusive for most people infected with HIV. HIV disease can be controlled with pharmacologic therapies; however, these treatments are expensive, may have severe side effects, and are not curative. Consequently, an improved means to control or eliminate HIV replication is needed. Cytotoxic T lymphocytes (CTLs) play a critical role in controlling viral replication and are an important part in the ability of the immune response to eradicate most viral infections. There are considerable efforts to enhance CTL responses in HIV-infected individuals in hopes of providing the immune response with armaments to more effectively control viral replication. In this review, we discuss some of these efforts and focus on the development of a gene therapy-based approach to engineer hematopoietic stem cells with an HIV-1-specific chimeric antigen receptor, which seeks to provide an inexhaustible source of HIV-1-specific immune cells that are MHC unrestricted and superior to natural antiviral T cell responses. These efforts provide the basis for further development of T cell functional enhancement to target and treat chronic HIV infection in hopes of eradicating the virus from the body.

Simian Immunodeficiency Virus (SIV)-Specific Chimeric Antigen Receptor-T Cells Engineered to Target B Cell Follicles and Suppress SIV Replication

“…CAR-T cells have shown great promise in treating certain B cell leukemias and lymphomas, and are being actively pursued to treat additional cancers including solid tumors ( 55 – 57 ). Several features make CAR technology particularly appealing in HIV functional cure efforts ( 58 – 61 ). CAR activity is MHC-independent, and thus not compromised by HIV-1 nef-mediated down-modulation of MHC-I in infected cells that facilitates their evasion from conventional cytotoxic T cells ( 62 ).…”

The Use of the Humanized Mouse Model in Gene Therapy and Immunotherapy for HIV and Cancer

“…To test the safety and efficacy of a stem cell-based CAR approach in HIV infection, Zhen et al used the BLT-humanized mouse model and modified HSPCs with a lentiviral vector expressing an anti-HIV CD4-based CAR to determine whether this can result in the generation of mature anti-HIV CAR + CTLs ( 17 ). This anti-HIV CAR is based on utilizing the HIV receptor CD4 molecule that is fused to an internal TCR-signaling domain ( 60 ). Stem cells from fetal liver were modified with anti-HIV CAR-expressing lentiviral vector and infused into NSG mice transplanted with fetal liver and thymus.…”

Targeting reservoirs of HIV replication in lymphoid follicles with cellular therapies to cure HIV

“…CAR‐engineered NK cells are also being explored for the treatment of various hematological and nonhematological cancers . In addition to treating cancers, HIV‐targeting CAR‐T cells and CAR‐NK cells are also being explored as a treatment for HIV . The approach of hematopoietic stem cell transplant with CAR‐transduced stem cell precursors is also being pursued .…”

“…There is a compelling argument to be made that combining HIV‐resistant cell strategies with follicular targeting CAR‐T, CAR‐NK, or virus‐specific CTL strategies may be complimentary and provide superior long‐term suppression of HIV. In fact, HIV‐resistant CAR‐T cells have already been engineered . In two studies, this was achieved by cleverly targeting an anti‐HIV‐CAR gene cassette into the CCR5 locus .…”

“…Many innovative and promising HIV functional cure strategies are currently being developed. These include broadly neutralizing antibodies, bi‐ and tri‐specific antibodies, BIKES, and TRIKES; inactivating HIV in latently infected cells; activating latently infected cells for clearance; creating T cells and macrophages that are resistant to infection; and cellular immunotherapies that target HIV‐replicating cells . Whilst detailed discussion of all of these and other exciting current HIV‐cure strategies are beyond the scope of this mini‐review, here I will focus on the three cell therapy approaches and discuss them in the context of targeting lymphoid follicle reservoirs of HIV replication.…”