Evolving Strategies to Eliminate the CD4 T Cells HIV Viral Reservoir via CAR T Cell Immunotherapy

Abstract

Although the advent of ART has significantly reduced the morbidity and mortality associated with HIV infection, the stable pool of HIV in latently infected cells requires lifelong treatment adherence, with the cessation of ART resulting in rapid reactivation of the virus and productive HIV infection. Therefore, these few cells containing replication-competent HIV, known as the latent HIV reservoir, act as the main barrier to immune clearance and HIV cure. While several strategies involving HIV silencing or its reactivation in latently infected cells for elimination by immune responses have been explored, exciting cell based immune therapies involving genetically engineered T cells expressing synthetic chimeric receptors (CAR T cells) are highly appealing and promising. CAR T cells, in contrast to endogenous cytotoxic T cells, can function independently of MHC to target HIV-infected cells, are efficacious and have demonstrated acceptable safety profiles and long-term persistence in peripheral blood. In this review, we present a comprehensive picture of the current efforts to target the HIV latent reservoir, with a focus on CAR T cell therapies. We highlight the current challenges and advances in this field, while discussing the importance of novel CAR designs in the efforts to find a HIV cure.

Keywords: CD4; CD8; HIV-1; chimeric antigen receptor; latency; reactivation.

Figure 1

(A) Structure of chimeric antigen receptor. Antigen receptor domains are linked to transmembrane domains and intracellular signalling domains consisting of co-stimulatory domains and CD3ζ by hinge regions. scFvs are common as antigen recognition domains, although ligands can be used to take advantage of ligand-receptor interactions. (B) Evolution of chimeric antigen receptors. Antigen recognition domains are linked to CD3ζ in first generation CARs and activity was improved by addition of co-stimulatory domains in second and third generations. Fourth generation TRUCKs include inducible transcription of transgenes (such as IL-12) to second generation CARs. scFv, single chain variable fragment; CAR, chimeric antigen receptor TRUCK, T cell redirected for universal cytokine killing; bnAb, broadly neutralising antibody; CRD, carbohydrate recognition domain. Created with BioRender. Adapted from Rafiq et al. (78).

Figure 2

Engineering CAR-T cells for improved function. (A) DuoCARs target independent antigens by CAR co-expression. (B) TanCARs adopt a tandem antigen recognition domain to target multiple antigens. (C) CD3ζ and costimulatory domains are split between independent antigen recognition domains in SplitCARs for T cell activation upon recognition of both antigens. (D) Upon recognition of antigen, synNotch receptors undergo transmembrane cleavage and release of their intracellular transcriptional domain which in turn induces the transcription of a secondary CAR for recognition of a second antigen and T cell activation. (E) convertibleCAR, a universal system where the antigen-targeting domain and the T cell signalling unit are split. Effector cells express CARs incorporating NKG2D, the natural receptor of the MIC/ULBP ligand family. MicAbody, comprised of the MICA ligand bound to the scFv of an antibody of interest, is administered separately. (F) DARPin linked to a Cage protein bind to surface antigens. Upon binding of a secondary DARPin linked to a key protein to its antigen, the latch is released exposing Bim to bind to a Bcl-2 CAR. CAR, chimeric antigen receptor; NKG2D, MICA receptor; MICA, NKG2D ligand; DARPin, designer ankyrin repeat proteins. Created with BioRender. Adapted from Guedan et al. (105).