Therapeutic Targeting of HIV Reservoirs: How to Give T Cells a New Direction

Abstract

HIV cannot be cured by current antiretroviral therapy (ART) because it persists in a transcriptionally silent form in long-lived CD4+ cells. Leading efforts to develop a functional cure have prioritized latency reversal to expose infected cells to immune surveillance, coupled with enhancement of the natural cytolytic function of immune effectors, or “kick and kill.” The most clinically advanced approach to improving the kill is therapeutic immunization, which aims to augment or re-focus HIV-specific cytolytic T cell responses. However, no vaccine strategy has enabled sustained virological control after ART withdrawal. Novel approaches are needed to overcome the limitations of natural adaptive immune responses, which relate to their specificity, potency, durability, and access to tissue reservoirs. Adoptive T cell therapy to treat HIV infection was first attempted over two decades ago, without success. Since then, progress in the field of cancer immunotherapy, together with recognition of the similarities in tumor microenvironments and HIV reservoirs has reignited interest in the application of T cell therapies to HIV eradication. Advances in engineering of chimeric antigen receptor (CAR)-transduced T cells have led to improved potency, persistence and latterly, resistance to HIV infection. Immune retargeting platforms have incorporated non-neutralizing and broadly neutralizing antibodies to generate Bispecific T cell Engagers (BiTEs) and Dual-Affinity Re-Targeting proteins (DARTs). T cell receptor engineering has enabled the development of the first bispecific Immune-mobilizing monoclonal T Cell receptors Against Viruses (ImmTAV) molecules. Here, we review the potential for these agents to provide a better “kill” and the challenges ahead for clinical development.

Designed Ankyrin Repeat Protein (DARPin) to target chimeric antigen receptor (CAR)-redirected T cells towards CD4+ T cells to reduce the latent HIV+ cell reservoir

“…One of the major challenges for curing HIV is the elimination of the reservoir of latently infected cells. CAR T cells targeting viral proteins have been investigated for the treatment of HIV infection [17]; however, the latent virus reservoir cannot be completely eliminated by this strategy [18,19]. Since CD4 is the entry receptor for HIV [20], we sought to eliminate CD4 + T cells using a DARPin targeted CAR as a proof-of-concept for complete HIV eradication.…”

CAR T cells: Living HIV drugs

“…scFv; single-chain fragment variable Further, CAR T cell therapy may represent a very useful strategy for targeting CD4 + T cells harboring intact provirus, which are inherently resistant to killing by CD8 + T cells. [47][48][49] In addition, similar to LRAs, cytokine secreting anti-HIV CAR-T cells may reactivate dormant HIV in cells. 50 Similar to other gene-engineered T cells, CAR T cell therapy utilizes healthy T cells that do not exhibit common characteristic features of exhausted T cells typical of HIV-specific T cells.…”

“…50 Similar to other gene-engineered T cells, CAR T cell therapy utilizes healthy T cells that do not exhibit common characteristic features of exhausted T cells typical of HIV-specific T cells. 47 Notably, gene-modified T cells can persist for a long time; therefore safety aspects along with the stability of retroviral vectors and efficient retroviral transduction should be considered for gene therapy for immune reconstruction. 40,51 Compared with other cell types in which retroviral vector engineering introduces risks of oncogenic transformation, CAR T cell products have more stability, potency, and safety, particularly in HIV patients where long-term persistence of treatment is required.…”

“…Given that, it could be helpful to use CAR cells to inhibit some HIV evasion mechanisms of the immune system. Further, CAR T cell therapy may represent a very useful strategy for targeting CD4 + T cells harboring intact provirus, which are inherently resistant to killing by CD8 + T cells 47‐49 . In addition, similar to LRAs, cytokine secreting anti‐HIV CAR‐T cells may reactivate dormant HIV in cells 50 .…”

A Trispecific Anti-HIV Chimeric Antigen Receptor Containing the CCR5 N-Terminal Region

“…These factors are fueling extensive efforts to develop HIV curative approaches that either eradicate the infection from the body ("sterilizing cure") or achieve long-term remission by durably suppressing the virus ("functional cure") (Siliciano and Siliciano, 2016;Davenport et al, 2019;Ndung'u et al, 2019;Peterson and Kiem, 2019). Amongst the diverse HIV cure concepts under development, enhancement/engineering of HIV-specific T cell function is receiving considerable attention (Patel et al, 2016;Yang et al, 2018). A rare subset of individuals, termed "elite controllers, " are able to naturally maintain virus loads below the level of detection in the absence of ART, thanks in large part to their strong HIV-specific CD8+ T cell responses (Goulder and Deeks, 2018).…”