T-cell therapies for HIV: Preclinical successes and current clinical strategies

Abstract

While antiretroviral therapy (ART) has been successful in controlling HIV infection, it does not provide a permanent cure solution, requires lifelong treatment, and HIV+ individuals are left with social dysmorphias such as stigma [1, 2]. The recent application of T cells to treat cancer and viral reactivations post-transplant offers a potential strategy to control HIV infection. It is known that naturally occurring HIV-specific T cells can inhibit HIV initially, but this response is not sustained in the majority of people living with HIV (PLWH). Genetically modifying T cells to target HIV, resist infection, and persist in the immunosuppressive environment found in chronically infected HIV+ individuals might provide a therapeutic solution for HIV. This review focuses on successful pre-clinical studies and current clinical strategies using T cell therapy to control HIV infection and mediate a functional cure solution.

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 .…”

“…In addition to CAR‐T and CAR‐NK cell therapies to treat HIV, autologous HIV‐specific T‐cell therapies are also being pursued and show promise as an HIV functional cure strategy . Virus‐specific T cells can be generated ex vivo from blood‐derived cells including PBMCs or enriched T cells that are incubated with antigen presenting cells (APCs) pulsed with viral‐derived peptides or genetically engineered to express antiviral T cell receptors (TCRs).…”

“…Unfortunately, clinical trials with autologous HIV‐specific T cells, while shown to be safe, have thus far not been successful at achieving long‐term suppression of HIV . While recent advances in ex vivo culturing and expansion of the repertoire of peptides used for T cell expansion including conserved nonescapable epitopes are certain to improve this approach, a method to target these cells into lymphoid follicles where HIV replication is most concentrated is needed.…”

“…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.…”

CRISPR/Cas9 in allergic and immunologic diseases

“…Perhaps the most notable of these has been devising CRISPR/Cas-based systems as possible treatments for HIV infection. There are excellent, recent reviews on this specific topic, but in general, the techniques focus on deleting and/or gene editing of C-C motif chemokine receptor 5 or C-X-C motif chemokine receptor 4 (co-receptors for HIV) and/or reactivating latent HIV infections [38–40]. Chang et al used CRISPR/Cas in induced pluripotent stem cells to develop an in vitro model of Janus kinase 3 (JAK3) deficiency, define a block in T cell development, and subsequently demonstrate restoration of normal T cell development after CRISPR/Cas-mediated correction of the JAK3 deficiency [41].…”