Broadly-specific Cytotoxic T Cells Targeting Multiple HIV Antigens Are Expanded From HIV+ Patients: Implications for Immunotherapy

Abstract

Antiretroviral therapy (ART) is unable to eradicate human immunodeficiency virus type 1 (HIV-1) infection. Therefore, there is an urgent need to develop novel therapies for this disease to augment anti-HIV immunity. T cell therapy is appealing in this regard as T cells have the ability to proliferate, migrate, and their antigen specificity reduces the possibility of off-target effects. However, past human studies in HIV-1 infection that administered T cells with limited specificity failed to provide ART-independent, long-term viral control. In this study, we sought to expand functional, broadly-specific cytotoxic T cells (HXTCs) from HIV-infected patients on suppressive ART as a first step toward developing cellular therapies for implementation in future HIV eradication protocols. Blood samples from seven HIV+ patients on suppressive ART were used to derive HXTCs. Multiantigen specificity was achieved by coculturing T cells with antigen-presenting cells pulsed with peptides representing Gag, Pol, and Nef. All but two lines were multispecific for all three antigens. HXTCs demonstrated efficacy as shown by release of proinflammatory cytokines, specific lysis of antigen-pulsed targets, and the ability to suppress HIV replication in vitro. In conclusion, we are able to generate broadly-specific cytotoxic T cell lines that simultaneously target multiple HIV antigens and show robust antiviral function.

Natural killer cells in HIV-1 infection and therapy

“…Alternatively, a potent NK cell-mediates anti-HIV-1 activity can be achieve through recombinant chimeric antigen receptor (CAR) engineering. CAR T cells therapy are increasingly demonstrating success for the treatment of cancers and have been proposed for use in combating HIV-1 viral reservoirs [184, 185]. The efficacy of CAR-expressing NK cells in cancer treatment is currently being tested at the pre-clinical stage [186], In this regard, the possible use of CAR-NK cells to treat HIV-1 infection by implementing the technology of hESC- and/or iPSC-derided NK cells is currently being debated [183].…”

HIV-specific CD8+ T cells and HIV eradication

“…CD8 + T cell effector activity can be substantially enhanced by short-term expansion with HIV antigens (8, 102,108). Successful in vitro demonstrations of the shock-and-kill concept have utilized such expanded HIV-specific CD8 + T cell lines (8, 102) and can be replicated in vivo by administering therapeutic vaccines aimed at boosting cellular immunity prior to administering LRAs (reviewed in ref.…”

Latent HIV reservoirs exhibit inherent resistance to elimination by CD8+ T cells

“…HIV-specific T cells were expanded and generated as previously described (75). Additional details are provided in the Supplemental Methods.…”