HIV-Specific T Cells Can Be Generated against Non-escaped T Cell Epitopes with a GMP-Compliant Manufacturing Platform

Abstract

Although anti-retroviral therapy (ART) is successful in suppressing HIV-1 replication, HIV latently infected reservoirs are not eliminated, representing a major hurdle in efforts to eradicate the virus. Current strategies to eradicate HIV involve two steps: (1) the reactivation of latently infected cells with latency reversing agents (LRAs) to expose persisting HIV, and (2) the elimination of these cells with immune effectors while continuing ART to prevent reinfection. HIV-specific T cells (HSTs) can kill reactivated HIV-infected cells and are currently being evaluated in early-stage immunotherapy trials. HIV can mutate sequences in T cell epitopes and evade T cell-mediated killing of HIV-infected cells. However, by directing T cells to target multiple conserved, non-escaped HIV epitopes, the opportunity for viral escape can be reduced. Using a good manufacturing practice (GMP)-compliant platform, we manufactured HSTs against non-escape epitope targets (HST-NEETs) from HIV+ and HIV-seronegative donors. HST-NEETs expanded to clinically relevant numbers, lysed autologous antigen-pulsed targets, and showed a polyfunctional pro-inflammatory cytokine response. Notably, HST-NEETs recognized multiple conserved, non-escaped HIV epitopes and their common variants. We propose that HST-NEETs could be used to eliminate reactivated virus from latently infected cells in HIV+ individuals following LRA treatment. Additionally, HST-NEETs derived from HIV-negative individuals could be used post-transplant for HIV+ individuals with hematologic malignancies to augment anti-viral immunity and destroy residual infected cells.

Emerging trends in COVID-19 treatment: learning from inflammatory conditions associated with cellular therapies

“…Virus-specific T cells (VSTs) have been successfully generated against several viruses including cytomegalovirus (CMV), Epstein-Barr virus, adenovirus,[51À55] human herpes virus (HHV)-6, BK polyomavirus (BK), [56] parainfluenza virus, [65] Zika virus, [57] mycobacteria, [58] norovirus, [59] herpes simplex virus (HSV-1), [60] HIV [61] and others. Of these, T cells targeting CMV, Epstein-Barr virus, adenovirus, HHV6, BK virus, parainfluenza and HIV [62] have been tested in patients, with a strong safety profile and many demonstrating promising clinical responses worthy of further clinical evaluation [63].…”

Latency reversal agents modulate HIV antigen processing and presentation to CD8 T cells

“…It will be critical to assess whether HIV epitope presentation is modulated by LRAs after latency reversal ex vivo in latently infected CD4 T cells from patients or in reservoirs in vivo. Improved ex vivo latency models [55,68], streamlined ways to generate or expand epitope-specific CTL [69] and the promising use of immunodeficient mice repopulated with HIV-infected patients' PBMCs [70] or of humanized BLT (bone-marrowliver-thymus) mice in recent latency reversal studies [30] may allow to test how the modulation of peptide presentation by LRAs affects immune responses and could be exploited for reservoir clearance.…”

Virus-Specific T Cell Therapies for HIV: Lessons Learned From Hematopoietic Stem Cell Transplantation

“…Moreover, HXTCs were also capable of controlling the outgrowth of autologous reservoir-derived HIV and, more importantly, clearing resting CD4 + T cell reservoir post LRA treatment in vitro (Sung et al, 2015 ). To further increase the ability of infused T cells to target HIV escape variants, a bivalent mosaic of peptides targeting the regions of Gag and Pol antigens known to be functionally conserved, common in escape variants, and associated with natural immune protection (Ondondo et al, 2016 ) along with the Nef peptide library were used to manufacture T cell products using a similar platform as HXTCs (Patel et al, 2020 ). These HIV-specific T cells targeting non-escape epitopes (HST-NEETs) demonstrated peptide specificity, but their ability to control viral spread remains to be determined.…”

“…These HIV-specific T cells targeting non-escape epitopes (HST-NEETs) demonstrated peptide specificity, but their ability to control viral spread remains to be determined. While a significant proportion of HXTCs or HST-NEETs were likely derived from pre-existing memory T cells in HIV-infected individuals, they can also be generated from seronegative adult or cord blood donors, broadening its applicability in settings such as post-HSCT treatment or third-party VST banks (Patel et al, 2016 , 2018 , 2020 ).…”

“…Obtaining clinically relevant numbers of T cells for infusion often requires multiple rounds of TCR stimulation, which can result in an effector memory (T EM )-enriched cell population lacking CD62L and CCR7 expression (Sung et al, 2018 ; Patel et al, 2020 ). T EM cells have been shown to demonstrate inferior persistence and anti-tumor function in vivo compared to T stem cell memory (T SCM ) or central memory (T CM ) cells (Berger et al, 2008 ; Gattinoni et al, 2011 ).…”