A T Cell Receptor Sequencing-Based Assay Identifies Cross-Reactive Recall CD8+ T Cell Clonotypes Against Autologous HIV-1 Epitope Variants

• Main Authors: Hok Yee Chan, Jiajia Zhang, Caroline C. Garliss, Abena K. Kwaa, Joel N. Blankson, Kellie N. Smith
• Format: Article
• Language: English
• Published: Frontiers Media S.A. 2020-04-01
• Series: Frontiers in Immunology
• Subjects: HIV; cure; elite suppressors; elite controllers; clonotype; CD8 lymphocytes+
• Online Access: https://www.frontiersin.org/article/10.3389/fimmu.2020.00591/full

HIV-1 positive elite controllers or suppressors control viral replication without antiretroviral therapy, likely via CTL-mediated elimination of infected cells, and therefore represent a model of an HIV-1 functional cure. Efforts to cure HIV-1 accordingly rely on the existence or generation of antigen-specific cytotoxic T lymphocytes (CTL) to eradicate infected cells upon reversal of latency. Detecting and quantifying these HIV-1-specific CTL responses will be crucial for developing vaccine and T cell-based immunotherapies. A recently developed assay, called MANAFEST, uses T cell receptor (TCR) Vβ sequencing of peptide-stimulated cultures followed by a bioinformatic pipeline to identify neoantigen-specific T cells in cancer patients. This assay is more sensitive than conventional immune assays and therefore has the possibility to identify HIV-1 antigenic targets that have not been previously explored for vaccine or T cell immunotherapeutic strategies. Here we show that a modified version of the MANAFEST assay, called ViraFEST, can identify memory CD8+ T cell responses against autologous HIV-1 Gag and Nef epitope variants in an elite suppressor. Nine TCR Vβ clonotypes were identified and 6 of these were cross-reactive for autologous variants or known escape variants. Our findings are a proof of principle that the ViraFEST assay can be used to detect and monitor these responses for downstream use in immunotherapeutic treatment approaches.