Abstract
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.
Highlights
Antiretroviral therapy (ART) reduces viral load to undetectable levels in the majority of HIV-1-infected patients
The only clone recognizing the HW9 family, TGTGCCATCAGCCTCATGG GCACTGAAGCTTTCTTT (CAISLMGTEAFF), was specific for the HTQGYFPDW consensus epitope which was present in replication-competent virus from 2018 and the NTQGYFPDW escape variant (Figure 3F, Supplementary Data 1). These data demonstrate the feasibility of using a modified ViraFEST analytical platform to identify crossreactive T cell clonotypes in an elite suppressors (ES). This is the first use of the MANAFEST assay to evaluate T cell responses to HIV-1 antigens
ES serve as a model of a T cell-mediated functional cure of HIV
Summary
Antiretroviral therapy (ART) reduces viral load to undetectable levels in the majority of HIV-1-infected patients. HIV elite suppressors (ES) are patients who control viral replication without ART [2]. It may be possible to control the rebound of viremia following the TCR Sequencing-Based Assay for HIV cessation of ART in patients with progressive disease with immunotherapy. One such strategy is the “shock and kill” approach [9], whereby viral replication is induced from within latent reservoirs and endogenously- or exogenously-generated cytotoxic T lymphocytes (CTL) specific for the patient’s own virus (autologous virus) kill infected cells. Several immunotherapeutic approaches have been evaluated to induce CTL killing of infected cells, including dendritic cell-based strategies [10], adoptive transfer of CAR T cells [11], and checkpoint inhibition therapy [12]
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