A Subset of Latency-Reversing Agents Expose HIV-Infected Resting CD4⁺ T-Cells to Recognition by Cytotoxic T-Lymphocytes

Resting CD4⁺ T-cells harboring inducible HIV proviruses are a critical reservoir in antiretroviral therapy (ART)-treated subjects. These cells express little to no viral protein, and thus neither die by viral cytopathic effects, nor are efficiently cleared by immune effectors. Elimination of this reservoir is theoretically possible by combining latency-reversing agents (LRAs) with immune effectors, such as CD8⁺ T-cells. However, the relative efficacy of different LRAs in sensitizing latently-infected cells for recognition by HIV-specific CD8⁺ T-cells has not been determined. To address this, we developed an assay that utilizes HIV-specific CD8⁺ T-cell clones as biosensors for HIV antigen expression. By testing multiple CD8⁺ T-cell clones against a primary cell model of HIV latency, we identified several single agents that primed latently-infected cells for CD8⁺ T-cell recognition, including IL-2, IL-15, two IL-15 superagonists (IL-15SA and ALT-803), prostratin, and the TLR-2 ligand Pam₃CSK₄. In contrast, we did not observe CD8⁺ T-cell recognition of target cells following treatment with histone deacetylase inhibitors or with hexamethylene bisacetamide (HMBA). In further experiments we demonstrate that a clinically achievable concentration of the IL-15 superagonist ‘ALT-803’, an agent presently in clinical trials for solid and hematological tumors, primes the natural ex vivo reservoir for CD8⁺ T-cell recognition. Thus, our results establish a novel experimental approach for comparative evaluation of LRAs, and highlight ALT-803 as an LRA with the potential to synergize with CD8⁺ T-cells in HIV eradication strategies.United States. National Institutes of Health (AI111860

Fifth European Dirofilaria and Angiostrongylus Days (FiEDAD) 2016

Peer reviewe

REiNS: Genotype-Phenotype Correlations in Neurofibromatosis and Their Potential Clinical use

Objective:As clinically validated biomarkers for neurofibromatosis 1 (NF1) and neurofibromatosis 2 (NF2), have not been identified to date, we wanted to determine whether genotype-phenotype correlations are usefull in clinical trials in Neurofibromatosis 1 and 2Methods:The biomarker group first performed a systematic literature search and reviewed existing data on genetic biomarkers in NF1 and NF2 and in in malignant peripheral nerve sheath tumours (MPNST). The group then met during a series of consensus meetings to develop a joint report.Results:We found that In NF2 the genetic severity score is clearly of potential clinical use. In NF1 despite over 3000 constitutional variants having been described in the NF1 gene, only four actionable genotype phenotype correlations currently exist. The diagnosis and treatment decision of these tumours should ideally include histopathology and compilation of some of the genetic markersConclusion:We summarized emerging clinical use of genotype-phenotype correlations in Neurofibromatosis.</jats:sec

Analysis

This report has been prepared by staff members of th