HDAC inhibition induces HIV-1 protein and enables immune-based clearance following latency reversal

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Abstract

Promising therapeutic approaches for eradicating HIV include transcriptional activation of provirus from latently infected cells using latency-reversing agents (LRAs) and immune-mediated clearance to purge reservoirs. Accurate detection of cells capable of producing viral antigens and virions, and the measurement of clearance of infected cells, is essential to assessing therapeutic efficacy. Here, we apply enhanced methodology extending the sensitivity limits for the rapid detection of subfemtomolar HIV gag p24 capsid protein in CD4+ T cells from ART-suppressed HIV+ individuals, and we show viral protein induction following treatment with LRAs. Importantly, we demonstrate that clinical administration of histone deacetylase inhibitors (HDACis; vorinostat and panobinostat) induced HIV gag p24, and ex vivo stimulation produced sufficient viral antigen to elicit immune-mediated cell killing using anti-gp120/CD3 bispecific antibody. These findings extend beyond classical nucleic acid endpoints, which are confounded by the predominance of mutated, defective proviruses and, of paramount importance, enable assessment of cells making HIV protein that can now be targeted by immunological approaches.

Authors

Guoxin Wu, Michael Swanson, Aarthi Talla, Donald Graham, Julie Strizki, Daniel Gorman, Richard J.O. Barnard, Wade Blair, Ole S. Søgaard, Martin Tolstrup, Lars Østergaard, Thomas A. Rasmussen, Rafick-Pierre Sekaly, Nancie M. Archin, David M. Margolis, Daria J. Hazuda, Bonnie J. Howell