HDAC inhibition induces HIV-1 protein and enables immune-based clearance following latency reversal
Guoxin Wu, … , Daria J. Hazuda, Bonnie J. Howell
Guoxin Wu, … , Daria J. Hazuda, Bonnie J. Howell
Published August 17, 2017
Citation Information: JCI Insight. 2017;2(16):e92901. https://doi.org/10.1172/jci.insight.92901.
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Research Article AIDS/HIV Infectious disease

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

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

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Figure 3

Clinical administration of HDACis induces HIV protein expression in ART-suppressed subject CD4+ T cells.

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Clinical administration of HDACis induces HIV protein expression in ART-...
(A–C) In vivo vorinostat administration induces p24 expression in CD4+ T cells following 1, 2 (A), or 10 (B) doses of vorinostat administered clinically every 72 hrs (refs. 7, 9; see ref. 34 for cell-associated HIV RNA levels corresponding to single and paired VOR dosing), and (C) for 10-dose VOR. (D) Clinical administration of panobinostat resulted in statistically significant increase in p24 above baseline, ***P < 0.001 student’s t test (see ref. 10 for RNA data; open circle represents 1 fg/ml p24, a value below analytical limit of detection [LOD]). (E) Comparison of post-/pre-HDACi ratios of mean cell-associated (ca) HIV gag RNA copies/ml and gag protein fg/ml following clinical administration of vorinostat (open squares) or panobinostat (closed circles), with statistical significance determined using linear regression (P < 0.01). n = 11. Note, subject V-1 was the only participant who was not observed to have an induction of ca-RNA (40) after VOR administration, although an increase of cell-associated p24 was detected. If this data point was excluded (asterisk), the correlation between induction of cell-associated p24 and ca-HIV RNA would be even more significant.