Multidose vorinostat in HIV-infected individuals on effective ART leads to an increase in regulatory T cells but no change in inducible virus or HIV-specific T cells

Background: Histone deacetylase inhibitors (HDACi) activate HIV transcription in latently infected T-cells in vitro and in HIV infected subjects on suppressive antiretroviral therapy (ART). HDACi have also been reported to have widespread largely suppressive effects on both the innate and adaptive immune response. This study aimed to examine whether administration of 14 days of vorinostat to HIV-infected patients on ART led to a change in inducible virus or adaptive immune response.
Methods: Vorinostat 400mg orally was given daily for 14 days to 20 HIV-infected individuals on ART. Staphylococcal enterotoxin B(SEB) and HIV-gag specific T-cells were measured using intracellular cytokine staining for interleukin(IL)-2, tumor necrosis factor(TNF)-α and interferon(IFN) γ (n=17). Intracellular FoxP3 staining was used to determine percentage of regulatory T-cells (Treg). Integrated HIV-DNA in CD4 T-cells was quantified by nested real time PCR at days 0, 14 and 84. Inducible reservoir was quantified by tat-rev inducible limiting dilution assay (TILDA) in CD4 T-cells stimulated with phorbol myristate acetate (PMA) and ionomycin prior to and following vorinsotat. The frequency of positive cells detected by qPCR for tat-rev multiply spliced (MS)-RNA was calculated using the maximum likelihood method. Significant changes over time were determined by generalised estimating equation (GEE).
Results: There was a significant increase in CD4+ Treg cell at day 14 (p=0.046) which returned to baseline by day 84. SEB-specific CD8 T-cells that produced IFN-γ also increased significantly during and following vorinostat (p=0.026) while there were no significant changes in other SEB-specific CD8+ T-cells and all SEB-specific CD4+ T-cells. There were no significant changes in gag-specific CD4 or CD8 T-cells. We saw no significant change in integrated DNA (n=11) or the frequency of CD4+ T-cells that produced msHIV RNA following mitogen stimulation measured by TILDA (n=7) compared to baseline indicating no change in inducible virus from the latent reservoir following vorinostat.
Conclusions: Administration of vorinostat to HIV-infected patients on ART led to significant potentially adverse immunological changes including an increase in T-regs without any significant change in HIV-specific T-cells. Future strategies to reduce the latent reservoir will require more potent latency reactivating agents and likely combination with immune modulators that boost HIV-specific immunity.

F. Wightman1,2, J.H. Elliot1,2,3, A.E. Solomon1,2, R. Fromentin4, F.A. Procopio4, J. Zeidan4, T. Spelman2, N. Chomont4, P.U. Cameron1,2,3, R.P. Sekaly4, S.R. Lewin1,2,3
1Monash University, Infectious Diseases, Melbourne, Australia, 2Burnet Insitute, Centre for Biomedical Research, Melbourne, Australia, 3Alfred Hospital, Infectious Diseases Unit, Melbourne, Australia, 4VGTI Florida, Port St Lucie, United States