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In vivo effects of Panobinostat and Romidepsin on HIV-1-specific CD8 T Cell Immunity
Rikke Olesen1, Thomas A. Rasmussen1, Mathias Lichterfeld2, Mette E. Graversen 1, Steffen Leth1, Lars Østergaard1, Ole S. Søgaard1, Martin Tolstrup1
1 Infectious Diseases, Aarhus University Hospital , Aarhus, Denmark. 2 Ragon Institute of MIT, MGH and Harvard, Boston, MA, United States.
Background: We recently showed that the histone deacetylase inhibitors (HDACi) panobinostat (PANO) and romidepsin (ROMI) activates HIV-1 from latency in HIV-1 infected patients on antiretroviral therapy (ART). However, concern has been raised that HDACi may diminish effector functions of CD8 T cells, thus impairing the elimination virus-expressing cells. Here, we evaluated HIV-1-specific CD8 T cell responses during clinical administration of PANO and ROMI.
Methods: In two separate clinical trials, PANO (20 mg per dose) or ROMI (5mg/m2 per dose) were administered to virologically suppressed HIV-1 infected adults on ART. In 14 of 15 PANO-treated and 6 of 6 ROMI-treated patients, cryo-preserved PBMCs isolated pre-HDACi (baseline), on-HDACi, and post-HDACi (follow-up) were analyzed by intracellular cytokine staining (ICS) following stimulation with a HIV-1 Gag peptide pool. Cells were labelled with Near-IR amino reactive dye, surface antibodies (CD4, CD8, CD45RA and CCR7) and IFNγ (ICS) and analyzed on a BD FACSVerse cytometer. Comparisons were performed using Wilcoxon matched-pairs test.
Results: We observed no overall statistical significant changes in total CD8 T cell counts before and after PANO or ROMI treatment. However, during PANO treatment the relative composition of CD8 T cell subsets changed significantly with increased proportions of effector memory (EM) (p=0.005) and central memory CD8 T cells (p=0.03); and decreased proportions of naïve CD8 T cells (p=0.04). These changes had returned to pre-HDACi levels at follow-up. During ROMI treatment we saw no statistical significant change in the CD8 T cell memory subset composition. The majority of HIV-specific cells in all subjects were EM CD8 T cells. In 11 of 14 (79%) PANO-treated patients and 5 of 6 (83%) ROMI-treated patients, we detected IFNγ+ HIV-specific EM CD8 T cells. In these patients, the mean IFNγ+ HIV-specific EM CD8 T cell responses were 0.80% (range 0.12-2.39%) and 0.95% (range 0.86-4.32%) at baseline for PANO- and ROMI-treated subjects, respectively. The frequency of IFNγ+ HIV-specific EM CD8 T cell responses did not change during PANO (p=0.7) or ROMI (p=0.1) treatment or at follow-up (PANO p=0.7, ROMI p=0.8).
Conclusions: In two clinical trials, treatment of HIV-1 infected patients with PANO or ROMI did not decrease the levels of HIV-1-specific EM CD8 T cells. These results provide support for the combination of HDACi and immune-based therapies in HIV-1 eradication trials.