In vivo Effects of Romidepsin on T-Cell Activation, Apoptosis and Function in the BCN02 HIV-1 Kick&Kill Clinical Trial

Abstract

Romidepsin (RMD) is a well-characterized histone deacetylase inhibitor approved for the treatment of cutaneous T-cell lymphoma. in vitro and in vivo studies have demonstrated that it is able to induce HIV-1 gene expression in latently infected CD4 + T cells from HIV-1 + individuals on suppressive antiretroviral therapy. However, in vitro experiments suggested that RMD could also impair T-cell functionality, particularly of activated T cells. Thus, the usefulness of RMD in HIV-1 kick&kill strategies, that aim to enhance the immune system elimination of infected cells after inducing HIV-1 viral reactivation, may be limited. In order to address whether the in vitro observations are replicated in vivo, we determined the effects of RMD on the total and HIV-1-specific T-cell populations in longitudinal samples from the BCN02 kick&kill clinical trial (NCT02616874). BCN02 was a proof-of-concept study in 15 early treated HIV-1 + individuals that combined MVA.HIVconsv vaccination with three weekly infusions of RMD given as a latency reversing agent. Our results show that RMD induced a transient increase in the frequency of apoptotic T cells and an enhanced activation of vaccine-induced T cells. Although RMD reduced the number of vaccine-elicited T cells secreting multiple cytokines, viral suppressive capacity of CD8 + T cells was preserved over the RMD treatment. These observations have important implications for the design of effective kick&kill strategies for the HIV-1 cure.

Successful Treatment of a Patient with Brentuximab Vedotin-Refractory ALK-Negative Anaplastic Large Cell Lymphoma with Romidepsin

“…Romidepsin is an oral histone deacetylase inhibitor; its effects on the immune system are not fully understood. Both immune cell-suppressive and -enhancing effects have been reported for romidepsin [13, 14]. In this patient, romidepsin had no impact on the reversal of the CD4/CD8 ratio, although the percentages of both CD4-positive and CD8-positive T lymphocytes decreased after 6 cycles of treatment (Fig.…”

Immune Profiles Identification by Vaccinomics After MVA Immunization in Randomized Clinical Study

“…The anti-vaccine responses were detected by measuring effector cell cytokines in the ICS assay. Briefly, to exclude dead cells, monocytes and B cells, cells were stained with the Live/Dead fixable Violet Dead cell stain kit (Invitrogen), CD14-Pacific Blue, and CD19-V450 and gated in a dump channel as described (20). Additional surface markers were used to study the T-cell lineages (CD3, CD4, and CD8), T-cell activation (CD38 and HLADR), and maturation phenotypes (CD45RA and CCR7).…”

Induction of selective cell death in HIV-1-infected cells by DDX3 inhibitors leads to depletion of the inducible reservoir

“…Some LRAs have also been demonstrated to promote cell death, as seen with benzolactam derivatives that are PKC agonists and induce apoptosis in latent HIV-1-infected cells 65, 66 . A recent report also demonstrated that romidepsin treatment in a clinical trial resulted in an increase in the frequency of apoptotic T cells 67 . Therefore, the link between apoptosis and latency reversal is highly promising to further exploit as a strategy to reactivate the viral reservoir and induce its selective elimination.…”