Impact of IL-15 and latency reversing agent combinations in the reactivation and NK cell-mediated suppression of the HIV reservoir

Abstract

Inhibitors of histone deacetylases (HDACis) are major latency reversing agent (LRA) candidates in ‘shock and kill’ strategies to eradicate the HIV reservoir in infected patients. The poor achievements of initial HDACi-based trials and subsequent studies have highlighted the need for more efficient approaches such as combinatory and immunostimulating therapies. Here we studied combinations of IL-15 with pan-HDACi (Vorinostat, Romidepsin, Panobinostat) or class I selective-HDACi (Entinostat) with or without a PKC agonist (Prostratin) for their impact on in vitro reactivation and NK cell-mediated suppression of latent HIV. Results showed that pan-HDACis but not Entinostat reduced NK cell viability and function; yet, combined IL-15 reverted the negative effects of pan-HDACis except for Panobinostat. All HDACis were ineffective at reactivating HIV in a CD4+ T cell model of latency, with pan-HDACis suppressing spontaneous and IL-15- or Prostratin-induced HIV release, while IL-15 + Prostratin combination showed maximal activity. Moreover, Panobinostat impaired STAT5 and NF-κB activation by IL-15 and Prostratin, respectively. Finally, by using effectors (NK) and targets (latently infected CD4+ T cells) equally exposed to drug combinations, we found that IL-15-mediated suppression of HIV reactivation by NK cells was inhibited by Panobinostat. Our data raise concerns and encouragements for therapeutic application of IL-15/LRA combinations.

IL-15 and N-803 for HIV Cure Approaches

“…Conversely, Jones et al showed increased viral p24 in supernatants from latently infected CD4 T cells in vitro and increased viral RNA in ex vivo CD4 T cell supernatants from ART-suppressed individuals after stimulation with both IL-15 and N-803 alone [ 78 ]. Additionally, reactivation of latent virus with IL-15 has also been observed in a different CD4 T cell model [ 79 ].…”

“…Additionally, ex vivo treatment of HIV-specific CD8 T cells from ART-suppressed PWH with N-803 enhanced the cytotoxicity as measured by IFNγ ELISPOT [ 83 ]. Similarly, IL-15 treatment of NK cells results in enhanced cytotoxicity [ 77 , 84 , 85 , 86 ], killing capacity of HIV-infected cells [ 79 , 84 , 85 , 87 , 88 ], production of IFN-γ [ 89 ], and antibody-dependent cellular cytotoxicity (ADCC) function [ 85 , 86 , 87 , 90 ].…”

HIV-1 transcriptional modulation: novel host factors and prospective therapeutic strategies

“…In-vitro studies using cell line models of HIV-1 latency and ex-vivo studies of patient-derived CD8 þ and CD4 þ T cells has shown promise [111][112][113]. For instance, immune check point inhibitors and cytokine (IL15) associated with protein kinase C agonist (prostratin) led to efficient HIV reactivation followed by natural killer (NK) cell clearance [114]. A similar study using prostratin in combination with a pan-caspase inhibitor successfully induced HIV-1 latency reversal in NK-infected cells [115].…”

Vaccinal effect of HIV-1 antibody therapy: dream or reality?

“…To further exploit this combinatorial approach, it may be necessary to take into account the effect of pan-HDACi on immune cells. For exemple, pan-HDACi have been described to reduce NK cell function, which is not the case with selective HDACi, such as Entinostat [57 ▪ ]. Interestingly, the use of pan-HDACi in combination with IL-15 reversed the negative effects of the former [57 ▪ ].…”

“…For exemple, pan-HDACi have been described to reduce NK cell function, which is not the case with selective HDACi, such as Entinostat [57 ▪ ]. Interestingly, the use of pan-HDACi in combination with IL-15 reversed the negative effects of the former [57 ▪ ]. In addition, the combination of HDACi with distinct LRA might also be of interest, as they have been shown to variably affect HIV reactivation and susceptibility to NK cell-mediated killing of T cells that exit viral latency [58].…”