Combinations of Histone Deacetylase Inhibitors with Distinct Latency Reversing Agents Variably Affect HIV Reactivation and Susceptibility to NK Cell-Mediated Killing of T Cells That Exit Viral Latency

Abstract

The ‘shock-and-kill’ strategy to purge the latent HIV reservoir relies on latency-reversing agents (LRAs) to reactivate the provirus and subsequent immune-mediated killing of HIV-expressing cells. Yet, clinical trials employing histone deacetylase inhibitors (HDACis; Vorinostat, Romidepsin, Panobinostat) as LRAs failed to reduce the HIV reservoir size, stressing the need for more effective latency reversal strategies, such as 2-LRA combinations, and enhancement of the immune responses. Interestingly, several LRAs are employed to treat cancer because they up-modulate ligands for the NKG2D NK-cell activating receptor on tumor cells. Therefore, using in vitro T cell models of HIV latency and NK cells, we investigated the capacity of HDACis, either alone or combined with a distinct LRA, to potentiate the NKG2D/NKG2D ligands axis. While Bortezomib proteasome inhibitor was toxic for both T and NK cells, the GS-9620 TLR-7 agonist antagonized HIV reactivation and NKG2D ligand expression by HDACis. Conversely, co-administration of the Prostratin PKC agonist attenuated HDACi toxicity and, when combined with Romidepsin, stimulated HIV reactivation and further up-modulated NKG2D ligands on HIV+ T cells and NKG2D on NK cells, ultimately boosting NKG2D-mediated viral suppression by NK cells. These findings disclose limitations of LRA candidates and provide evidence that NK cell suppression of reactivated HIV may be modulated by specific 2-LRA combinations.

Valganciclovir as Add-On Therapy Modifies the Frequency of NK and NKT Cell Subpopulations in Disseminated Kaposi Sarcoma Patients

“…In contrast, in vitro, it has been reported that histone deacetylase inhibitors up-modulate the expression of ligands such as NKG2D on NK cells. Thus, it is necessary for NKG2D-mediated viral suppression by NK cells [ 35 , 36 ].…”

“…They were followed up at 12 weeks and divided depending on the received scheme treatment, CT, and MT for this study. The median age for the CT group was 32 (26)(27)(28)(29)(30)(31)(32)(33)(34)(35)(36)(37)(38)(39)(40)(41)(42)(43)(44)(45) years and 34 (27)(28)(29)(30)(31)(32)(33)(34)(35)(36)(37)(38)(39)(40)(41) years for MT group.…”

Negative Regulation and Protective Function of Natural Killer Cells in HIV Infection: Two Sides of a Coin

“…Although LRAs are widely used in the treatment of virus reservoirs, some LRAs can be toxic and damage immune cells ( 121 , 122 ). Many recent studies have explored various LRAs that enhance NK cell function.…”

“…PRO, a protein kinase C agonist, activates NK cells and markedly increases CD69 and CD107a expression ( 122 ). PRO/romidepsin combination treatment was shown to enhance NKG2D-mediated NK cell killing of P24 targets compared with single-drug treatment ( 121 ). TLR agonists also reverse HIV latency and enhance innate antiviral immunity ( 124 ).…”

Advances in HIV Eradication Strategies

“…Clinical trials have shown that some LRAs can effectively activate latently infected cells, but are not able to reduce the size of the latent pool, possibly due to ineffective killing by the HIVspecific cytotoxic T lymphocyte (CTL) response. 45 The lack of specificity of LRAs, coupled with heterogeneity of the repository, leads to limitations in the treatment with LRAs. Therefore, although there have been many studies on the activation of latent reservoirs by various LRAs, there is still a need for screening of efficient and suitable LRAs.…”