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.
Highlights
The combinatorial antiretroviral therapy (ART) against HIV effectively suppresses viral replication but does not eliminate integrated provirus that persists in a small fraction of latently infected cells, mainly resting CD4+ T lymphocytes [1,2,3]
We used the J1.1 T cell line latently infected with HIV to investigate the simultaneous effect on virus reactivation and NKG2DLs expression of 2-drug combinations composed of one histone deacetylase inhibitors (HDACis) (VOR, ROM, PAN) and a mechanistically distinct latency-reversing agents (LRAs) including a protein kinase C agonists (PKCa) (PRO), a proteasome inhibitor (BOR), and a TLR-7 agonist (GS-9620)
Combining VOR, ROM, or PAN with BOR significantly increased the frequency of p24+ cells induced by each LRA used one at a time, indicating the existence of a general cooperative interaction between HDACis and BOR
Summary
The combinatorial antiretroviral therapy (ART) against HIV effectively suppresses viral replication but does not eliminate integrated provirus that persists in a small fraction of latently infected cells, mainly resting CD4+ T lymphocytes [1,2,3]. HIV reservoirs through pharmacologic viral reactivation and killing of cells harbouring reactivated virus by a combination of host immune responses, viral cytopathic effects, and ART. For this approach, referred to as ‘shock-and-kill’, a plethora of compounds functioning as latency-reversing agents (LRAs) have been identified [4,5,6]. Reflecting the complexity of mechanisms that contribute to suppress HIV expression in latently infected cells (i.e., epigenetic, transcriptional, and post-transcriptional mechanisms) [7], candidate LRAs belong to distinct functional categories that include, but are not limited to: histone deacetylase inhibitors (HDACi), protein kinase C agonists (PKCa), Toll-like receptor agonists (TLRa), and activators of the PI3K/Akt pathway. Administration to ART patients of an HDACi such as Vorinostat (VOR), Romidepsin (ROM), or Panobinostat (LBH589; PAN), of the PI3K/Akt activator
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