Targeting Cellular and Tissue HIV Reservoirs With Toll-Like Receptor Agonists

Abstract

The elimination of both cellular and tissue latent reservoirs is a challenge toward a successful HIV cure. “Shock and Kill” are among the therapeutic strategies that have been more extensively studied to target these reservoirs. These strategies are aimed toward the reactivation of the latent reservoir using a latency-reversal agent (LRA) with the subsequent killing of the reactivated cell either by the cytotoxic arm of the immune system, including NK and CD8 T cells, or by viral cytopathic mechanisms. Numerous LRAs are currently being investigated in vitro, ex vivo as well as in vivo for their ability to reactivate and reduce latent reservoirs. Among those, several toll-like receptor (TLR) agonists have been shown to reactivate latent HIV. In humans, there are 10 TLRs that recognize different pathogen-associated molecular patterns. TLRs are present in several cell types, including CD4 T cells, the cell compartment that harbors the majority of the latent reservoir. Besides their ability to reactivate latent HIV, TLR agonists also increase immune activation and promote an antiviral response. These combined properties make TLR agonists unique among the different LRAs characterized to date. Additionally, some of these agonists have shown promise toward finding an HIV cure in animal models. When in combination with broadly neutralizing antibodies, TLR-7 agonists have shown to impact the SIV latent reservoir and delay viral rebound. Moreover, there are FDA-approved TLR agonists that are currently being investigated for cancer therapy and other diseases. All these has prompted clinical trials using TLR agonists either alone or in combination toward HIV eradication approaches. In this review, we provide an extensive characterization of the state-of-the-art of the use of TLR agonists toward HIV eradication strategies and the mechanism behind how TLR agonists target both cellular and tissue HIV reservoirs.

Agonist and antagonist ligands of toll-like receptors 7 and 8: Ingenious tools for therapeutic purposes

“…The key challenge to cure for HIV-1 infection is represented by the more extensively studied therapeutic strategies known as "Shock and kill". These strategies are aimed toward the reactivation of the latent reservoir using a latency-reversal agent (LRA) with the subsequent killing of the reactivated cell either by the cytotoxic arm of the immune system, including NK and CD8 T cells, or by viral cytopathic mechanisms [155,156]. Borducchi et al show that administration of the V3 glycan-dependent bNAb PGT121 together with GS-9620 during ART delayed viral rebound following discontinuation of ART in simianehuman immunodeficiency virus (SHIV)-SF162P3infected rhesus monkeys in which ART was initiated during early acute infection [157].…”

Extensive proteomic and transcriptomic changes quench the TCR/CD3 activation signal of latently HIV-1 infected T cells

“…TCR/CD3 inertness was not the only functional consequence of the molecular changes that can occur in host cells of latent HIV-1 infected T cells. While we do not detail this phenomenon, we found that TLR pathway signaling can also be impaired (Figure 3), which would have implications for efforts to identify HIV-1 reactivating agents that address the TLR/Myd88 pathway [52][53][54][55][56]. Given that our data detail the dysfunctional nature of latently HIV-1 infected T cells, and the seemingly random nature of observed changes, it needs to be assumed that the further upstream a NF-B activating pathway is targeted, the less likely it is that an efficient, HIV-1 reactivating NF-B signal is being triggered.…”

“…This was also observed at the population level, where flagellin stimulation only triggered HIV-1 reactivation in a fraction of the latently HIV-1 infected T cell population ( Figure 3H). Changes to the host cell signaling network that were induced during HIV-1 infection thus may not be limited to the TCR/CD3 signaling pathway and extend to other activating receptors/pathways that are currently investigated as targets of latency reversing agents (LRA) [52][53][54][55][56].…”

Reduce and Control: A Combinatorial Strategy for Achieving Sustained HIV Remissions in the Absence of Antiretroviral Therapy

“…After binding to their ligands, the TLRs commonly induce activation of NF-κB, AP1 and various interferon regulatory factors (IRFs). Many TLR agonists are now being evaluated as potential LRAs, with agonists of TLR3, TLR7 and TLR9 already advancing into human trials [99]. MGN1703, a TLR9 agonist, induced HIV plasma RNA in 6 of 15 study participants concomitant with increased activation of NK and CD8 T cells, but no reduction in latent reservoir size was observed [100].…”