Dual TLR2 and TLR7 agonists as HIV latency-reversing agents.

Amanda B Macedo,Vicente Planelles,Camille L Novis,Alberto Bosque,Szu-Han Huang,Adam M Spivak,Caroline M De Assis,Eric S Sorensen,Yanqin Ren,R Brad Jones,Paula Moszczynski

doi:10.1172/jci.insight.122673

Amanda B Macedo, Vicente Planelles + Show 9 more

Open Access

https://doi.org/10.1172/jci.insight.122673

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Abstract

The presence of a reservoir of latently infected cells in HIV-infected patients is a major barrier towards finding a cure. One active cure strategy is to find latency-reversing agents that induce viral reactivation, thus leading to immune cell recognition and elimination of latently infected cells, known as the shock-and-kill strategy. Therefore, the identification of molecules that reactivate latent HIV and increase immune activation has the potential to further these strategies into the clinic. Here, we characterized synthetic molecules composed of a TLR2 and a TLR7 agonist (dual TLR2/7 agonists) as latency-reversing agents and compared their activity with that of the TLR2 agonist Pam2CSK4 and the TLR7 agonist GS-9620. We found that these dual TLR2/7 agonists reactivate latency by 2 complementary mechanisms. The TLR2 component reactivates HIV by inducing NF-κB activation in memory CD4+ T cells, while the TLR7 component induces the secretion of TNF-α by monocytes and plasmacytoid dendritic cells, promoting viral reactivation in CD4+ T cells. Furthermore, the TLR2 component induces the secretion of IL-22, which promotes an antiviral state and blocks HIV infection in CD4+ T cells. Our study provides insight into the use of these agonists as a multipronged approach targeting eradication of latent HIV.

Highlights

Antiretroviral therapy (ART) effectively suppresses HIV replication and converts HIV from a lethal infection to a chronic and manageable disease [1,2,3]
CL413 induced higher levels of TNF-α than each of the agonists, either alone or combined (Supplemental Figure 6A). The ability of these supernatants to reactivate latent HIV in JLAT10.6 correlated with the concentration of TNF-α in the same supernatants (Supplemental Figure 6B). These results indicate that TNF-α is one of the factors secreted by monocytes and plasmacytoid DCs (pDCs) after treatment with TLR2, TLR7, and dual TLR2/7 agonists that promotes viral reactivation from latency
We have characterized in vitro the TLR2 agonist Pam2CSK4, 2 single TLR7 agonists (CL264 and GS-9620), and 4 synthetic dual TLR2/7 agonists (CL401, CL413, CL531, and CL572) (Supplemental Figure 1)

Summary

Introduction

Antiretroviral therapy (ART) effectively suppresses HIV replication and converts HIV from a lethal infection to a chronic and manageable disease [1,2,3]. Long-lived memory CD4+ T cells are thought to be the predominant cell type harboring latent virus [11,12,13] This latent reservoir is able to resume disease progression once ART is interrupted [1, 11, 14, 15]. Current strategies aim to reverse HIV proviral latency using a latency-reversing agent (LRA), allowing the cytotoxic T cell arm of the immune system, or other immunotherapies, to clear residual infected cells. These strategies are collectively referred to as shock-and-kill [16]. Molecules that reactivate HIV and increase immune cell function of effector cells such as CD8+ T cells and NK cells could help with the clearance of latently infected cells [17]

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Conclusion