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Dual TLR2 and TLR7 agonists as HIV latency-reversing agents
Amanda B. Macedo, … , Vicente Planelles, Alberto Bosque
Amanda B. Macedo, … , Vicente Planelles, Alberto Bosque
Published October 4, 2018
Citation Information: JCI Insight. 2018;3(19):e122673. https://doi.org/10.1172/jci.insight.122673.
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Research Article AIDS/HIV Immunology

Dual TLR2 and TLR7 agonists as HIV latency-reversing agents

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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.

Authors

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

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Figure 1

Dual TLR2/7 agonists induce HIV reactivation in latently infected CD4+ T cells.

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Dual TLR2/7 agonists induce HIV reactivation in latently infected CD4+ T...
(A) Viral reactivation mediated by TLR agonists in JLAT10.6 and JLAT-TLR2. Data represent the mean ± SD of a representative experiment from 3 independent experiments performed in triplicate. (B) Dose-response of Pam2CSK4, Pam3CSK4, CL401, CL413, CL531, and CL572 ranging from 0.1 pM to 1 μM in JLAT-TLR2. Data represent the mean ± SD of a representative experiment from 3 independent experiments preformed in triplicate. (C and D) Reactivation of latent HIV in the Tcm model with IL-2 alone (untreated), IL-2 plus 1 μM of the indicated TLR agonist or αCD3αCD28 (n = 5). (E) Expression of CD69 in total isolated CD4+ T cells treated with the indicated TLR agonist or αCD3αCD28 (n = 3). Data represent the mean ± SD. (F) Percentage of p65 phosphorylation on serine 529 in memory CD4+ T cells after 15 minutes of stimulation with the indicated TLR agonist or PMA (n = 8–10). Data represent the mean ± SD. (G) Spearman’s correlation of the levels of phosphorylated p65 with the normalized reactivation levels in the Tcm model. Data represent the mean ± SD. (H) Reactivation of latent HIV in the Tcm model induced by HODHBt at 100 μM alone or combined with 1 μM Pam2CSK4 or 1 μM CL413; values were normalized relative to αCD3αCD28 (n = 6). *P < 0.05, **P < 0.01 by 2-tailed Wilcoxon’s matched-pairs signed-rank test for all comparisons. ns, not significant.

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