Dual TLR2 and TLR7 agonists as HIV latency-reversing agents.
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.
['Macedo|Amanda B|AB|', 'Novis|Camille L|CL|', 'De Assis|Caroline M|CM|', 'Sorensen|Eric S|ES|', 'Moszczynski|Paula|P|', 'Huang|Szu-Han|SH|', 'Ren|Yanqin|Y|', 'Spivak|Adam M|AM|', 'Jones|R Brad|RB|', 'Planelles|Vicente|V|', 'Bosque|Alberto|A|']
D000293:Adolescent D000328:Adult D000368:Aged D019380:Anti-HIV Agents D015496:CD4-Positive T-Lymphocytes D003713:Dendritic Cells D004353:Drug Evaluation, Preclinical D005260:Female D015658:HIV Infections D015497:HIV-1 D006801:Humans D007378:Interleukins D019169:Jurkat Cells D055666:Lipopeptides D008297:Male D008875:Middle Aged D061251:Primary Cell Culture D011621:Pteridines D051195:Toll-Like Receptor 2 D051199:Toll-Like Receptor 7 D014775:Virus Activation D017735:Virus Latency D055815:Young Adult
T cells AIDS/HIV Immunology Innate immunity NF-kappaB