Rational Design and Identification of Highly Selective TLR8 Agonists as Potent HIV-1 Latency Reversal Agents

Area of Science:

• Immunology
• Virology
• Pharmacology

Background:

• Highly active antiretroviral therapy (HAART) suppresses HIV-1 but does not eliminate latent viral reservoirs.
• The

Purpose of the Study:

• To investigate the potential of TLR8 agonists in eradicating latent HIV-1 reservoirs.
• To evaluate compound 23a, a selective TLR8 agonist, for its efficacy in HIV-1 latency reversal and immune-mediated clearance.

Main Methods:

• Identification and characterization of compound 23a as a potent and selective TLR8 agonist.
• Assessment of compound 23a's ability to reactivate latent HIV-1 in infected cell lines and primary peripheral blood mononuclear cells (PBMCs).
• Evaluation of compound 23a's effect on innate cytolytic effector cells, including natural killer (NK) cells.

Main Results:

• Compound 23a demonstrated potent TLR8 agonistic activity (EC50 = 19 nM) with high selectivity over TLR7.
• Compound 23a effectively reactivated latent HIV-1 reservoirs in both cell lines and PBMCs, outperforming the TLR7 agonist GS-9620.
• Compound 23a activated NK cells, leading to targeted clearance of HIV-infected CD4+ T cells.

Conclusions:

• TLR8 agonists, exemplified by compound 23a (SV-128), represent a promising therapeutic strategy for HIV-1 eradication.
• Compound 23a combines latency reversal (