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

Highly active antiretroviral therapy (HAART) for HIV-1 infection suppresses but does not cure the disease due to persistent latent viral reservoirs. The "shock and kill" strategy aims to eradicate these reservoirs completely. In exploring the role of TLR8 activation in this context, extensive efforts have been devoted to identify compound <b>23a</b>, a potent and selective TLR8 agonist with strong agonistic activity (EC₅₀ = 19 nM) and high selectivity (∼1300-fold) over TLR7. Notably, compound <b>23a</b> exhibits potent reactivation of latent HIV-1 reservoirs in both infected cell lines and primary PBMCs from HAART-treated patients, demonstrating superior efficacy compared to the TLR7 agonist <b>GS-9620</b> (NCT05281510). Additionally, <b>23a</b> (<b>SV-128</b>) effectively activated innate cytolytic effectors, including natural killer (NK) cells, which targeted HIV-infected CD4⁺ T cells. These findings demonstrate the promising therapeutic potential of TLR8 agonists for HIV-1 eradication, combining both "shock" (latency reversal) and "kill" (immune-mediated clearance) mechanisms.