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 23a, a potent and selective TLR8
agonist with strong agonistic activity (EC50 = 19 nM) and
high selectivity (∼1300-fold) over TLR7. Notably, compound 23a 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 GS-9620 (NCT05281510). Additionally, 23a (SV-128) 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.