The Role of TLR7 and/or TLR8 Agonists in HIV Cure

Abstract

The latent viral reservoir is the roadblock on the way of curing HIV. Reversing latency followed by killing of cells harboring HIV, the “shock and kill” approach, is widely investigated. Toll-Like receptor (TLR) agonists, especially those targeting TLR7 and/or TLR8, are candidates in achieving HIV cure. This review analyzes and compares in vivo research conducted on these agonists, and provides an in-depth overview of benefits, limitations, and challenges regarding TLR7 and/or TLR8 agonist therapy for curing HIV. PubMed was searched for relevant literature, and after screening, nine articles were included in this review. TLR8 agonist treatment has not yet been assessed in vivo, but may play crucial roles in eliminating the viral reservoir in cells from monocytic origin. TLR7 agonist monotherapy using vesatolimod is thus far the only treatment investigated in HIV-infected humans, and does not affect the size of the viral reservoir, although one study reports an increase in time to rebound after ART cessation. Combination therapy of TLR7 agonists with broadly neutralizing antibodies or prime-boost immunization yields variable results regarding effects on reservoir size and time to rebound. This review has failed to observe the ability of TLR7 agonists to achieve latency reversal, although immune modulation was observed. The latter might be a key effect of TLR7 agonists rather than the former, indicating roles for TLR agonists as adjuvants. Overall, inconsistent results, together with limited clinical relevance, and study and population heterogeneity, pose significant challenges in taking TLR7 agonists as treatment for HIV to the clinic.