Background: Globally, 2.1 million children are living with HIV-1 and the majority of new infections occur postnatally through breast milk transmission. The major obstacle to HIV/AIDS cure is the presence of a reservoir of latently infected cells that persists even under ART treatment. Recent studies have demonstrated that a toll-like receptor 7 agonist can reverse viral latency and alone or with use of a therapeutic CD8-inducing vaccine may facilitate reduction of the viral reservoir. In this study, two dose levels of an orally delivered TLR7 agonist (GS-986) were administered to SIV-infected ART-suppressed 7-month old rhesus macaques (RMs) to evaluate tolerability and pharmacodynamic responses.
Methods: Two 5-week-old RMs were infected with SIVmac251 orally in two doses 24 h apart and placed on daily ART beginning at 4 wks post infection. Both animals were virologically suppressed for over 3 months before administration of GS-986. At 7 months of age, RMs received 0.1 mg/kg GS-986 via oral gavage (o.g.). Complete blood count (CBC), serum chemistry, plasma viral loads, plasma cytokine concentrations, and immune cell activation were monitored prior to administration, 24 h, and 1 wk post administration. Plasma was collected prior to and 30 min following administration for pharmacokinetic (PK) analysis. Following 4 wks of rest, animals received a second dose of 0.3 mg/kg (o.g.) and analyses were repeated.
Results: GS-986 was well tolerated at both administered doses with no adverse clinical observations and normal CBC and chemistry at 24 h and 7 d post administration. Both RMs maintained undetectable viremia following administration. Concentrations of IFN-α, IL-1RA, IL-6, IP-10, and I-TAC were elevated in the plasma at 24 h post-administration and returned to pre-dosing levels by 7 d post-administration. Increases in monocytes (CD3^-CD4^int CD14⁺ CD16⁺) and circulating (CD169⁺) macrophages was observed 24 h following GS-986 administration with a return to baseline by day 7.
Conclusions: In summary, we have demonstrated that oral administration of GS-986 is tolerated in infant RMs, with induction of expected immune parameters. Future work will involve investigating the effect of GS-986 with a therapeutic vaccination on viral reservoir and viral rebound following analytical treatment interruption.