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Repeated TLR7 Agonist Treatment of SIV+ Monkeys on ART Can Lead to Viral Remission
James B. Whitney1; So-Yon Lim1; Christa E. Osuna1; Srisowmya Sanisetty1; Tiffany L. Barnes2; Tomas Cihlar2; Michael Miller2; Romas Geleziunas2; Joseph Hesselgesser2
1Beth Israel Deaconess Med Cntr, Boston, MA, USA;2Gilead Sciences, Foster City, CA, USA
The identification of pharmaceutical agents capable of safely reversing HIV-1 latentcy in ART-treated patients is urgently needed. We have previously reported that an oral TLR7 agonist GS-986, at doses that produce peripheral IFN-alpha, induces transient plasma viremia in SIV-infected rhesus macaques (RMs) on antiretroviral therapy (ART). In this follow up study, we assessed if lower clinically relevant doses of the TLR7 agonist GS-986 and the clinical compound GS-9620, which produce low or no detectable peripheral IFN-alpha, could induce transient plasma viremia or perturb viral reservoirs.
11 RMs were infected with SIVmac251 and started on daily suppressive ART at 65 days post-infection. Virologic suppression (<50 SIV RNA copies/mL) was achieved and maintained through 67 weeks. The cohort was divided into 4 groups receiving: (1) 19 doses of vehicle (n=2), (2) 19 doses of 0.1mg/kg GS-986 (n=3), (3) 19 doses of 0.05mg/kg GS-9620 (n=3), or (4) 10 doses of 0.15mg/kg GS-9620 (n=3) once every two weeks while maintaining ART. We longitudinally assessed plasma SIV RNA, total SIV DNA in PBMCs, lymph node (LN) and colon biopsies, and ex vivo SIV production from LN mononuclear cells and PBMC cultures stimulated with ConA.
The first two TLR7 doses did not induce detectable plasma viremia. However, doses 3-10 led to transient but inconsistent production of plasma SIV RNA “blips” in all TLR7-treated RMs, while additional doses (11 to19) did not induce SIV. After completing TLR7 dosing but prior stopping ART, SIV DNA levels were reduced in PBMC, colon and LN biopsies, and levels of ex vivo stimulated virus production were also diminished, with no such changes in the control group. To assess the impact of TLR7 treatment on viral reservoirs, ART was discontinued 2 weeks after the last TLR7 dose. Plasma virus rebound in 7 of the 9 TLR7-treated RMs was similar to that of the control group. However, two RMs having received either 19 doses of GS-986 or 10 doses of GS-9620 maintained undetectable plasma viral load for >60 days after stopping ART. Prior to ART cessation, these same two RMs were negative for ex vivo virus induction.
Repeated low doses of TLR7 producing minimal to undetectable peripheral IFN-alpha in SIV-infected ART-suppressed RMs induced transient plasma viremia, decreased viral DNA levels, and delayed plasma virus rebound after stopping ART in some RMs. These data support the ongoing clinical testing of GS-9620 in HIV-infected persons on ART.