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Treatment With a TLR7 Agonist Induces Transient Viremia in SIV-Infected ART-Suppressed Monkeys
James B. Whitney1, So-Yon Lim1, Christa E. Osuna1, Srisowmya Sanisetty1, Tiffany L. Barnes2, Peter T. Hraber3, Tomas Cihlar2, Romas Geleziunas2, Joseph Hesselgesser 2
1 Center for Virology and Vaccine Research, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, United States. 2 Gilead Sciences, Inc., Foster City, CA, United States. 3 Los Alamos National Laboratories, Los Alamos, NM, United States.
Background: Latent reservoirs of replication competent HIV-1 persist in patients on antiretroviral therapy (ART) and represent the major obstacle to HIV eradication efforts. Considerable effort has been directed to identify pharmaceutical agents capable of safely reactivating latent HIV-1 in ART-suppressed patients.
Methods: A study was conducted in SIV-infected rhesus macaques (RM) on ART to determine if administration of an oral toll-like receptor 7 (TLR7) agonist would induce transient plasma viremia and reduce viral reservoirs. Ten RM were infected with SIVmac251 by rectal challenge. Plasma SIV RNA levels were measured by RT-PCR (limit of detection 50 copies/mL). The RM received ART at ~9 weeks post-infection (PI) and became virologically suppressed by 24 weeks PI; virologic suppression was maintained through week 45. At 45 weeks PI, 4 RM were administered 7 doses of the TLR7 agonist at twice monthly intervals, while on ART. The first 3 doses were 0.1, 0.2 and 0.3 mg/kg and the last 4 doses remained constant at 0.3 mg/kg. Total viral DNA was quantified in peripheral blood mononuclear cells (PBMC), colon and lymph node biopsies taken pre- and post-completion of TLR7 treatment. Two weeks after TLR7 dosing, ART was discontinued.
Results: The first 3 doses of TLR7 agonist administered to the SIV-infected ART-suppressed RM had limited effect on plasma viremia. However, doses 4 through 7 led to transient and consistent increases in plasma virus (500 - 1000 SIV RNA copies/mL) in all treated RMs with a return to < 50 copies/mL within 4-7 days of TLR7 dosing. After completion of the TLR7 regimen, SIV DNA levels were reduced by 56-75% in PBMC, colon and lymphoid tissues. Viral DNA levels remained unchanged in the placebo control RM. To determine if these transient plasma virus blips and decreases in viral DNA content also reduced the size of the viral reservoir, ART was discontinued. While the plasma virus rebound kinetics in animals dosed with the TLR7 agonist were comparable to the placebo group after discontinuation of ART, the TLR7 treated animals showed a ~0.5 log10 reduction in plasma virus setpoint as compared to the placebo group.
Conclusions: Multiple oral administrations of a TLR7 agonist in SIV-infected ART-suppressed RM was safe, induced transient plasma viremia, reduced viral DNA content in PBMCs, colon and lymphoid tissues and established lower viral setpoint after ART cessation. These novel findings support clinical investigation of a TLR7 agonist in HIV-1 infected patients on ART.