CROI 2017 Abstract e-Book

Abstract eBook

Poster and Themed Discussion Abstracts

338LB TLR7 AGONIST TREATMENT OF SIV+ MONKEYS ON ART CAN LEAD TO COMPLETE VIRAL REMISSION So-Yon Lim 1 , Christa Osuna 1 , Joseph Hesselgesser 2 , Alison Hill 3 , Michael D. Miller 2 , Tomas Cihlar 2 , Romas Geleziunas 2 , William Lee 2 , James Whitney 1 1 Beth Israel Deaconess Med Cntr, Boston, MA, USA, 2 Gilead Scis, Inc, Foster City, PA, USA, 3 Boston College, Chestnut Hill, MA, USA Background: The persistence of an HIV-1 reservoir in patients on antiretroviral therapy (ART) represents the major obstacle to HIV remission. We have previously reported that oral TLR7 agonists (GS-9620 and GS-986) can induce transient viremia in SIV-infected, ART-treated rhesus monkeys (RMs). After ART release of nine TLR7 agonist-treated RMs, complete remission was noted in two RMs, and two other RMs have exhibited significant control of recrudescent viremia. Methods: After repeated GS-9620 or GS-986 adminsitration and ART stop, we have conducted a long-term follow up of two “remission” RMs. We also monitored 2 RMs that had rebound viremia after ART stop, as controls. We assessed multiple endpoints including: viral outgrowth (VOA) and viral co-culture (VCC) using lymph node mononuclear cells (LNMC) and PBMC. We assessed SIV-specific T cell responses at multiple time points. We also conducted in vivo CD8+ T cell depletion in remission and viremic control RMs. Finally, we adoptively transferred PBMC and LNMC cells into SIV naïve RMs, from remission RMs prior to TLR7 agonist treatment. In parallel, we also transferred PBMC and LNMC, into SIV naïve RMs, isolated from remisson RMs after GS-9620 or GS-986 treatment and ART stop. Results: To date, both TLR7 agonist-treated RMs have remained aviremic for more than 1 year after ART cessation. Longitudinal assesment of VOA or VCC in the two remission RMs was uniformly negative, whereas viremic RMs scored consistently postive. Longitudal SIV-specific immune monitoring revealed sustained responses in viremic RMs, but no detectable SIV-specific T cell responses in remission RMs. In vivo CD8+ T cell depletion did not induce rebound viremia in remission RMs, but viremic control RMs exhibited significant increases in SIV RNA levels that later waned as CD8+ T cells recovered. Finally, the adoptive transfer of PBMC and LNMC samples (prior to TLR7 agonist treamtent) induced a persistent SIV infection into naïve RMs. Adoptive transfer of PBMC and LMNC cells from remission RMs did not induce SIV infection in naïve recipients. Conclusion: Administration of GS-9620 or GS-986 to SIV+ ART-suppressed RM is safe, induces transient viremia and impacts SIV DNA levels. GS-986 or GS-9620 treatment can delay viral rebound or induce durable long-term remisison after ART cessation in some RMs. These novel findings highlight a possible mechanism of SIV remission after ART cessation and underscore the need for continued investigation of GS-9620 in HIV-1 infected patients on ART. 339 HEIGHTENED SYSTEMIC AND CNS IMMUNE ACTIVATION IN ACUTE HIV INFECTION WITH SYPHILIS Phillip Chan 1 , Donn Colby 1 , Eugene Kroon 1 , Victor Valcour 2 , Napapon Sailasuta 3 , Joanna Hellmuth 4 , Shelly J. Krebs 5 , Jintanat Ananworanich 5 , Serena Spudich 6 , for the RV254/ SEARCH 010 Study Group 1 SEARCH, The Thai Red Cross AIDS Rsr Cntr, Bangkok, Thailand, 2 Univ of California San Francisco, San Francisco, USA, 3 Univ of Hawaii, Honolulu, HI, USA, 5 US Military HIV Rsr Prog, Silver Spring, MD, USA, 6 Yale Univ, New Haven, CT, USA Background: HIV and Treponema pallidum infection are known to alter each other’s course, and both impact the central nervous system (CNS). During chronic HIV, syphilis associates with reduced CD4 count, elevated HIV viral load (VL) and impaired cognition. In a cohort with a high prevalence of syphilis, we examined systemic and CNS immune activation and neurologic performance with respect to syphilis status during acute HIV infection (AHI). Methods: In a retrospective, cross-sectional analysis of pre-ART baseline data in the RV254/SEARCH010 Thai AHI cohort, we defined syphilis status based on serology and history: TPHA- (never syphilis), TPHA+ (any syphilis), TPHA+/VDRL+ (recent syphilis), and TPHA+/VDRL+ untreated or post-syphilis treatment ≤ 3 months (strictly active syphilis). Data included Fiebig stage, presence of acute retroviral syndrome (ARS), blood CD4 and CD8 count and VL, summarized performance on four neuropsychological tests (NPZ-4), and, in a subset, cerebral metabolite ratios on 1.5 T magnetic resonance spectroscopy and cerebrospinal fluid (CSF) VL and immune activation markers including CSF IP-10, MCP-1, neopterin, IL-6 and IFN-g. Comparisons were performed with the Chi-square and Mann-Whitney U tests. Results: Of 377 AHI participants enrolled between May 2009 and June 2016, 69 were TPHA+ (any syphilis), 47 of these were VDRL+ (recent/active syphilis). The prevalence of VDRL+ rose from 0/10 (0%) in 2009 to 9/41 (22%) in 2016. Among VDRL+ participants, 46 had NPZ-4, 13 underwent MRS and 11 had CSF sampling. Participant characteristics were similar across groups (Table 1), except blood CD8 count which was higher in the strictly active syphilis (n=37) vs. never syphilis group (TPHA-), p=0.028. NPZ-4 performance was lower in those who ever had syphilis (all TPHA+) vs. the TPHA- group (p=0.029). Most of the CSF immune markers level were similar across groups except IFN-g statistically increased in the VDRL+ group vs. the TPHA- group (p=0.040). Conclusion: Active syphilis associates with elevated systemic and CNS immune activation (higher blood CD8 counts and CSF IFN-g) in AHI. Additionally, during AHI, those who have ever had syphilis (all TPHA+) have lower cognitive performance than those who have not. These findings suggest that interactions between HIV and syphilis start early in HIV, and that syphilis should be evaluated as a possible contributing factor to immune activation and neurocognitive impairment that persists even after HIV treatment.

Poster and Themed Discussion Abstracts

CROI 2017 133