CROI 2017 Abstract e-Book

Abstract eBook

Poster and Themed Discussion Abstracts

PPAR-γ agonist with anti-inflammatory and anti-fibrotic properties. We hypothesized that telmisartan would decrease LN or AT fibrosis in HIV-1 infected adults on suppressive antiretroviral therapy (ART). Methods: In this completed, randomized-controlled trial, HIV-infected participants age ≥18 years with HIV-1 RNA <50 copies/mL on ART for ≥48 weeks received telmisartan 40mg daily for 4 weeks then 80mg daily for 44 weeks or no drug while continuing ART. Primary endpoints were changes in % collagen I deposition by immunohistochemistry (IHC) in inguinal LN and subcutaneous lower abdominal AT after 48 weeks. IHC was performed and interpreted by a blinded central reader. 36 participants would power the study to detect a 4% difference in change in collagen. Statistical testing used two-sided rank-sum and signed-rank tests (α=0.05). Results: Of 44 randomized participants, 93%were male and 50%white non-Hispanic. Median age was 48 years, body mass index 25 kg/m², and CD4+ T-cell count 588 cells/ mm³. Paired AT samples were available from 34 participants and LN from 29 due to participant consent and sample quality. Baseline median (interquartile range) tissue area with collagen I deposition was 13.7% (7.5%, 21.4%) for LN and 1.9% (0.4%, 3.4%) for AT. No statistically significant between-group differences in LN or AT collagen I deposition change were observed (Table), although a larger than expected variability in LN collagen likely reduced power to see a significant LN effect. In both arms, collagen I deposition tended to decrease in LN and significantly decreased in AT over 48 weeks. Conclusion: In HIV-1-infected adults on suppressive ART, angiotensin receptor blockade and PPAR-γ agonismwith telmisartan for 48 weeks did not improve LN or AT fibrosis more than continued ART alone. Notably, continued ART decreased both LN and AT fibrosis over 48 weeks. This trial is the first longitudinal study of LN and AT fibrosis in treated HIV infection and will inform design of future studies with tissue endpoints. Analyses of tissue HIV expression and circulating and tissue-level inflammatory and fibrotic signatures are ongoing.

Poster and Themed Discussion Abstracts

252 PHARMACOLOGIC INHIBITION OF IDO BLUNTS FEATURES OF SIV-RELATED CHRONIC INFLAMMATION Richard M. Dunham 1 , Kevin W. Brown 1 , James M. Billingsley 2 , Zhong-Min Ma 3 , Gregory K. Tharp 2 , Christopher J. Miller 3 , Steven E. Bosinger 2 , Brian A. Johns 1 , David Favre 1 1 GlaxoSmithKline, Durham, NC, USA, 2 Yerkes Natl Primate Rsr Cntr, Atlanta, GA, USA, 3 Univ of California Davis, Davis, CA, USA Background: The immunomodulatory and neurotoxic activities of kynurenines derived from tryptophan catabolism by indoleamine-2,3-dioxygenase (IDO1) play a role in sustaining a cycle of inflammation and immune dysfunction during HIV infection. Such a cycle may lead to increased risks of non-AIDS diseases, such as liver disease and neurocognitive impairment, despite effective cART. We hypothesized that inhibition of IDO1 may break this cycle, reversing immune dysfunction, decreasing systemic inflammation, and ultimately decreasing the incidence of non-AIDS diseases. We tested this hypothesis in a pilot study of virologically suppressed, SIV-infected rhesus macaques treated with an optimized regimen of an IDO1 inhibitor (IDOi) currently under clinical investigation (INCB024360). Methods: Twelve rhesus macaques were infected with SIVmac251, treated with cART, and divided into two groups after virologic suppression to receive either placebo or IDOi for 8 weeks while continuing ART. Blood, lymphatic tissue, and mucosal tissues were evaluated to determine the pharmacologic, immunologic, metabolic, microbiological, and transcriptomic features of IDOi during SIV infection. Results: SIV infection increased plasma levels of kynurenine even after ART and kynurenine was transiently suppressed after each IDOi dose. Pharmacologic inhibition of IDO1 led to increased CD4/CD8 ratio in blood and significantly decreased markers of T cell and monocyte activation in blood and lymphoid tissues. In gut mucosa, we observed a trend to increased frequency of CD4+ T cells producing IL-17, IL-22, and/or IL-21. Interestingly, we found increased plasma levels of microbial metabolites of tryptophan, such as indoleacetate, which are AHR agonists that promote intestinal barrier function through induction of IL-22 and have neuroprotective properties. Conclusion: These results support the hypothesis that IDOi disrupts the vicious cycle of IDO1-mediated inflammation and immune dysfunction during SIV infection. This effect is associated with a shift in microbiota function characterized by increased production of anti-inflammatory postbiotic metabolites that may serve as novel biomarkers of disease and therapeutic responses. These data suggest further investigation of IDOi as a strategy to blunt or prevent non-AIDS diseases in suppressed HIV infection by targeting host and microbial metabolism in the setting of chronic inflammation. 253 HIV-SPECIFIC ANTIBODIES ENHANCE TYPE I INTERFERON PRODUCTION FROM PLASMACYTOID DCS Rebecca Veenhuis 1 , Zachary Freeman 1 , Jack Korleski 1 , Alessandra Tomasi 1 , Austin Boesch 2 , Margaret Ackerman 2 , Joseph B. Margolick 1 , Joel Blankson 1 , Michael Chattergoon 1 , Andrea Cox 1 1 The Johns Hopkins Univ, Baltimore, MD, USA, 2 Dartmouth Coll, Hanover, NH, USA Background: Type I interferon (IFN) production is essential in innate control of acute viral infection, but prolonged IFN production is associated with chronic immune activation in HIV. The mechanisms that maintain high-level IFN production following the acute phase are unknown. Plasmacytoid dendritic cells (pDCs) are the primary producers of type I IFN in viral infections. HIV is sensed by pDCs through endosomal Toll like receptor (TLR) 7 recognition of RNA. In this study, we further define the mechanism through which HIV activates pDC to produce IFN and demonstrate that antibodies (Abs) generated in persistent HIV infection enhance IFN production by pDCs. Methods: Using an in vitro co-culture system of primary human pDCs and HIV cell culture isolates, we analyzed the mechanism through which HIV activates pDCs to produce IFN. We assessed whether endocytosis, HIV receptor and co-receptor engagement, fusion, uncoating, and subsequent stages of the HIV life cycle were required for IFN production. Additionally, we evaluated Toll-like receptor (TLR) utilization and downstream signaling in pDCs exposed to HIV. We next analyzed how both monoclonal HIV-specific Abs and Abs induced in natural HIV infection modulated normal pDC sensing of HIV. Results: We found that HIV-driven activation of pDCs to produce IFN required TLR7 signaling, receptor-mediated entry, fusion, and viral uncoating, but not endocytosis or life cycle stages after uncoating. Abs directed against the HIV envelope that do not interfere with CD4 binding significantly enhanced the IFN response irrespective of capacity to neutralize CD4 T cell infection. Ab-mediated enhancement of IFN production required pDC Fc gamma receptor engagement, bypassed fusion, and initiated signaling through both TLR7 and TLR9, which was not utilized without Ab present. Polyclonal Ab isolated from 13 untreated HIV-infected subjects universally enhanced pDC production of IFN in response to HIV. Conclusion: Identifying the cause of persistent, high-level IFN responses during chronic HIV infection is important in understanding its pathogenesis. Our data suggest that Abs produced in vivo in untreated HIV infection contributes to persistent high-level IFN responses during chronic HIV infection, representing a novel mechanism of immune activation.

CROI 2017 101