CROI 2019 Abstract eBook

Abstract eBook

Poster Abstracts

Conclusion: MET in combination with ICB may improve poly-functional HIV- specific CD8 T cell effector function. The presence of certain monocyte subsets correlated with favorable T cell responses, suggesting that monocytes may play an important role in ICB efficacy. MET may have value as an adjunctive therapy in “Shock and Kill” HIV remission studies.

report results from a clinical trial conceived to evaluate the effect of 12 weeks of metformin (mTOR inhibitor) therapy on the size of HIV reservoirs (primary objective) and immune activation (secondary objective) in ART-treated HIV- infected adults (HIV+ART). Methods: Metformin (850 mg bid) was administered orally for 12 weeks in n=22 HIV+ART. Participants were non-diabetic, on ART for >3 years, with <40 HIV-RNA copies/ml plasma for >3 months, and CD4/CD8 ratios ≤0.7. Blood was collected at baseline (Visit 1), after 12 weeks of metformin (Visit 2), and 12 weeks after metformin discontinuation (Visit 3). Sigmoid colon biopsies (≈32 biopsies/participant) were collected at Visits 1-2 from n=13 participants. HIV-DNA was quantified by real-time nested PCR. Replication-competent HIV was quantified by viral outgrowth assay (VOA). Matched blood/colon memory CD4+ T-cells were analyzed for surface/intracellular molecule expression and simultaneously sorted by flow cytometry (BD AriaIII). Plasma soluble factors were quantified using R&D Systems Multiplex Assay and ELISA. Results: Metformin was well tolerated. Total HIV-DNA levels in blood/colon CD4+ T-cells and the frequency of blood CD4+ T-cells carrying replication- competent HIV was stable between Visits 1-3. However, investigations on matched blood/colon samples revealed a positive effect of metformin as reflected by i) decreased infiltration of CD4+ T-cells in the colon (median: 7.3% vs. 4.7%, Visit 1 vs. 2; p=0.019), indicative of reduced colon inflammation; ii) decreased mTOR phosphorylation in colon CCR6+CD4+ T-cells (median: 13.0% vs. 7.9%, Visit 1 vs. 2; p=0.0087); iii) a tendency for decreased expression of the HIV co-receptors CCR5 and integrin β7, and increased expression of the HIV restriction factor SAMHD1 in colon CCR6+CD4+ T-cells; and iv) decreased sCD14 plasma levels (mean: 1,893 vs. 1,519 ng/ml; Visit 1 vs. 3; p=0.02). Conclusion: This pilot study reveals metformin-mediated benefits in controlling inflammation, in part via mTOR regulation, and prompts us to further investigate the immunological/virological benefits of long-term metformin supplementation in HIV+ART individuals. 302 METFORMIN THERAPY WITH IMMUNE CHECKPOINT INHIBITORS IMPACTS ANTI-HIV T-CELL RESPONSES Glen M. Chew 1 , Dominic Chow 1 , Scott A. Souza 1 , Danielle M. Clements 1 , Michael J. Corley 1 , Alina P. Pang 1 , Alan J. Korman 2 , Mariana Gerschenson 1 , Cecilia M. Shikuma 1 , Lishomwa C. Ndhlovu 1 1 University of Hawaii at Manoa, Honolulu, HI, USA, 2 Bristol-Myers Squibb, Redwood City, CA, USA Background: Despite suppressive antiretroviral therapy (ART), chronic HIV is associated with T cell exhaustion, defined by the overexpression of negative immune checkpoint receptors. The efficacy of immune checkpoint blockade (ICB) in reversing T cell dysfunction and improving cancer survival is variable. Metformin (MET) is an oral hypoglycemic therapy for type II diabetes and has previously unrecognized therapeutic effects against age-related conditions. Recently, ICB in combination with MET has yielded favorable clinical outcomes in oncology (MZ. Afzal et.al. 2018). We assessed the ex vivo anti-HIV T cell responses to ICB during adjunctive MET therapy in banked blood from a clinical trial of MET conducted in HIV+ adults. Methods: We conducted an open label, 8-week (wk) pilot study in seven euglycemic adults on ART, stable for >1 year with plasma HIV RNA <50 copies/ ml, median age of 60.5 years and all male. MET dosing was 500mg at entry increasing to 1000mg at wk4. In cryopreserved PBMCs, we measured ex-vivo HIV-specific T cell responses (CD107a, IFN-γ, IL-2) to an HIV Gag peptide pool in the presence of blocking anti-TIGIT and/or anti-PD-L1 monoclonal antibodies and an isotype control (IgG1). Since monocyte frequencies (%) at entry have been shown to be associated with melanoma survival in response to anti-PD-1 blockade (C. Krieg et.al. 2018), we also quantified monocyte subsets by flow cytometry. Statistical analysis included non-parametric Wilcoxon rank-sum test and Spearman’s rho for correlations. Results: MET did not improve HIV-specific CD8 T cell responses in the absence of blockade. In the presence of anti-PD-L1, MET improved HIV-specific CD8 T cell responses (CD107a+IFN-γ+IL-2+) (Fold Change between IgG1 and anti-PD-L1; (entry: 0.19 (-0.28, 0.41), wk 8; 1.21 (-0.06, 2.39) p=0.04). Monocyte frequencies (%) remained unchanged. Baseline % of inflammatory (CD14+CD16+) and patrolling (CD14lowCD16+) monocytes positively correlated with wk8 HIV- specific T cell responses (CD107a+IFN-γ+IL-2+) to anti-PD-L1 blockade (r=0.89, p=0.01 and r=0.92, p=0.006, respectively), whereas classical monocytes inversely associated with these responses (r=0.78, p=0.04).

Poster Abstracts

303 ZINC SUPPLEMENTATION AND INFLAMMATION IN TREATED HIV

Sahera Dirajlal-Fargo 1 , Jiao Yu 2 , Manjusha Kulkarni 3 , Abdus Sattar 2 , Nicholas Funderburg 3 , Grace A. McComsey 4 1 Rainbow Babies and Children’s Hospital–Case Western School of Medicine, Cleveland, OH, USA, 2 Case Western Reserve University, Cleveland, OH, USA, 3 The Ohio State University, Columbus, OH, USA, 4 University Hospitals Cleveland Medical Center, Cleveland, OH, USA Background: In HIV, the prevalence of zinc deficiency appears to be high and low plasma zinc levels have been linked with disease progression and an increased risk of death. In this study, we explored the effect of zinc supplementation on the heightened state of inflammation and monocyte activation observed in ART-treated HIV infection. Methods: This is a pilot open labeled randomized double arm study, studying the efficacy and safety of zinc therapy on inflammation in ≥ 18 years old HIV-infected patients , on stable ART (for at least 12 weeks) and with zinc levels ≤75 µg/dL in the last 60 days. Patients were randomized 1:1 to zinc gluconate capsules at a dose of 45mg (low-dose), or 90mg (high-dose) elemental zinc daily for 16 weeks. We assessed the following markers at baseline and 16 weeks: high sensitivity C reactive protein (hsCRP), soluble CD14 (sCD14), soluble tumor necrosis alpha receptor I and II (sTNFR-I and II), lipopolysaccharide binding protein (LBP) and intestinal fatty acid binding protein (IFABP). We performed significance tests for the shift of distributions using Kolmogorov –Smironow test. Effect size was reported as Cohen’s d. Results: Overall, a total of 52 participants were enrolled (25 participants in the low-dose arm and 27 participants in the high-dose arm). Mean age was 49 years, 77%were males and 73%were African Americans. At baseline, mean zinc levels were 75 µg/dL. After 16 weeks, loss to follow up was minimal with 92% retention. One patient developed nausea possibly related to the zinc capsules, there were no other study related adverse events. Mean circulating zinc levels increased to 91 µg/dL in the low-dose arm and to 105 µg/dL in the high-dose arm. In addition, 88% of participants in the low-dose arm and 96% in the high- dose arm reached zinc levels >75 µg/dL. Overall, biomarkers decreased with a margin of reduction ranging between 8 and 33% (figure 1). There was a larger

CROI 2019 110