CROI 2016 Abstract eBook

Abstract Listing

Poster Abstracts

Methods: A multicenter case controlled prospective study (IMPAACTP1073) was conducted to assess incidence of BCG and TB IRIS in infants and children (age 1-72 months) and associated immunopathology. Of 202 enrolled participants, BCG IRIS was diagnosed in 21 children (10.4%) at periods ranging from 2-8 wks after ART initiation. T cell phenotypes (maturation, activation and exhaustion markers), regulatory T cells, monocyte subsets, NK cells and functional studies for intracellular expression of IFNg, TNFa, IL2, IL17, IL22, CD154 and IL10 in CD4 T cells upon stimulation with BCG or gag peptides at study entry (Pre-ART) and at diagnosis of BCG IRIS were investigated. Cases were compared with 21 non-IRIS controls matched by age, nadir CD4 frequency and duration of ART at time of IRIS diagnosis. Groups were compared by Mann-Whitney test. Results: At entry, compared to controls, cases exhibited reduced absolute CD3 (889 vs 1098 cells/µl, p=0.02) and CD4 (182 vs 409 cells/µl, p=0.005) T cells, higher frequencies of CD14 + CD16 + inflammatory monocytes (3.5% vs 1.2%, p=0.03) and NK cells (34% vs 14%, p=0.01); lower frequencies of BCG-specific IL22 + CD4 + T cells (p=0.004) and gag-specific CD4 T cells expressing IFNg (p=0.004), TNFa (p=0.0005), IL10 (p=0.03) and CD154 (p=0.04). Frequencies of other BCG-specific cytokine-expressing T cells were not different. CD4 T cells increased from entry to the time of IRIS event in cases (p=0.004) and controls (p=0.002), but significant increase in CD4 absolute counts was evident only in cases (p=0.02). A dramatic immune reconstitution of BCG-specific Th1 cells were observed at IRIS diagnosis, compared to control samples (IFNg p=0.005; IL2 p=0.01; TNFa p=0.004). By contrast, reconstitution of gag-specific CD4 T cells was not different across groups. At time of IRIS diagnosis frequencies of NK cells were higher in cases compared to controls (p=0.006). Conclusions: These findings imply that underlying immune deficiency and lack of BCG-specific Th22 cells coupled with inflammation involving monocytes contributes to the pathophysiology of BCG IRIS. 825 Enhanced Inflammation and Rotavirus Vaccine Responses in Perinatal HIV-1 Infection Priyanka Uprety 1 ; Jane Lindsey 2 ; Myron Levin 3 ; Kaitlin Rainwater-Lovett 1 ; Carrie Ziemniak 1 ; Susan Kaplan 4 ; Micki Nelson 4 ; Amanda Zadzilka 5 ; AdrianaWeinberg 6 ; Deborah Persaud 1 1 Johns Hopkins Univ, Baltimore, MD, USA; 2 Harvard Sch of PH, Boston, MA, USA; 3 Univ of Colorado Anschutz Med Campus, Aurora, CO, USA; 4 Merck Rsr Lab, North Wales, PA, USA; 5 Frontier Sci & Tech Rsr Fndn, Inc, Amherst, NY, USA; 6 Univ of Colorado, Denver, CO, USA Background: Altered gut mucosa from HIV-1 infection leads to microbial translocation, persistent inflammation (IF) and significant morbidity in adults. The effects of IF in perinatal infection are unknown but may modify immune responses to oral live- vaccines in infancy. Methods: Markers of IF (IFN-γ, IL-1β, IL-10, IL-2, IL-6, IL-8, TNF-α, IL-4, IL-13 and IL-12p70) and sCD14 were quantified in plasma of HIV-1-infected (HIV+) and HIV-1-exposed uninfected (HEU) African infants enrolled in a double-blind, placebo-controlled clinical trial (IMPAACT P1072) of the safety and immunogenicity of 3 doses of pentavalent rotavirus vaccine (RV5) by age 32 weeks. IF markers and sCD14 were measured at study entry and 21 days post vaccine dose (PD) 1; sCD14 was also measured at 14 and 42 days PD3. Non- parametric tests and correlations were used to compare biomarkers between groups and censored normal regression to explore associations at entry between biomarker levels and IgA and serum neutralizing antibodies (SNA) against RV proteins (G1-G4 and P1) l PD3 in RV5 recipients. Results: This analysis included 68 HIV+ (median age at entry 93 days; 63% breast-fed; 69% received antiretroviral [ARV] prophylaxis for prevention of mother-to-child transmission (pMTCT) and 116 HEU (median age 82 days; 64% breast-fed and 91% received ARV prophylaxis for pMTCT) of 202 infants enrolled. 36/68 HIV+ and 59/116 HEU received RV5, respectively. At entry, the median plasma viral load was 39,827 c/ml; 93% HIV+ were on antiretroviral treatment. HIV+ infants had higher mean concentrations of IFN-γ, IL-1 β, IL-10, IL-2, IL-6, TNFα, and sCD14 than HEU (ranging from 16% [sCD14] to 204% [IL-6] higher across markers, p≤0.05) after adjusting for age, breastfeeding and ARVs for pMTCT. In HIV+, lower concentrations of IFN-γ (r= -0.44, p=0.009) and IL-10 (r= -0.39, p=0.022) at entry correlated with higher SNA G1 at PD3 and lower IL-10 (r= -0.37, p=0.029) with higher SNA P1. No correlations were found between entry IF biomarkers and serum IgA titers at PD3. Antibody titers PD3 in RV5 recipients were similar in HIV+ and HEU. There were no significant differences in biomarker changes between placebo and vaccine recipients in either HIV+ or HEU infants. Conclusions: Heightened IF in perinatal HIV-1 infection did not impact humoral responses to RV5. However, whether IF in infancy affects long-term immunity to childhood vaccines requires further study. 826 Vitamin D Supplementation Decreases Immune Activation and Exhaustion in HIV+ Youth Allison R. Eckard 1 ; Ann Chahroudi 2 ; Julia C. Rosebush 2 ; Mary Ann O’Riordan 3 ; Julie E. Daniels 2 ; Monika Uribe-Leitz 2 ; Bruce Kinley 3 ; Danielle Labbato 3 ;VinTangpricha 2 ; Grace A. McComsey 3 1 Med Univ of South Carolina, Charleston, SC, USA; 2 Emory Univ Sch of Med, Atlanta, GA, USA; 3 Case Western Reserve Univ, Cleveland, OH, USA Background: Heightened immune activation and exhaustion drive HIV disease progression and co-morbidities. Vitamin D has pleiotropic effects on the immune system, but little is known about the effects of supplementation in HIV infection. Our study investigates these potential effects after 12 months of supplementation in virologically-suppressed HIV+ youth with vitamin D insufficiency. Methods: This is a randomized, active-control, double-blind trial investigating 2 different monthly vitamin D 3 doses [60,000 (medium) or 120,000 (high) IU/month] vs. a control arm of 18,000 IU/month in 8-26 year old HIV+ youth on ART with baseline 25-hydroxyvitamin D (25(OH)D) ≤30 ng/mL and HIV-1 RNA <1000 copies/mL. Randomization was stratified by EFV use. Only subjects who maintained an undetectable HIV-1 RNA level for 12 months and had available PBMCs at baseline (BL) and 12 months were included in this analysis. Markers of immune activation and exhaustion were measured by flow cytometry. Comparisons of marker changes from BL to 12 months were made within each of the three dosing groups and between groups (medium vs. control, high vs. control) using appropriate two-sample tests. Results: 50% of enrolled participants (N=51) were included in the analysis: 63%male, 86% black with median (Q1, Q3) age of 20 (15, 22) years and CD4 count of 654 (451, 888) cells/mm 3 (all similar to the rest of the study participants). HIV and ARV duration were 11 (3, 18) and 7 (2, 11) years, respectively. Overall, BL 25(OH)D was 17 (13, 25) ng/mL and not different between arms or to the rest of the study participants. By 12 months, 25(OH)D increased statistically within each dosing group (control: +12 (6, 17); medium: +19 (10, 32); high: +31 (16, 41) ng/mL; all P<0.001) with greater increases in the medium group vs. controls (P=0.04) and high group vs. controls (P=0.008). Overall, all measured markers decreased with CD4 activation (CD4+CD38+HLA-DR+), CD8 activation (CD8+CD38+HLA-DR+), CD4 exhaustion (CD4+CD38+HLA-DR+PD1+), and inflammatory monocytes (CD14+CD16+) reaching statistical significance. These decreases were mostly driven by subjects in the high dose group (Table). Conclusions: Vitamin D supplementation decreased markers of T-cell activation and exhaustion, and monocyte activation regardless of dose in HIV+ youth, but subjects given the highest dose (120,000 IU/month) showed the greatest improvements. These data suggest that high-dose vitamin D may further attenuate immune activation and exhaustion HIV+ youth on ART.

Poster Abstracts

345

CROI 2016