CROI 2018 Abstract eBook

Abstract eBook

Poster Abstracts

868 LASTING IMMUNE IMPACTS OF AGE AT START OF ART IN VERTICALLY HIV- INFECTED ADOLESCENTS Mark Cameron 1 , Stefano Rinaldi 2 , Brian Richardson 1 , Nicola Cotugno 3 , Sion Williams 2 , Suresh Pallikkuth 2 , Lesley R. de Armas 2 , Cheryl Cameron 1 , Rajendra Pahwa 2 , Paolo Palma 3 , Savita Pahwa 2 1 Case Western Reserve University, Cleveland, OH, USA, 2 University of Miami, Miami, FL, USA, 3 Bambino Gesu Children’s Hospitalital, Rome, Italy Background: Timely implementation of antiretroviral therapy (ART) in vertically HIV-infected children provides an opportunity to limit the size of reservoir, but whether time of ART treatment initiation can durably impact host immune responses associated with establishment of infection is unknown. We analyzed HIV-specific CD4 T cell functionality along with host transcriptome analysis in young adults who were vertically HIV-infected and initiated ART earlier or later after birth. Methods: PBMCs were collected from HIV-infected donors between 9-15 Y of age enrolled at Bambino Gesù Children’s Hospital. Three groups of donors (n=5-6/group) were profiled via RNA-Seq: (i) Early Treated (ET): Age at ART 0-0.5 Y, (ii) Late Treated (LT): Age at ART 1-12 Y, and (iii) HIV negative controls. All HIV-infected donors had been suppressed for plasma HIV. Low input libraries were generated using Kapa RNA Hyper library kits and sequenced on an Illumina NextSeq500 (75 bp, paired-end, 40 million reads/sample). Differentially expressed genes (DEG) were found by two-group t test (P≤0.05) and organized into top pathways by P value (P≤0.05) via gene set variation analysis (GSVA) in R Bioconductor. Antigen-specific CD40L+ CD4 T cells were evaluated by flow cytometry for intracellular cytokines (IL2, IFNG, TNFA, IL21) following 18hrs stimulation with gp140. Results: We found that a T cell signaling DEG signature could distinguish ET and LT despite current age. Through GSVA, this signature was ascribed to differences seen in naïve vs central or effector CD4 memory T cell datasets (see figure). Regression analysis revealed that different patterns of T cell signaling pathway DEG correlated with age of ART initiation, % of naïve, central memory, effector memory T cells, and NK cells, e.g. CXCL9/10, GZMA/B, TNFSF8/10/14, and CD160/244. CD4 T cell functional profiles also differed in ET versus LT in that ET showed increased frequencies of gp140-specific polyfunctional CD4 T cells dominated by IL2 production whereas response in LT was paucifunctional. Interestingly, the frequency of gp140sp CD4+ T cells was the same between ET and LT. Conclusion: Our results suggest that delayed ART initiation in HIV-infected children has a long-term impact on host T cell memory distinguishable by a candidate DEG signature and HIV-specific T cell immune responses. Larger studies are warranted to assess these novel profiles of host immunity in vertically HIV-infected children under ART and whether they can be targeted in functional cure approaches.

867 INTESTINAL DAMAGE AND INFLAMMATION IN PERINATALLY HIV-1- INFECTED AFRICAN INFANTS Wei Li A. Koay 1 , Jane Lindsey 2 , Priyanka Uprety 3 , Mutsa Bwakura- Dangarembizi 4 , Adriana Weinberg 5 , Myron Levin 5 , Deborah Persaud 1 1 Johns Hopkins Hospital, Baltimore, MD, USA, 2 Harvard University, Cambridge, MA, USA, 3 University of Pennsylvania, Philadelphia, PA, USA, 4 University of Zimbabwe, Harare, Zimbabwe, 5 University of Colorado Denver, Denver, CO, USA Background: Heightened inflammation and immune activation are features of HIV-1 infection, for which impaired intestinal integrity with microbial translocation are implicated. We compare markers of gut integrity and inflammation in perinatal HIV-1 infection. Methods: We compared plasma levels of intestinal barrier markers (iFABP and zonulin) in HIV-1-infected (HIV+) infants and HIV-1-exposed uninfected (HEU) African infants enrolled in a clinical trial (IMPAACT P1072) of rotavirus vaccine (RotaTeq™). In prior analyses, significantly higher levels of sCD14, IFNγ, IL1-β, IL-2, IL-6 and IL-10 were found in the HIV+ vs. HEU infants. iFABP and zonulin were measured pre-vaccine and after the last vaccine (PD3). Categorical variables were compared by Fisher’s exact test and continuous variables by Wilcoxon rank sum tests. Spearman correlations and linear regression (log 10 scale) were used to compare levels by HIV-1, breastfeeding and vaccine received. Results: This analysis includes 56 HIV+ (ART-treated) and 53 HEU infants of similar age and breastfeeding status (Table 1). At entry, HIV+ had lower WHO weight-for-age Z (WAZ) scores and CD4% than HEU infants. iFABP levels did not differ significantly by HIV-1 status. In HIV+ infants, iFABP levels did not significantly correlate with viral load, CD4%, sCD14 and WAZ scores, but positively correlated with IL-6 (r=0.3, p=0.03) and was lower in breastfed infants. iFABP levels did not change by PD3 and did not correlate with serum anti-rotavirus IgA PD3. Zonulin levels at entry did not differ significantly by HIV-1, breastfeeding, or WAZ scores, and levels in HIV+ did not associate with CD4% or sCD14, but negatively correlated with viral load (r=-0.28, p=0.045) and IL-10 (r=-0.32, p=0.02). In contrast, to iFABP, between entry and PD3, zonulin levels in HIV+ increased compared to a decrease in HEU (p=0.010). In HEU infants, zonulin levels positively correlated serum anti-rotavirus IgA PD3 (r=0.48, p=0.014). Conclusion: Despite higher levels of inflammation and immune activation in HIV+ compared with HEU at entry, iFABP and zonulin levels did not differ, suggesting alternate mechanisms for HIV-associated inflammation and immune activation in perinatal HIV-1 infection. Across both groups, iFABP was significantly lower in breastfed infants and zonulin differentially increased in HIV+ but decreased in HEU infants by PD3. Changes in zonulin in HIV+ over time may imply the loss of tight junction regulation in perinatal HIV-1 infection despite early ART.

Poster Abstracts

CROI 2018 329