CROI 2019 Abstract eBook

Abstract eBook

Poster Abstracts

(WC), years on ART, pre-ART HIV RNA, pre-ART CD4 count, initial ART regimen (PI, NNRTI or INSTI) on HIV persistence. Assessments were done at study entry or, for WC, at pre-study visit. Results: 295 participants (53 females) were evaluated; median (IQR) age 48yr (41, 54); yrs on ART 7 (6, 10); BMI 27 (24, 31); WC 94cm (87, 102). CA-DNA, CA-RNA and plasma SCA were positively correlated with pre-ART HIV RNA (r=0.35, 0.29, 0.20; respectively, p-values <0.001), and negatively with pre-ART CD4 count (-0.35, -0.21, -0.12, respectively, all p <0.05). Regimen type was not associated with HIV persistence markers after controlling for ART duration. Males were more likely than females to have plasma SCA values ≥0.4 copies/mL (52% vs 29%, p=0.003) (Figure), even after adjusting for age, pre-ART HIV RNA and CD4 count, years on ART and BMI (p=0.004). Higher BMI and higher WC were each associated with higher SCA levels (r=0.12 and 0.13, p<0.04) after adjustment for age, sex, pre-ART HIV RNA and CD4 count, and years on ART. The proportion of participants with detectable residual viremia increased in a step-wise fashion by BMI category: normal/underweight 38%; overweight 50%; obese 55% (Figure). Sex, BMI and WC were not associated with CA-DNA or CA-RNA. Conclusion: Higher BMI and obesity are associated with higher levels of residual viremia in persons on long-term ART. Adipose tissue may be an important site of HIV production due to its proinflammatory milieu or altered ARV penetration. The finding that females have lower residual viremia than males may reflect effects of estrogen on HIV expression or other biologic and immunologic differences. Studies of the mechanism by which obesity and sex affect HIV persistence are needed to inform cure strategies.

lower levels of cell-associated HIV RNA when compared to cells with high cell-surface fucose (P<0.05 Wilcoxon test; 17.2 fold for core fucose and 8.2 fold for branched fucose). Principal component analysis of the transcriptomic profiles showed a clear clustering between the two groups, with the activity of carbohydrate metabolism, glycolysis, T-cell trafficking, mTOR signaling, and ERK/MAPK signaling, being significantly elevated in high-fucose cells when compared to low-fucose cells (FDR<0.0001). Conclusion: Cell-surface fucosylation and enhanced carbohydrate metabolic activity are associated with higher T cell activation and persistent HIV transcriptional activity during suppressive ART. T cell surface fucosylation is known to be critical for memory T cell activation and trafficking. Together, the role of T cell-surface fucosylation and altered carbohydrate metabolic activity in HIV persistence warrants further investigation, in order to identify glycan-based interactions that can be targeted for novel HIV immunotherapies.

Poster Abstracts

385 CD4+ T-CELL-SURFACE FUCOSYLATION DEFINES PERSISTENT HIV TRANSCRIPTION IN VIVO Florent Colomb 1 , Leila B. Giron 1 , Andrew V. Kossenkov 1 , Emilie Battivelli 2 , Emmanouil Papasavvas 1 , Luis Montaner 1 , Eric Verdin 2 , Clovis S. Palmer 3 , Mohamed Abdel-Mohsen 1 1 Wistar Institute, Philadelphia, PA, USA, 2 The Buck Institute for Research on Aging, Novato, CA, USA, 3 Burnet Institute, Melbourne, VIC, Australia Background: Cell-surface glycosylation and glycan-lectin signaling play critical roles in modulating several immunological responses. However, the relevance of host glycosylation machinery to HIV persistence is yet to be determined. We characterized the relationship between cell-surface glycomic signatures of HIV+ cells and levels of persistent HIV transcription, in vitro and in vivo. Methods: Primary CD4+ T cells were infected with a dual-reporter virus that enables isolation and characterization of transcriptionally inactive HIV+, transcriptionally active HIV+, or uninfected cells. Lectin microarray was used to examine the cell-surface glycomic signatures of sorted populations. We validated our in vitro analysis in vivo by sorting CD4+ T cells from 7 HIV+ individuals on suppressive antiretroviral therapy (ART) into populations with distinct glycomic profiles, using fluorescently-labeled lectins. RNA-Seq and qPCR were used in the sorted population to 1) characterize the transcriptomes, and 2) measure levels of HIV DNA and cell-associated HIV RNA, respectively. Ingenuity pathway analysis was used to evaluate the functional significance of differentially expressed genes. Results: The glycomic signature of in-vitro sorted transcriptionally inactive HIV+ cells clustered distinctly from the other populations due to the lower binding intensity of a selective set of lectins specific for core and branched fucose. Low-fucose sorted CD4+ T cells from HIV+ ART+ individuals exhibited


Florent Colomb 1 , Leila B. Giron 1 , Thomas Premeaux 2 , Toshiro Niki 3 , Emmanouil Papasavvas 1 , Luis Montaner 1 , Lishomwa C. Ndhlovu 2 , Mohamed Abdel-Mohsen 1 1 Wistar Institute, Philadelphia, PA, USA, 2 University of Hawaii at Manoa, Honolulu, HI, USA, 3 GalPharma Co., Ltd., Takamatsu-shi, Japan Background: Endogenous plasma levels of the immunomodulatory carbohydrate-binding protein galectin-9 (Gal-9) are elevated during HIV infection and remain elevated after antiretroviral therapy (ART) suppression. We recently reported that Gal-9 regulates HIV transcription and potently reactivates latent HIV [PMID 27253379]. Given that galectins are known to modulate TCR- signaling, we hypothesized that TCR signaling transduction contributes to the pharmacological inhibitor of Lck activity, we evaluated the role of TCR signaling in Gal-9-mediated 1) latent HIV reactivation, 2) T cell activation, and 3) cytokine secretion using the J-Lat 5A8 HIV latency model and CD4+ T cells from 5 HIV+ individuals on suppressive ART. Effects of Gal-9 on TCR-downstream kinase phosphorylation was examined by Phospho-Kinase antibody arrays. Results: Gal-9 induced CD3-ζ phosphorylation (11.2% to 32.1%; P=0.008). Inhibition of Lck activity reduced Gal-9-mediated viral reactivation in the JLat 5A8 cells (15.8% to 1.5%; P<0.0001). In addition, Lck inhibitor reduced both Gal-9-mediated T cell activation (10.4% to 1.6% CD69/CD25 co-expression; P<0.0001), and IL-2/TNF secretion (P<0.001), in primary CD4+ T cells. Gal-9 increased the phosphorylation of the TCR-downstream signaling molecules Gal-9-mediated modulation of HIV transcriptional activity. Methods: Using an anti-phosphorylated-CD3-ζ antibody and a

CROI 2019 138

Made with FlippingBook - Online Brochure Maker