CROI 2019 Abstract eBook

Abstract eBook

Oral Abstracts

1 Wistar Institute, Philadelphia, PA, USA, 2 Genos Glycoscience Research Laboratory, Zagreb, Croatia, 3 Philadelphia FIGHT, Philadelphia, PA, USA, 4 Blood Systems Research Institute, San Francisco, CA, USA, 5 Rush University, Chicago, IL, USA, 6 University of Hawaii, Honolulu, HI, USA, 7 University of Zagreb, Zagreb, Croatia Background: A comprehensive understanding of the pathophysiological mechanisms driving HIV-associated chronic inflammation can lead to the development of strategies to delay or prevent age-associated co-morbidities that are increasingly prevalent despite suppressive antiretroviral therapy (ART). Glycans on circulating glycoproteins and immunoglobulin G (IgGs) are known to modulate systemic inflammatory responses. However, whether HIV-associated chronic inflammation, at least in part, is promoted by alterations in the host glycome remains unknown. Methods: We profiled the glycomes of plasma and IgGs from 40 HIV+ individuals (ART-suppressed and viremic) and 10 matched HIV- controls, including a subset of ART-suppressed individuals with variation in levels of HIV- associated cognitive impairment as measured by clinical global deficit scores (GDS). We also measured levels of 16 pro- and anti-inflammatory cytokines, and markers of T-cell activation, using Luminex and flow cytometry, respectively. False discovery rates (FDR) were computed to adjust for multiple comparisons. Results: HIV infection was associated with persistent alterations in plasma and IgG glycomes, including decreased levels of the anti-inflammatory highly-sialylated glycans when compared to HIV- controls (FDR < 0.05). Levels of IgGs highly-sialylated glycans were reduced with age in HIV+ ART+ individuals (rho = -0.72, p = 0.005). Levels of plasma highly-sialylated glycans (A4G4S3) correlated with higher CD4 count (rho=0.57, p=0.03), lower levels of CD4+ T cell activation (rho = -0.66, p = 0.004), and lower levels of the pro-inflammatory cytokine TNFα (rho = -0.8, p = 0.0009). Finally, when we compared levels of glycan structures between HIV+ ART+ individuals with and without cognitive impairment (with comparable CD4 count, nadir CD4, and age), we found that levels of seven glycan structures were statistically different between the two groups (FDR<0.05). When the levels of these seven glycan structures were correlated with GDS, we found that levels of hypo- sialylated oligosaccharides positively correlate with the degree of neurological impairment (rho = 0.84, p = 0.0001). Conclusion: Our data show that altered glycosylation patterns persist despite suppressive ART, and suggest that lower levels of sialylated glycans, with documented anti-inflammatory roles, may contribute to immune activation, chronic inflammation, and the pathogenesis of combinatorial HIV- and age- associated co-morbidities affecting the central nervous system.

Oral Abstracts

123 DEEP-LEARNING CEREBRAL BLOOD FLOW FOR COGNITIVE-IMPAIRMENT CLASSIFICATION IN HIV Patrick Luckett , Julie Wisch, Sarah A. Cooley, Beau M. Ances Washington University in St Louis, St Louis, MO, USA Background: Despite the use of combination antiretroviral therapy (cART), HIV-associated neurocognitive disorders (HAND) remain prevalent in people living with HIV (PLWH). A potential biomarker reflective of HAND is changes in cerebral blood flow (CBF) over time, which can be measured with Arterial Spin Labeling. We propose a method of approximating and classifying cognitive impairment (CI) in PLWH using longitudinal CBF data and deep neural networks (DNN). Methods: Virologically controlled (viral load < 50 copies/mL) PLWH (n=63) participants and HIV- controls (n=33) with at least 2 separate imaging sessions were analyzed. The majority were male (54%) and the mean age was 48 years (+/-13.1). Free Surfer regions were combined to get an average CBF for 12 brain regions (cerebellum, thalamus, caudate, putamen, pallidum, hippocampus, amygdala, frontal, parietal, temporal, cingulate, occipital). Participants completed neuropsychological testing representing 3 cognitive domains (learning, memory, and executive). Raw scores were transformed into Z-scores using demographic-corrected norms, and Z-scores within a cognitive domain were averaged for domain Z-scores. A domain Z-score < -1 was classified as CI. Average rates of change (AROC) were calculated by subtracting the CBF of time point 1 from time point 2 and dividing by the time between the scans. A DNN was trained for each cognitive domain on the CBF and AROC using cross- validation, and evaluated based on mean squared error (MSE). A low MSE (< .2) indicates good approximation. Results: A DNN could discriminate between PLWH and HIV- controls with AUC .94 using CBF and AROC. The best individual brain regions for discriminating these 2 groups were the thalamus, amygdala, pallidum, and hippocampus. For CI prediction in PLWH, the MSE for the DNNs across all brain regions in PLWH was .11 and AUC .86. The best predictors of impairment in the learning domain in PLWH using CBF and AROC were the caudate, thalamus, and putamen. The best predictors in the memory domain in PLWH were the putamen and amygdala. The best predictors in the executive domain in PLWH were the cerebellum cortex and cingulate. All regions showed a reduction in CBF over time in PLWH. Conclusion: HAND persist in spite of cART. Our models indicates a decrease in CBF is associated with HIV in specific brain regions, and the rate of decrease of CBF is indicative of impairment. These changes are involved in various domains and are primarily subcortical in nature. 124 HOST GLYCOMIC DETERMINANTS OF HIV-ASSOCIATED NEUROCOGNITIVE IMPAIRMENT DURING THERAPY Leila B. Giron 1 , Irena Trbojevic-Akmacic 2 , Kenneth M. Lynn 1 , Surya Vadrevu 1 , Alitzel Anzurez 1 , KaramMounzer 3 , Philip J. Norris 4 , Alan Landay 5 , Thomas Premeaux 6 , Gordan Lauc 7 , Cecilia Shikuma 6 , Luis Montaner 1 , Lishomwa C. Ndhlovu 6 , Mohamed Abdel-Mohsen 1

125 CSF SCD30 ELEVATION DESPITE SUPPRESSIVE ART SUGGESTS CNS HIV PERSISTENCE Michael Peluso 1 , Cassandra Thanh 1 , Louise Hogan 1 , Sophie Stephenson 1 , Steven G. Deeks 1 , Magnus Gisslén 2 , Richard W. Price 1 , Timothy J. Henrich 1 1 University of California San Francisco, San Francisco, CA, USA, 2 University of Gothenburg, Gothenburg, Sweden Background: HIV-1 RNA is often but variably enriched in CD30+ CD4 T cells in HIV-infected individuals on suppressive ART. ART reduces soluble CD30 (sCD30) levels in plasma, but not surface expression on T cells, and treatment with an anti-CD30 antibody-drug conjugate reduces HIV burden in cells from ART- suppressed individuals in vitro and in vivo. This study investigates sCD30 in the central nervous system (CNS), a potential HIV reservoir, as a marker of persistent HIV infection.

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CROI 2019