CROI 2020 Abstract eBook

Abstract eBook

Poster Abstracts

analysis showed BMI increase was significantly associated with low body weight and low CD4 counts before ART, use of tenofovir alafenamide (TAF) as the treatment backbone, smoking, and the SNP −420G allele in the INSTI group. In this group, the fully adjusted multiple linear regression analysis showed low body weight (p=0.016) before ART, use of TAF(p=0.028), smoking (p=0.027), and the SNP −420G allele (p=0.005) were associated with BMI increase. PSs was significantly associated with smoking and the SNP −420G allele in simple (p=0.027, p=0.004) and fully adjusted (p=0.026, p=0.001) linear regression analyses. In the PI group, BMI increase was associated with low BMI before ART (p=0.0014), but no factors were associated with PSs. Conclusion: We showed that the −420C>G resistin gene is independently associated with weight gain and PSs in PLWH on INSTI. This highlights the pivotal role of resistin in linking INSTI-related symptoms characterized by insulin resistance. 671 ADIPOCYTE DYSFUNCTION DESPITE REDUCED ADIPOSE INFLAMMATION IN DIABETICS WITH HIV Samuel Bailin 1 , Spyros Kalams 1 , Simon Mallal 1 , Fei Ye 1 , Run Fan 1 , Mona Mashayekhi 1 , Curtis Gabriel 1 , John Koethe 1 , Celestine Wanjalla 1 1 Vanderbilt University, Nashville, TN, USA Background: Adipose tissue has a central role in the regulation of metabolism. Exposure to early antiretroviral therapy (ART) regimens, including thymidine analogues, was associated with increased adipose tissue inflammation and risk of diabetes in persons with HIV (PWH). Few studies have assessed the relationship of adipose tissue inflammation and insulin resistance in PWH on newer ART regimens. Methods: 73 PWH with > 12 months sustained viral suppression, principally on integrase inhibitor-based ART and < 10%with historic thymidine analogue exposure, were classified as insulin sensitive (n = 46; hemoglobin A1c < 5.7% and fasting blood sugar < 100 mg/dL) vs. diabetic (n = 27; on anti-diabetic medications) and underwent subcutaneous abdominal adipose tissue liposuction. Tissue was immediately flash frozen for subsequent total RNA extraction, and mRNA was quantified using the Nanostring nCounter® human inflammation panel containing 250 genes, and a separate panel containing 77 genes modified from the KEGG adipocytokine pathway. mRNA expression was compared by diabetes status adjusting for age, sex, and body mass index (BMI). Results: 78% of study participants were male. The median age was 45 years and 55 years, and median BMI 31 kg/m 2 and 34 kg/m 2 , for non-diabetic and diabetic participants, respectively. Analysis of adipocyte-related genes revealed that diabetic individuals had lower expression of genes involved in the AMPK signaling (FASN, PPARG, PCK2) and fatty acid biosynthesis (FASN, ACSL6) pathways, and increased expression of genes involved in fatty acid degradation (ACOX1, ACSL3) (FDR-adjusted p value < 0.05; Figure 1). Inflammatory gene analysis showed that diabetics had lower expression of genes related to inflammation than non-diabetics, including NF-kappa B signaling and cytokine- cytokine interaction pathways (FDR-adjusted p value < 0.05; Figure 1). Conclusion: In one of the largest and broadest assessments of adipose tissue gene expression in non-diabetic vs. diabetic PWH on modern ART, we found pronounced differences in adipocyte-related genes, consistent with dysregulation of metabolic pathways in diabetes, but less evidence of increased adipose tissue inflammation in contrast to studies of PWH on older ART. Single- cell studies are planned to investigate whether adaptive immune cells or other mechanisms that may not be captured in whole tissue contribute to adipocyte dysfunction and diabetes.

672 INCREASED INFLAMMATORY CX3CR1+GPR56+CD57+ CD4+ T CELLS IN FAT FROM HIV+ DIABETICS Celestine Wanjalla 1 , Wyatt J. McDonnell 1 , Ramesh Ram 2 , Abha Chopra 2 , Rama Gangula 1 , Shay Leary 2 , Beverly O. Woodward 1 , Mark Pilkinton 1 , Mona Mashayekhi 1 , Samuel Bailin 1 , Curtis Gabriel 1 , Alyssa Hasty 1 , Simon Mallal 1 , Spyros Kalams 1 , John Koethe 1 1 Vanderbilt University, Nashville, TN, USA, 2 Murdoch University, Murdoch, Australia Background: Persons with HIV are at higher risk of diabetes mellitus compared to the general population, which may be due, in part, to altered lipid metabolism and storage. Compared to HIV+ non-diabetics, adipose tissue from HIV+ diabetics is enriched for CX3CR1+ GPR56+ CD57+ (i.e., ‘C-G-C’) CD4+ T cells and a separate population of CD69+ CD4+ T cells. CX3CR1 and GPR56 are associated with anti-viral responses, including against cytomegalovirus (CMV). To assess if these cells are also common in HIV-negative diabetics, we compared C-G-C and CD69+ T cells in the adipose tissue of HIV+ vs. HIV-negative diabetics of similar age and body mass index. Methods: We performed subcutaneous abdominal liposuction and T cell isolation on 11 diabetic persons (6 HIV+ and 5 HIV-negative, all subjects CMV+), followed by flow cytometry phenotyping and single-cell sorting of memory T cells. Single-cell cDNA libraries were created using well-specific barcodes followed by 3’ and 5’ amplification and sequencing. Pooled data were demultiplexed and the transcriptome was linked to the indexed flow cytometry phenotype. We compared the proportion of C-G-C and CD69+ CD4+ T cells by HIV status using Mann-Whitney tests. Differential expression and pathway analyses were performed for immune genes in C-G-C and CD69+ CD4+ T cells in the HIV+ and HIV-negative participants. Results: A larger fraction of the adipose tissue memory CD4+ T cells from HIV+ diabetics expressed the C-G-C combination (23% versus 3% in HIV-negative, p<0.05; Fig. A), CD69+ cells trended higher in the HIV-negative (54% versus 28% in HIV-positive, p= 0.18). The proportion of adipose tissue C-G-C cells was positively correlated with the percent of T effector memory RA+ cells (p < 0.01), a subset expanded in CMV infection. Compared to adipose tissue C-G-Clo cells, pathway analysis of the top 100 immune genes expressed by C-G-C cells in the HIV+ diabetics indicated TH1, interferon-gamma response (Fig. B) and IL-27 signaling pathways (a promoter of TH1 polarization). Conclusion: Adipose tissue of diabetic HIV+ is enriched for an inflammatory population of potentially anti-viral CD4+ T cells expressing CX3CR1, GPR56 and CD57, which are present at far lower levels in HIV-negative diabetics. Adipose tissue serves as a reservoir for HIV, CMV, and other viruses, and further studies will determine if C-G-C cell responses target viral antigens and may impair adipocyte function.

Poster Abstracts

CROI 2020 245