T cell activation and B cell interaction signatures in rectal tissues are associated with HIV replication in ex vivo model of infection.

• Type of Material: Article
• Authors: Stacey Abigail Smith, Emory University; Phillip M. Murray, Emory University; Praveen K. Amancha, Emory University; Cassie Grimsley Ackerley, Emory University; Gregory K. Tharp, Emory University; Steven Bosinger, Emory University; Rama Rao Amara, Emory University; Colleen Kelley, Emory University
• Language: English
• Date: 2022-08-12
• Publisher: Wolters Kluwer Health, Inc.
• Publication Version: Author Accepted Manuscript (After Peer Review)
• Copyright Statement: © 2022 Wolters Kluwer Health, Inc. All rights reserved.
• Final Published Version (URL): https://doi.org/10.1097/QAD.0000000000003356
• Title of Journal or Parent Work: AIDS
• Volume: 36
• Issue: 15
• Start Page: 2101
• End Page: 2106
• Grant/Funding Information: This work was funded by NIH R01 AI108335 and HD092033 (CFK). Next generation sequencing services were provided by the Emory National Primate Research Center Genomics Core, which is supported in part by NIH P51 OD011132. CMG was supported by T32 DK108735 and K12 HD085850. Additional services and support made available by Emory CFAR (P30 AI050409).
• Keywords: rectal tissue transcriptomic signatures; rectal mucosa; men who have sex with men; ex vivo model; HIV
• Research Categories: Health Sciences, Epidemiology; Health Sciences, Public Health

Abstract

Objective: The rectal mucosa is a critical site of HIV vulnerability. We sought to identify transcriptomic features of rectal mucosal tissue prior to exposure associated with support or restriction of HIV replication. Design: Rectal tissue from HIV-negative cisgender men (n=57) underwent concurrent i) RNAseq transcriptomic analyses (2 biopsies/participant) and ii) challenge with HIV in the ex vivo explant model of infection (3 biopsies challenged/participant) as part of a larger cohort study to understand the rectal mucosal immune environment among men who have sex with men. Methods: P24 was quantified in the explant supernatants over a culture period of 18 days via ELISA. Participant median p24 log Area Under the Curve was correlated with bulk transcriptomic data (Illumina HiSeq3000) to identify associations between gene expression and p24 production. Significant differentially expressed genes (DEG) were identified via DESeq2 analysis, and analyzed with Reactome to identify pathways of interest. Results: 183 DEG (181 upregulated, 2 downregulated) were associated with higher p24 accumulation in the ex vivo challenge model, including T cell activation, B cell function, and chemokine DEG. Reactome analysis of the upregulated genes identified ‘Adaptive Immune System’, ‘Cytokine Signaling in Immune System’, and ‘Innate Immune System’ as significant upregulated pathways. Conclusions: For the first time, we identified rectal tissue transcriptomic signatures associated with increased p24 production utilizing an ex vivo model. Our findings are highly relevant to HIV transmission and the early establishment of HIV reservoirs in humans, and future studies should examine the identified pathways as targets for new or improved biomedical prevention or treatment interventions.