Atlas of HIV cis-regulatory elements reveals extensive transcriptional variation across clades, isolates, and within individuals
Year: 2026
Type: preprint
Abstract: Human immunodeficiency virus (HIV) replication, persistence, and reactivation depend on transcription from integrated proviruses. Despite extensive sequence variation, how viral genetic diversity influences transcriptional regulation remains poorly understood. Here, we generate a functional regulatory atlas of HIV-1 and HIV-2 by combining tiling and saturation mutagenesis massively parallel reporter assays (MPRAs) with comparative sequence analysis and predictive modeling. By profiling thousands of HIV isolates in Jurkat and human primary CD4+T cells, we reveal extensive variation in baseline and stimulus-induced long terminal repeat (LTR) activity across and within clades, driven by distinct transcription factor configurations. These activities frequently differ among proviruses from the same individual and shift over infection and transmission without consistent selection for activity. Beyond the LTR, we identify conserved intragenic cis-regulatory elements, revealing regulatory architectures that complement LTR activity. Finally, we develop sequence-based models that accurately predict transcriptional activity, enabling scalable functional annotation of viral diversity and evolution.
Authors: Berkay Engin, Mohamed Yousry ElSadec, Joseph Alexander Finkelberg, Tommy Henry Taslim, Daniel L. Bryant, Luis Soto-Ugaldi, Susan Kales, Ching-Huang Ho, Maryam Dashtiahangar, George Muñoz-Esquivel, Elvis Morara, Jacob Purinton, Benedetta D’Elia, Rodrigo Castro, Harshpreet Chandok, Matias Alejandro Paz, Trevor Siggers, John P. Ray, Andrew J. Henderson, Ryan Tewhey, Juan I. Fuxman Bass
Language: English
Topic: HIV Research and Treatment
Subfield: Virology
Field: Immunology and Microbiology
Domain: Life Sciences
Open Access status: green
Funders: Crohn's and Colitis Foundation, National Institutes of Health, National Institute on Drug Abuse, National Human Genome Research Institute, National Institute of General Medical Sciences, National Institute of Allergy and Infectious Diseases, National Institute of Diabetes and Digestive and Kidney Diseases
Awards: G2988374255, T cells promoting transitions toward autoimmunity, Investigating Genetic and Epigenetic Control of T Cell Function in Autoimmunity, Biophysical and functional characterization of immune-related regulatory elements and noncoding variants, G9000166209, Providence/Boston Center for AIDS Research (CFAR), Structure and Function of Immune Gene Regulatory Networks, Defective HIV proviruses and Persistent Innate Immune Activation, Genetic variants guiding pathogenicity of colitogenic T cells, Persistent HIV-1 expression and microglia dysfunction, BU Clinical HIV/AIDS Research Training Program (BU-CHART, Synthetic Biology and Biotechnology (SB2) Predoctoral Training Program, Functional Mapping of Enhancer Conservation Between Species to Enable Mechanistic Insights into Polygenic Disease, Predoctoral Training in Bioinformatics and Computational Biology
OpenAlex ID: W7150784368