Authors
Mangold, J. F., Schrode, N., Fortune, T., Keane, A. M., Shroff, S., Petri, S., Tweel, B., Beaumont, K. G., Swartz, T. H.
Abstract
Human immunodeficiency virus (HIV-1) persistence in lymphoid tissue remains a major barrier to cure, yet infected cells are commonly represented using discrete categories that may obscure biologically meaningful heterogeneity. Using an ex vivo human tonsil explant model and single-cell RNA sequencing of more than 42,000 T cells, we show that HIV transcription spans a structured continuum and that viral transcriptional burden functions as an organizing axis of host-cell biology. Across the continuum, increasing HIV transcription is associated with coordinated remodeling of immune, inflammatory, metabolic, and redox-associated programs. Lower transcriptional tiers were enriched for innate sensing and inflammasome-associated responses, whereas higher tiers exhibited activation of oxidative phosphorylation and redox-buffering pathways. Antiretroviral therapy preferentially depleted highly transcriptionally active populations while preserving lower and intermediate tiers, resulting in compression rather than elimination of the continuum. Together, these findings provide a quantitative framework for interpreting HIV transcriptional heterogeneity within human lymphoid tissue and suggest that persistent viral activity reflects a spectrum of host-virus states rather than a single infected-cell population. By linking viral transcriptional burden to distinct host-cell programs, this framework may inform future strategies to reduce HIV persistence and its associated inflammatory consequences.
Preprint server:
bioRxiv
The authors list and abstract were imported from bioRxiv on 12 Jul 2026.
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