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Researchers used single-cell RNA sequencing of over 42,000 T cells from human tonsil tissue to show that HIV infection exists on a continuous spectrum rather than in discrete categories, with viral transcriptional activity serving as a key organizing principle of infected cell biology. As viral transcription increases along this continuum, infected cells undergo coordinated changes in immune, metabolic, and inflammatory programs, with lower-activity cells showing innate immune responses and higher-activity cells exhibiting metabolic activation. Antiretroviral therapy reduced highly active infected cells but preserved lower-activity populations, compressing rather than eliminating the viral continuum.
Why it matters
This work challenges the traditional view of HIV-infected cells as a single population and provides a quantitative framework for understanding viral persistence in lymphoid tissue, the main barrier to HIV cure. The finding that antiretroviral therapy fails to eliminate lower-activity infected cells may help explain why the virus rebounds after treatment interruption and could guide development of new therapeutic strategies targeting the full spectrum of infected cell states.
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⚠️ Preprint – Noch nicht peer-reviewed
Dieser Artikel wurde noch nicht von unabhängigen Experten begutachtet. Die Ergebnisse sind vorläufig und sollten mit Vorsicht interpretiert werden.
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.
Source: A transcriptional continuum links viral burden and host-cell biology in human lymphoid tissue