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Background <p>Despite effective antiretroviral therapy (ART), people living with HIV (PLWH) often exhibit persistent immune activation, the mechanisms of which remain unclear. Increasing evidence suggests that residual low-level viremia and ongoing viral protein expression may persist even under long-term suppressive ART, underscoring the need for a better understanding of residual HIV persistence.</p> Methods <p>We therefore optimized a digital single-molecule array (Simoa®) technology to detect ultra-low levels of HIV p24 antigen in plasma, achieving femtogram sensitivity. In addition, we used flow cytometry to analyze HIV-specific T cell responses.</p> Results <p>Here we show that in a cohort of 108 participants with chronic HIV on long-term ART with HIV-1 RNA &lt; 30 copies/mL for &gt;4 years, p24 is detectable (17 − 370 fg/mL) in 42. Dual protease inhibitor therapy is associated with significantly lower p24 levels (p  &lt;  0.05), while age, ART duration or CD4/CD8 ratio show no effect. Monitoring 41 individuals who initiated ART during acute HIV, p24 remains detectable in 20% after two years. Although p24 correlates with viral RNA early in ART (r = 0.83, p &lt; 0.0001), this association is lost after two months (r = 0.20, p = 0.21). Importantly, p24+ individuals show significantly higher frequencies of PD-1 + , CD38 + , and CD38 + HLA-DR + CD8 T cells (p  &lt;  0.01; p  &lt;  0.05), alongside enhanced TNF-α and CD107a responses to HIV Gag (p  &lt;  0.01; p  &lt;  0.05).</p> Conclusions <p>To best of our knowledge, our findings provide the first large-cohort evidence of low-level p24 persistence during suppressive ART and suggest that ongoing p24 production may contribute to residual immune activation in treated PLWH.</p>

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Ultra-low level HIV p24 drives immune activation in antiretroviral therapy-treated people living with HIV

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年12月2日

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  • Enrico Richter,
  • Julia König,
  • Antonia Büning,
  • Theresa Bechtel,
  • Andrea Casado,
  • Jernej Pušnik,
  • Trevor A. Crowell,
  • Heiko Jessen,
  • Jürgen K. Rockstroh,
  • Christoph Boesecke,
  • Stefan Esser,
  • Christoph Stephan,
  • Hendrik Streeck

摘要

Background

Despite effective antiretroviral therapy (ART), people living with HIV (PLWH) often exhibit persistent immune activation, the mechanisms of which remain unclear. Increasing evidence suggests that residual low-level viremia and ongoing viral protein expression may persist even under long-term suppressive ART, underscoring the need for a better understanding of residual HIV persistence.

Methods

We therefore optimized a digital single-molecule array (Simoa®) technology to detect ultra-low levels of HIV p24 antigen in plasma, achieving femtogram sensitivity. In addition, we used flow cytometry to analyze HIV-specific T cell responses.

Results

Here we show that in a cohort of 108 participants with chronic HIV on long-term ART with HIV-1 RNA < 30 copies/mL for >4 years, p24 is detectable (17 − 370 fg/mL) in 42. Dual protease inhibitor therapy is associated with significantly lower p24 levels (p  <  0.05), while age, ART duration or CD4/CD8 ratio show no effect. Monitoring 41 individuals who initiated ART during acute HIV, p24 remains detectable in 20% after two years. Although p24 correlates with viral RNA early in ART (r = 0.83, p < 0.0001), this association is lost after two months (r = 0.20, p = 0.21). Importantly, p24+ individuals show significantly higher frequencies of PD-1 + , CD38 + , and CD38 + HLA-DR + CD8 T cells (p  <  0.01; p  <  0.05), alongside enhanced TNF-α and CD107a responses to HIV Gag (p  <  0.01; p  <  0.05).

Conclusions

To best of our knowledge, our findings provide the first large-cohort evidence of low-level p24 persistence during suppressive ART and suggest that ongoing p24 production may contribute to residual immune activation in treated PLWH.