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<p>Microglia serve as a long-lived reservoir for HIV in the brain and are resistant to the cytopathic effects of infection. As such, they pose a significant barrier to eradication strategies and contribute to chronic neuroinflammation in people living with HIV. We previously identified that triggering receptor expressed on myeloid cells-1 (TREM1) is upregulated in HIV-infected human microglia and is associated with resistance to virus-associated cellular stress.</p><p>In this study, we examined the upstream mechanisms by which the HIV-1 envelope protein gp120 induces TREM1 expression in human monocyte-derived microglia. We found that gp120 induces TREM1 transcription through Toll-like receptor 2 (TLR2) and Toll-like receptor 4 (TLR4) signalling, and that this process requires prostaglandin E₂ (PGE₂) signalling through prostaglandin E₂ receptor EP4. Inhibition of TREM1 increased apoptotic DNA fragmentation and cytotoxicity in gp120-exposed microglia, consistent with a functional contribution of TREM1 in modulating apoptotic signalling under these conditions.</p><p>Together, these findings identify a TLR–PGE₂–TREM1 signalling axis that regulates innate immune responses and apoptotic marker modulation following HIV-1 envelope protein exposure. Given the contribution of long-lived microglia to HIV-associated neurocognitive disorders, the TREM1 pathway may represent a therapeutic target for modifying neuroinflammatory responses in the context of HIV infection.</p>

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HIV gp120 induces TREM1 expression through TLR–PGE₂ signalling in human monocyte-derived microglia

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年3月5日

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  • Ayisha Mahama,
  • Pratima Rawat,
  • Carmen Teodorof-Diedrich,
  • Stephen A. Spector,
  • Grant R. Campbell

摘要

Microglia serve as a long-lived reservoir for HIV in the brain and are resistant to the cytopathic effects of infection. As such, they pose a significant barrier to eradication strategies and contribute to chronic neuroinflammation in people living with HIV. We previously identified that triggering receptor expressed on myeloid cells-1 (TREM1) is upregulated in HIV-infected human microglia and is associated with resistance to virus-associated cellular stress.

In this study, we examined the upstream mechanisms by which the HIV-1 envelope protein gp120 induces TREM1 expression in human monocyte-derived microglia. We found that gp120 induces TREM1 transcription through Toll-like receptor 2 (TLR2) and Toll-like receptor 4 (TLR4) signalling, and that this process requires prostaglandin E₂ (PGE₂) signalling through prostaglandin E₂ receptor EP4. Inhibition of TREM1 increased apoptotic DNA fragmentation and cytotoxicity in gp120-exposed microglia, consistent with a functional contribution of TREM1 in modulating apoptotic signalling under these conditions.

Together, these findings identify a TLR–PGE₂–TREM1 signalling axis that regulates innate immune responses and apoptotic marker modulation following HIV-1 envelope protein exposure. Given the contribution of long-lived microglia to HIV-associated neurocognitive disorders, the TREM1 pathway may represent a therapeutic target for modifying neuroinflammatory responses in the context of HIV infection.