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

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.