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Published on: September 19, 2010
HIV-1 Tat Upregulates TREM1 Expression in Human Microglia
Grant R Campbell1, Pratima Rawat2, Rachel K To2
1Division of Basic Biomedical Sciences, Sanford School of Medicine, University of South Dakota, Vermillion, SD.
Abstract:
Because microglia are a reservoir for HIV and are resistant to the cytopathic effects of HIV infection, they are a roadblock for any HIV cure strategy. We have previously identified that triggering receptor expressed on myeloid cells 1 (TREM1) plays a key role in human macrophage resistance to HIV-mediated cytopathogenesis. In this article, we show that HIV-infected human microglia express increased levels of TREM1 and are resistant to HIV-induced apoptosis. Moreover, upon genetic inhibition of TREM1, HIV-infected microglia undergo cell death in the absence of increased viral or proinflammatory cytokine expression or the targeting of uninfected cells. We also show that the expression of TREM1 is mediated by HIV Tat through a TLR4, TICAM1, PG-endoperoxide synthase 2, PGE synthase, and PGE2-dependent manner. These findings highlight the potential of TREM1 as a therapeutic target to eradicate HIV-infected microglia without inducing a proinflammatory response.
Insights
HIV-infected microglia resist cell death via TREM1 (triggering receptor expressed on myeloid cells 1). Inhibiting TREM1 causes HIV-infected microglia death, offering a potential HIV cure strategy.
Area of Science:
- Neuroimmunology
- Virology
- Cellular Biology
Background:
- Microglia serve as a reservoir for HIV.
- Microglia are resistant to HIV-induced cell damage, hindering HIV cure efforts.
- Triggering receptor expressed on myeloid cells 1 (TREM1) is implicated in macrophage resistance to HIV.
Purpose of the Study:
- To investigate the role of TREM1 in HIV-infected microglia resistance to apoptosis.
- To explore TREM1 as a therapeutic target for eradicating HIV from microglia.
Main Methods:
- Assessed TREM1 expression in HIV-infected human microglia.
- Genetically inhibited TREM1 in HIV-infected microglia.
- Analyzed cell death, viral load, and cytokine expression.
- Investigated TREM1 regulation by HIV Tat via TLR4 signaling pathway.
Main Results:
- HIV-infected microglia exhibit increased TREM1 expression and resistance to apoptosis.
- Genetic inhibition of TREM1 leads to HIV-infected microglia cell death without increased viral or inflammatory markers.
- HIV Tat upregulates TREM1 through a pathway involving TLR4, TICAM1, PTGS2, and PGE2.
Conclusions:
- TREM1 is crucial for HIV-infected microglia survival.
- Targeting TREM1 can induce selective death of HIV-infected microglia.
- This approach offers a potential strategy for HIV eradication without causing inflammation.
