HIV-1 Tat Upregulates TREM1 Expression in Human Microglia

Overview

Journal J Immunol

Specialty Allergy & Immunology

Date 2023 Jun 16

PMID 37326481

Authors

Grant R Campbell

Pratima Rawat

Rachel K To

Stephen A Spector

Affiliations

Soon will be listed here.

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.

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References

Wei X, Decker J, Liu H, Zhang Z, Arani R, Michael Kilby J . Emergence of resistant human immunodeficiency virus type 1 in patients receiving fusion inhibitor (T-20) monotherapy. Antimicrob Agents Chemother. 2002; 46(6):1896-905. PMC: 127242. DOI: 10.1128/AAC.46.6.1896-1905.2002. View

Hogan P, Chen L, Nardone J, Rao A . Transcriptional regulation by calcium, calcineurin, and NFAT. Genes Dev. 2003; 17(18):2205-32. DOI: 10.1101/gad.1102703. View

Griffin D, Wesselingh S, McArthur J . Elevated central nervous system prostaglandins in human immunodeficiency virus-associated dementia. Ann Neurol. 1994; 35(5):592-7. DOI: 10.1002/ana.410350513. View

Ko A, Kang G, Hattler J, Galadima H, Zhang J, Li Q . Macrophages but not Astrocytes Harbor HIV DNA in the Brains of HIV-1-Infected Aviremic Individuals on Suppressive Antiretroviral Therapy. J Neuroimmune Pharmacol. 2018; 14(1):110-119. PMC: 6391194. DOI: 10.1007/s11481-018-9809-2. View

Gorantla S, Makarov E, Finke-Dwyer J, Castanedo A, Holguin A, Gebhart C . Links between progressive HIV-1 infection of humanized mice and viral neuropathogenesis. Am J Pathol. 2010; 177(6):2938-49. PMC: 2993281. DOI: 10.2353/ajpath.2010.100536. View

Fernandez Larrosa P, Croci D, Riva D, Bibini M, Luzzi R, Saracco M . Apoptosis resistance in HIV-1 persistently-infected cells is independent of active viral replication and involves modulation of the apoptotic mitochondrial pathway. Retrovirology. 2008; 5:19. PMC: 2276517. DOI: 10.1186/1742-4690-5-19. View

Das Sarma J . Microglia-mediated neuroinflammation is an amplifier of virus-induced neuropathology. J Neurovirol. 2013; 20(2):122-36. DOI: 10.1007/s13365-013-0188-4. View

Kaufmann W, Worley P, Pegg J, Bremer M, Isakson P . COX-2, a synaptically induced enzyme, is expressed by excitatory neurons at postsynaptic sites in rat cerebral cortex. Proc Natl Acad Sci U S A. 1996; 93(6):2317-21. PMC: 39793. DOI: 10.1073/pnas.93.6.2317. View

Campbell G, Watkins J, Loret E, Spector S . Differential induction of rat neuronal excitotoxic cell death by human immunodeficiency virus type 1 clade B and C tat proteins. AIDS Res Hum Retroviruses. 2010; 27(6):647-54. PMC: 3101084. DOI: 10.1089/AID.2010.0192. View

10.

Donoso M, DAmico D, Valdebenito S, Hernandez C, Prideaux B, Eugenin E . Identification, Quantification, and Characterization of HIV-1 Reservoirs in the Human Brain. Cells. 2022; 11(15). PMC: 9367788. DOI: 10.3390/cells11152379. View

11.

Bardini Silveira D, Americo M, Flores N, Terenzi H, Pinto A . Pharmacological inhibition of UPR sensor PERK attenuates HIV Tat-induced inflammatory M1 phenotype in microglial cells. Cell Biochem Funct. 2022; 40(2):163-174. DOI: 10.1002/cbf.3685. View

12.

Hudson L, Liu J, Nath A, Jones M, Raghavan R, Narayan O . Detection of the human immunodeficiency virus regulatory protein tat in CNS tissues. J Neurovirol. 2000; 6(2):145-55. DOI: 10.3109/13550280009013158. View

13.

Ben Haij N, Leghmari K, Planes R, Thieblemont N, Bahraoui E . HIV-1 Tat protein binds to TLR4-MD2 and signals to induce TNF-α and IL-10. Retrovirology. 2013; 10:123. PMC: 4231456. DOI: 10.1186/1742-4690-10-123. View

14.

Tsujii M, DuBois R . Alterations in cellular adhesion and apoptosis in epithelial cells overexpressing prostaglandin endoperoxide synthase 2. Cell. 1995; 83(3):493-501. DOI: 10.1016/0092-8674(95)90127-2. View

15.

Sun X, Duan H, Jing G, Wang G, Hou Y, Zhang M . Inhibition of TREM-1 attenuates early brain injury after subarachnoid hemorrhage via downregulation of p38MAPK/MMP-9 and preservation of ZO-1. Neuroscience. 2019; 406:369-375. DOI: 10.1016/j.neuroscience.2019.03.032. View

16.

Castellano P, Prevedel L, Eugenin E . HIV-infected macrophages and microglia that survive acute infection become viral reservoirs by a mechanism involving Bim. Sci Rep. 2017; 7(1):12866. PMC: 5634422. DOI: 10.1038/s41598-017-12758-w. View

17.

Okamura H, Garcia-Rodriguez C, Martinson H, Qin J, Virshup D, Rao A . A conserved docking motif for CK1 binding controls the nuclear localization of NFAT1. Mol Cell Biol. 2004; 24(10):4184-95. PMC: 400483. DOI: 10.1128/MCB.24.10.4184-4195.2004. View

18.

Albini A, Ferrini S, Benelli R, Sforzini S, Giunciuglio D, Aluigi M . HIV-1 Tat protein mimicry of chemokines. Proc Natl Acad Sci U S A. 1998; 95(22):13153-8. PMC: 23742. DOI: 10.1073/pnas.95.22.13153. View

19.

Guillemard E, Jacquemot C, Aillet F, Schmitt N, Barre-Sinoussi F, Israel N . Human immunodeficiency virus 1 favors the persistence of infection by activating macrophages through TNF. Virology. 2004; 329(2):371-80. DOI: 10.1016/j.virol.2004.08.030. View

20.

Swingler S, Mann A, Zhou J, Swingler C, Stevenson M . Apoptotic killing of HIV-1-infected macrophages is subverted by the viral envelope glycoprotein. PLoS Pathog. 2007; 3(9):1281-90. PMC: 2323301. DOI: 10.1371/journal.ppat.0030134. View