xCT/SLC7A11 antiporter function inhibits HIV-1 infection.

Jesse Rabinowitz, Hamayun J Sharifi, Hunter Martin, Anthony Marchese, Michael Robek, Binshan Shi, Alexander A Mongin, Carlos M C de Noronha

Journal: Virology 2021;556():149-160

PMID: 33631414

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Abstract

Human macrophages are protected by intrinsic antiviral defenses that provide moderate protection against HIV-1 infection. Macrophages that do become infected can serve as long-lived reservoirs, to disseminate HIV-1 to CD4⁺ T cells. Infection of macrophages with HIV-1 and HIV-2 is inhibited by constitutive mobilization of antioxidant response master transcription regulator Nrf2. The downstream mediator of this restriction was not identified. Among the tens of genes controlled directly by Nrf2 in macrophages, we found that xCT/SLC7A11, a 12-transmembrane, cystine-glutamate antiporter promotes antiretroviral activity. We show here that depletion of xCT mRNA increases HIV-1 infection. Reconstitution of xCT knock out cells with wild-type xCT but not a transport-deficient mutant restores anti-HIV-1 activity. Pharmacological inhibitors of xCT amino acid transport also increase infection. The block is independent of known restriction factors and acts against HIV-1 and HIV-2. Like the block triggered through Nrf2, xCT function impedes infection immediately before 2-LTR circle formation.

Address: Department of Immunology and Microbial Disease, Albany Medical College, 47 New Scotland Avenue, Albany, NY, 12208, USA.; Albany College of Pharmacy and Health Sciences, 106 New Scotland Avenue, Albany, NY, 12208, USA.; Department of Neuroscience and Experimental Therapeutics, Albany Medical College, 47 New Scotland Avenue, Albany, NY, 12208, USA.; Department of Immunology and Microbial Disease, Albany Medical College, 47 New Scotland Avenue, Albany, NY, 12208, USA. Electronic address: [email protected].

DOI: 10.1016/j.virol.2021.01.008