xCT/SLC7A11 antiporter function inhibits HIV-1 infection.
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Issue Date
4/1/2021
Authors
Rabinowitz, Jesse
Sharifi, Hamayun J
Martin, Hunter
Marchese, Anthony
Robek, Michael
Shi, Binshan
Mongin, Alexander A
de Noronha, Carlos M C
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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.
Citation
Rabinowitz J, Sharifi HJ, Martin H, Marchese A, Robek M, Shi B, Mongin AA, de Noronha CMC. xCT/SLC7A11 antiporter function inhibits HIV-1 infection. Virology. 2021 Apr;556:149-160. doi: 10.1016/j.virol.2021.01.008. Epub 2021 Jan 20. PMID: 33631414; PMCID: PMC7925438.
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R21 AI140993/AI/NIAID NIH HHS/United States