xCT/SLC7A11 antiporter function inhibits HIV-1 infection

Area of Science:

• Immunology
• Virology
• Cell Biology

Background:

• Human macrophages possess intrinsic antiviral defenses against HIV-1.
• Infected macrophages act as persistent reservoirs, facilitating HIV-1 dissemination to CD4+ T cells.
• The antioxidant response master transcription regulator Nrf2 inhibits HIV-1 and HIV-2 infection in macrophages, but its downstream mediator was unknown.

Purpose of the Study:

• To identify the downstream mediator of Nrf2-induced antiretroviral activity in macrophages.
• To investigate the role of xCT/SLC7A11, a cystine-glutamate antiporter, in macrophage restriction of HIV infection.

Main Methods:

• Depletion of xCT mRNA using siRNA.
• Reconstitution of xCT knockout cells with wild-type or transport-deficient xCT mutants.
• Treatment with pharmacological inhibitors of xCT amino acid transport.
• Assessment of HIV-1 and HIV-2 infection levels.
• Analysis of viral DNA forms, including 2-LTR circles.

Main Results:

• Depletion of xCT mRNA significantly increased HIV-1 infection in macrophages.
• Reconstitution with wild-type xCT restored antiretroviral activity, while a transport-deficient mutant did not.
• Pharmacological inhibition of xCT amino acid transport also led to increased HIV infection.
• The restriction mediated by xCT is effective against both HIV-1 and HIV-2 and acts prior to 2-LTR circle formation.
• This restriction mechanism is independent of known HIV restriction factors.

Conclusions:

• The cystine-glutamate antiporter xCT/SLC7A11 is a key downstream mediator of Nrf2-induced antiretroviral activity in human macrophages.
• xCT function is crucial for restricting HIV-1 and HIV-2 infection, acting early in the viral life cycle.
• Targeting xCT or its transport function represents a potential strategy for enhancing intrinsic macrophage resistance to HIV.