Fatty acid synthesis restricts HIV-1 infection through regulation of the nuclear envelope in CD4+ T cells

HIV-1, the virus responsible for AIDS, must overcome the defenses of CD4+ T cells to establish an infection. The ways in which these immune cells defend themselves against the virus are not fully understood. A recent study has revealed that fatty acid synthesis plays a crucial role in protecting these cells from HIV-1 infection.

The researchers used a small molecule screen to identify this unexpected determinant of resistance. They found that inhibiting the enzymes acetyl-CoA carboxylase 1 (ACC1) and fatty acid synthase (FASN) increased the susceptibility of cells to HIV-1 infection. Remarkably, supplementing the cells with fatty acids restored their anti-viral resistance. The study suggests that the strength of protection depends on both the metabolic state of the cells and the composition of the extracellular lipid environment.

Cells that were unable to synthesize fatty acids experienced a change in the composition of their lipid pool, particularly in the membrane lipid phosphatidylcholine. This alteration was accompanied by a disruption in the structure of the nuclear envelope, a critical barrier that prevents HIV-1 from entering the nucleus. The inhibition of FASN also selectively altered the cells' sensitivity to antiretroviral drugs that target the interaction between the virus's capsid and the nuclear pore.

Overall, this research uncovers a previously unknown role for cellular fatty acid synthesis in maintaining the nuclear envelope and highlights the possibility that anti-viral strategies could emerge at the intersection of cellular state and exposure to the virus.