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

HIV-1 must breach intracellular defenses to establish infection in CD4+ T cells, yet the metabolic activities that sustain these barriers remain poorly understood. Using a metabolically targeted small molecule screen, we identify de novo fatty acid synthesis as an unexpected determinant of resistance to HIV-1 infection in activated CD4+ T cells. Inhibition of acetyl-CoA carboxylase 1 (ACC1) or fatty acid synthase (FASN) increased cellular susceptibility to infection, while fatty acid supplementation restored baseline levels of anti-viral resistance. Saturated fatty acids conferred the strongest protection, revealing that susceptibility depends on both cellular metabolic state and the composition of the extracellular lipid environment. Blocking fatty acid synthesis remodeled the cellular lipid pool, particularly for the membrane lipid phosphatidylcholine, and was accompanied by structural disruption of the nuclear envelope that serves as a physical barrier limiting passage of the HIV-1 capsid into the nucleus. FASN inhibition also selectively altered sensitivity to antiretroviral drugs that target the interaction between capsid and the nuclear pore. Broadly, these findings uncover a previously unrecognized role for cellular fat synthesis in the maintenance of the nuclear envelope and reveal that anti-viral pathways can emerge at the interface between cellular state and exposure.