We measured de novo lipogenesis in human immunodeficiency virus (HIV) infected men using a newly developed stable isotope method. HIV-infected subjects with a history of weight loss (n = 17, mean weight loss 14.9 +/- 3.2 kg), asymptomatic HIV-seropositive subjects with normal CD4 T-cell counts (n = 7) and healthy HIV seronegative controls (n = 11) were studied. Hepatic lipogenesis was determined by infusion of [2-13C]-acetate, using the recently described xenobiotic probe technique with mass isotopomer analysis. Hepatic acetyl-coenzyme A enrichment was measured by high performance liquid chromatography/mass spectrometry of secreted sulfamethoxazole-acetate, with measurement of incorporation into very low density lipoprotein-fatty acids by gas chromatography-mass spectrometry. Circulating tumor necrosis factor (TNF), interleukin-1 (IL-1), interferon alpha (IFN alpha), insulin, and triglycerides were measured concurrently, and 7-day weighed food records were performed. De novo hepatic lipogenesis was increased 3- to 4-fold in HIV-infected subjects with weight loss compared to normal controls (P < 0.05 for palmitate and stearate in both overnight-fasted and fed states), and was also significantly increased in asymptomatic HIV seropositive subjects. Circulating TNF and IL-1 were not measurable in any subject (detection limit 2 pg/ml for IL-1 and 20 pg/ml for TNF). Serum IFN alpha was measurable in 11 out of 17 subjects with wasting and correlated significantly with de novo lipogenesis in overnight-fasted but not fed states. Serum IFN alpha was unmeasurable in asymptomatic HIV-infected subjects despite elevated lipogenic rates. Serum triglyceride concentrations were elevated in subjects with weight loss (2.09 +/- 0.28 mmol/L) and asymptomatic HIV-positives (1.34 +/- 0.34 mmol/L) in comparison to controls (0.67 +/- 0.08 mmol/L), and correlated with lipogenesis. Food intake correlated inversely with lipogenesis in the overnight-fasted state. We conclude that HIV infection is characterized by abnormal fat anabolism. This applies to subjects with reduced lean body mass and to asymptomatic HIV-positive subjects with normal T-cell counts. The former observation may have implications for the pathophysiology and treatment of the wasting syndrome. The latter observation is consistent with activation of the immune response and a state of viral nonlatency in early HIV disease.