Hepatic γ-Cystathionase Deficiency in Patients With AIDS

To the Editor: Patients infected with the human immunodeficiency virus (HIV) exhibit low plasma cysteine levels at all stages of the disease.¹ Glutathione (GSH) levels are also reduced in plasma, T lymphocytes, erythrocytes, and lung epithelial-lining fluid in patients with HIV infection.^{2 - 3}

Most circulating GSH is synthesized in the liver where L-cysteine concentration is a rate-limiting factor. The liver obtains most of its cysteine from L-methionine through the trans-sulfuration pathway, which involves γ-cystathionase activity. Jahoor et al³ reported that the low GSH levels found in erythrocytes from HIV-infected subjects are due, at least in part, to a diminished availability of L-cysteine.³ However, the cause of this cysteine deficiency is not clear.

We followed the method described by Sturman et al⁴ to measure γ-cystathionase activity in liver samples obtained from autopsies of 3 men with the acquired immunodeficiency syndrome (AIDS) and 6 healthy men (17-44 years old) who died in automobile crashes. The first patient with AIDS was 27 years old and died of multiple organ failure and Pneumocystis carinii bronchopneumonia; the second patient was 38 years old and died of cytomegalovirus pneumonia and gastric hemorrhage; and the third patient was 59 years old and died of generalized Kaposi sarcoma.

We found that γ-cystathionase activity was substantially reduced in the liver samples of the 3 men with AIDS compared with the 6 control subjects (Figure 1).

Reduced γ-cystathionase activity would be expected to result in low L-cysteine and GSH levels. Consequently, our results may help explain why AIDS is associated with a systemic deficiency of GSH and also provide a rationale for treating patients with AIDS with N-acetyl cysteine, which is a source of L-cysteine that is independent of the trans-sulfuration pathway.

We reported previously that inhibition of γ-cystathionase causes high rates of proteolysis in animals.⁵ The findings reported herein may provide a partial explanation for the increased proteolysis and cachexia that occurs in AIDS. Moreover, the very low γ-cystathionase activity renders L-cysteine an essential amino acid for patients with AIDS.