Chronic elevation of plasma thioredoxin: inhibition of chemotaxis and curtailment of life expectancy in AIDS.
Thioredoxin (Trx) is an intracellular redox protein with extracellular cytokine-like and chemokine-like activities. We show here that, although plasma Trx levels are unrelated to survival of HIV-infected individuals with CD4 cell counts above 200/microl blood, survival is significantly impaired (P = 0.003) when plasma Trx is chronically elevated in HIV-infected subjects with CD4 T cell counts below this level (i.e., with Centers for Disease Control (CDC)-defined AIDS). Relevant to the mechanism potentially underlying this finding, we also present data from experimental studies in mice showing that elevated plasma Trx efficiently blocks lipopolysaccharide (LPS)-induced chemotaxis, an innate immune mechanism that is particularly crucial when adaptive immunity is compromised. Thus, we propose that elevated plasma Trx in HIV-infected individuals with low CD4 T cell counts directly impairs survival by blocking pathogen-induced chemotaxis, effectively eliminating the last (innate) barrier against establishment of opportunistic and other infections in these immunodeficient individuals.
Department of Genetics, Stanford University Medical School, Stanford, CA 94305-5318, USA.
H
H
Nakamura
S C
SC
De Rosa
J
J
Yodoi
A
A
Holmgren
P
P
Ghezzi
L A
LA
Herzenberg
L A
LA
Herzenberg
D000111:Acetylcysteine / Q000494:pharmacology; D000163:Acquired Immunodeficiency Syndrome / Q000097:blood* / Q000503:physiopathology; D018791:CD4 Lymphocyte Count; D002469:Cell Separation; D002633:Chemotaxis; D005434:Flow Cytometry; D005978:Glutathione / Q000096:biosynthesis; D006801:Humans; D008017:Life Expectancy; D016019:Survival Analysis; D013879:Thioredoxins / Q000037:antagonists & inhibitors / Q000097:blood*
D013879:Thioredoxins; D005978:Glutathione; D000111:Acetylcysteine