Oxidative stress and thiol depletion in plasma and peripheral blood lymphocytes from HIV-infected patients: toxicological and pathological implications.
OBJECTIVE
To determine, first, whether the plasma and lymphocytes of HIV-positive individuals and AIDS patients have alterations in the major thiols glutathione and cysteine, and/or their oxidative disulphide and mixed disulphide products; and, secondly, whether thiol/disulphide status differs in patients with sulphonamide drug hypersensitivity reactions.


METHODS
Thiols provide critical cellular defence against toxic drug reactive intermediates and endogenous oxidative stress, and may modulate HIV replication. Glutathione is reported to be low in HIV-positive individuals and AIDS patients, but this is controversial and the mechanism responsible is unknown. Also unknown is whether altered thiol/disulphide status determines the predisposition of HIV-positive and AIDS patients to drug reactions.


METHODS
Thiols and disulphides were measured by high-performance liquid chromatography.


RESULTS
Both plasma thiols were decreased by approximately 58% in HIV-positive individuals and AIDS patients compared with uninfected controls (P < 0.05), with increases of up to threefold in oxidized products (P < 0.05). Similarly, in lymphocytes, thiols were decreased by 30-35% (P < 0.05), with apparent increases in oxidized products. For both glutathione and cysteine, the thiol/disulphide ratios also were decreased (P < 0.05). The plasma and lymphocyte glutathione thiol/disulphide ratios were highly correlated (r = 0.7661; P = 0.0001) among all subjects. No parameters differed in patients with drug reactions, or with antiretroviral therapy.


CONCLUSIONS
The enhanced thiol oxidation in HIV-positive individuals and AIDS patients indicates oxidative stress, which also contributes to thiol depletion, and may enhance damage to macromolecular targets. These mechanisms may contribute to enhanced viral replication and other pathological outcomes. HIV-positive individuals' and AIDS patients' predisposition to drug hypersensitivity reactions appears to be unrelated to thiol/disulphide status.
Walmsley
S L
SL
Department of Medicine, University of Toronto, Ontario, Canada.
Winn
L M
LM
Harrison
M L
ML
Uetrecht
J P
JP
Wells
P G
PG
D000704:Analysis of Variance; D003545:Cysteine / Q000031:analogs & derivatives / Q000097:blood*; D004220:Disulfides / Q000097:blood*; D004342:Drug Hypersensitivity; D005978:Glutathione / Q000031:analogs & derivatives / Q000097:blood*; D019803:Glutathione Disulfide / Q000097:blood; D015658:HIV Infections / Q000097:blood*; D006801:Humans; D007963:Leukocytes, Mononuclear / Q000166:cytology / Q000378:metabolism; D018384:Oxidative Stress; D013449:Sulfonamides / Q000009:adverse effects
D004220:Disulfides; D013449:Sulfonamides; C031586:cysteine-glutathione disulfide; D005978:Glutathione; D003545:Cysteine; D019803:Glutathione Disulfide