Leonore A. Herzenberg*,
J. Gregson Dubs*,
Mario Roederer*,
Michael T. Anderson*,
Stephen W. Ela*,
Stanley C. Deresinski‡, and
Leonard A. Herzenberg*
https://www.pnas.org/doi/full/10.1073/pnas.94.5.1967
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Abstract
Glutathione (GSH), a cysteine-containing tripeptide, is essential for the viability and function of virtually all cells. In vitro studies showing that low GSH levels both promote HIV expression and impair T cell function suggested a link between GSH depletion and HIV disease progression. Clinical studies presented here directly demonstrate that low GSH levels predict poor survival in otherwise indistinguishable HIV-infected subjects. Specifically, we show that GSH deficiency in CD4 T cells from such subjects is associated with markedly decreased survival 2–3 years after baseline data collection (Kaplan–Meier and logistic regression analyses, P < 0.0001 for both analyses). This finding, supported by evidence demonstrating that oral administration of the GSH prodrug N-acetylcysteine replenishes GSH in these subjects and suggesting that N-acetylcysteine administration can improve their survival, establishes GSH deficiency as a key determinant of survival in HIV disease. Further, it argues strongly that the unnecessary or excessive use of acetaminophen, alcohol, or other drugs known to deplete GSH should be avoided by HIV-infected individuals.
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CD4 GSB levels are lower in HIV-infected subjects
Subjects | n * | CD4 GSB† | CD4 T cells/μl | ||
|---|---|---|---|---|---|
Mean | SD† | Median | IQR† | ||
Uninfected | 79 | 1.24 | 0.31 | 730‡ | 640–920 |
All HIV+ | 204 | 0.97 | 0.28 | 209 | 79–371 |
CD4 T Cells ≥ 200 | |||||
All | 107 | 1.05 | 0.25 | 356 | 278–480 |
CD4 T cells < 200§ | |||||
All | 97 | 0.88 | 0.29 | 72 | 30–129 |
NoTS cohort | 60 | 0.98 | 0.31 | 74 | 29–128 |
Trial subjects | 37 | 0.72 | 0.16 | 72 | 43–142 |
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*
Number of subjects for whom survival status was recorded. Overall HIV-infected study group composition: total, 204; male, 198; Caucasian, 155; mean age, 40.4 ± 7.8, range, 23–68.
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CD4 GSB levels predict survival in HIV disease
HIV-infected subjects | Variable | Risk ratio* | P value† | |
|---|---|---|---|---|
All | GSB | Continuous | 2.7 (1.8–4.1) | <0.0001 |
| GSB | Continuous | 1.6 (1.1–2.5) | 0.009 |
| CD4 T cells | Continuous | 1.2 (1.1–1.3) | <0.0001 |
CD4 T cells < 200/μl blood | GSB | Continuous | 2.0 (1.3–3.2) | 0.0004 |
| GSB | Continuous | 1.8 (1.2–2.8) | 0.004 |
| CD4 T cells | Continuous | 1.2 (1.0–1.3) | 0.01 |
| GSB | Continuous | 2.4 (1.6–3.7) | <0.0001 |
| NAC | Yes:no | 1.8 (1.2–2.8) | 0.003 |
CD4 T cells < 200/μl blood; NoTS cohort | GSB | Continuous | 2.4 (1.5–3.8) | 0.0001 |
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*
Proportional hazard analysis of risk ratio (continuous variables) = increase in probability of surviving per 0.3 GSB unit (GSB standard deviation) or per 20 CD4 T cells/μl blood; 95% confidence limits shown in parentheses.
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At a more immediate level, the demonstration here that prognosis worsens as GSH levels decrease suggests that certain precautions be taken to minimize GSH deficiency in HIV-infected individuals. In general, it may be prudent for these individuals to avoid excessive exposure to UV irradiation and unnecessary use of drugs that can deplete GSH—e.g., alcohol and prescription or over-the-counter formulations containing acetaminophen.
ABBREVIATIONS
GSH: glutathione
NAC: N-acetylcysteine
GSB: glutathione-S-bimane fluorescence in CD4 T cells
PBMC: peripheral blood mononuclear cells
FACS: fluorescence-activated cell sorter
ROC: receiver operating characteristic
NoTS: no trial subjects