Glutathione,
whey protein and HIV-AIDS
Glutathione
inhibits HIV replication by acting at late stages of the virus
life cycle
Palamara AT, Perno CF, Aquaro S, Bue MC, Dini L, Garaci E.
[AIDS Res Hum Retroviruses 1996 Nov 1;12(16):1537-41] We investigated
the effect of glutathione on the replication of human immunodeficiency
virus (HIV) in chronically infected macrophages, a known reservoir
of the virus in the body.... exogenous GSH strongly suppresses
the production of p24gag protein as well as the virus infectivity.
This is related to a dramatic decrease in both budding and release
of virus particles from chronically infected cells (either macrophages
or lymphocytes)... Overall data suggest that GSH can interfere
with late stages of virus replication. ...the suppression of virus
replication by GSH is related to the selective inhibition of envelope
glycoproteins. These results suggest a potential role of GSH in
combination with other antivirals in the treatment of virus-related
diseases.
Intracellular
glutathione as a possible direct blocker of HIV type 1 reverse
transcription
Kameoka M, Okada Y, Tobiume M, Kimura T, Ikuta K.
[AIDS Res Hum Retroviruses. 1996 Nov 20;12(17):1635-8.] In AIDS
patients, chronic inflammation and elevated levels of cytokines
seem to be associated with reduced levels of glutathione (GSH).
GSH has been proposed to inhibit the activation of NF-kB, which
results in the inhibition of HIV-1 replication. Here, we show
the evidence that GSH and N-acetylcysteine...could inhibit
the reverse transcriptase (RT) process of HIV-1.
Glutathione
and N-acetylcysteine suppression of human immunodeficiency virus
replication in human monocyte /macrophages in vitro Ho
WZ, Douglas SD. [AIDS Res Hum Retroviruses 1992 Jul;8(7):1249-53]
The inhibitory effects of GSH and NAC were concentration dependent.
This anti-HIV-1 effect persisted in these cultures for at least
35 days without evidence of significant increase in HIV-1 expression.
Thus, a single pulse exposure of HIV-1-infected monocyte/macrophages
with GSH or NAC led to a sustained, concentration-dependent decrease
in HIV-1 p24 antigen levels, as well as, reverse transcriptase
activity without producing detectable cellular toxicity in monocyte/macrophages.
Cysteine,
glutathione (GSH) and zinc and copper ions together are effective,
natural, intracellular inhibitors of (AIDS) viruses
Sprietsma JE. [Med Hypotheses. 1999 Jun;52(6):529-38. Review]
Comment
in: Med Hypotheses. 2000 Nov;55(5):456-7. The way in which
the right amount of cysteine, glutathione (GSH), and copper and
zinc ions made available in the right place at the right time
and in the right form can prevent an unchecked multiplication
of (AIDS) viruses in a more passive or active way forms the basis
for the AIDS zinc-deficiency hypothesis (A-Z hypothesis) presented
in this article. Zinc and copper ions that remain available in
sufficient amounts via cysteine/GSH are effective natural inhibitors/combaters
of (AIDS) viruses and thereby prevent the development of chronic
virus diseases that can lead to AIDS, autoimmune diseases, (food)
allergies and/or cancer. A safe, relatively inexpensive and extensively
tested medicine such as N-acetylcysteine (NAC) can help in supplying
extra cysteine.
Glutathione
deficiency is associated with impaired survival in HIV disease
Herzenberg LA, De Rosa SC, Dubs JG, Roederer M, Anderson
MT, Ela SW, Deresinski SC, Herzenberg LA. 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. This finding ...establishes GSH deficiency as
a key determinant of survival in HIV disease... the unnecessary
or excessive use of acetaminophen, alcohol, or other drugs known
to deplete GSH should be avoided by HIV-infected individuals.
Publication Types: Clinical Trial
Randomized Controlled Trial
Low
serum thiol levels predict shorter times-to-death among HIV-infected
injecting drug users
Michael
Marmor, Philip Alcabes, Stephen Titus, Krystyna Frenkel, Keith
Krasinski, Arthur Penn and Ronald W. Pero [AIDS 1997, 11:1389–1393]
Among HIV-infected persons, low serum thiols, especially in concert
with a history of AIDS, predict mortality risk. These findings
support the hypothesis that oxidative stress is critical to the
pathogenesis of HIV infection.
Oral
supplementation with whey proteins increases plasma glutathione
levels of HIV-infected patients
Micke P, Beeh KM, Schlaak JF, Buhl R. [Eur J Clin
Invest. 2001 Feb;31(2):171-8.] HIV infection is characterized
by an enhanced oxidant burden and a systemic deficiency of the
tripeptide glutathione (GSH), a major antioxidant......different
strategies to supplement cysteine supply have been suggested to
increase glutathione levels in HIV-infected individuals......
to evaluate the effect of oral supplementation with two different
cysteine-rich whey protein formulas on plasma GSH levels and parameters
of oxidative stress and immune status in HIV-infected patients.....In
glutathione-deficient patients with advanced HIV-infection, short-term
oral supplementation with whey proteins increases plasma glutathione
levels. A long-term clinical trial is clearly warranted to see
if this "biochemical efficacy" of whey proteins translates into
a more favourable course of the disease.
Effects
of long-term supplementation with whey proteins on plasma glutathione
levels of HIV-infected patients
Micke P, Beeh KM, Buhl R. [Eur J Nutr 2002 Feb;41(1):12-8]
HIV infection is characterized by an enhanced oxidant burden and
a systemic deficiency of the tripeptide glutathione (GSH), a major
antioxidant. Whey proteins are rich in cysteine as well as in
GSH precursor peptides. In order to evaluate the effects of whey
supplementation on plasma GSH levels, HIV-infected patients were
treated with whey proteins for a period of six months. Supplementation
with whey proteins persistently increased plasma glutathione levels
in patients with advanced HIV-infection.
Nutriceutical
Modulation Of Glutathione With A Humanized Native Milk Serum Protein
Isolate: Application In AIDS And Cancer.
S. Baruchel, G. Viau, R. Olivier, G. Bounous, M.A. Wainberg
[Oxidative Stress in Cancer, AIDS, and Neurodegenerative Diseases
V Luc Montagnier et al., (Ed.) Marcel Dekker Inc., New York: 447-461,
1998 . ABSTRACT V] The biological activity of the proteins isolated
from cow's milk in the whey protein isolate depends on the preservation
of those labile proteins which share with the predominant human
milk proteins the same extremely rare glutathione (GSH)-promoting
components. In a pilot study, this type of whey protein concentrate
was found to be well tolerated in children with AIDS and wasting
syndrome and was found associated with an improvement of the
nutritional status of the patient. Moreover, the GSH promoting
activity on the peripheral blood lymphocyte of this protein concentrate
was validated in patients with initial low GSH levels.
Immuno-Enhancing
Properties Of Undenatured Milk Serum Protein Isolate In HIV Patients.
G. Bounous [International Diary Federation: WHEY: 293-305,
1998] ABSTRACT – When GSH is depleted, as in the lymphocytes of
mice during the immune response or in the lymphocyte of AIDS patients,
the cysteine delivery system in a patented whey potein isolate
produces a substantial increase in cellular GSH up to, but not
above, normal values. Preliminary data in AIDS patients demonstrate
that this is associated with major improvements in health. These
clinical data and the in vitro demonstration that whey
potein isolate inhibits the HIV virus while increasing
GSH synthesis strongly suggest that an antagonistic relation exists
between the virus and cellular GSH. Unlike specific antiretroviral
drugs which may induce mutation, hence resistance of the virus
to therapy, the normalization of the lymphocyte glutathione levels
and redox status through a cysteine delivery system represents
a totally different approach by which the natural cellular defense
system is boosted. It is conceivable that GSH restoration by whey
protein could prevent to a certain extent the adverse effect of
AZT.
L-Glutathione
decreases replication of HIV and other viruses - increases CD8
counts and function
Chen P. and Schwartz D [Int Conf AIDS 1993 (abstract PO-A13-0248)]
Depletion of intracellular GSH (Glutathione)....decreases the
proportion of CD8+ cells (i.e. increases the CD4/CD8 ratio) ...and
inhibits ....cytotoxic T lymphocyte (CTL) activity.” Low levels
of Glutathione in the cells not only decreases the total CD8 counts
but decrease the functioning of the CD8 Cytotoxic T cells, that
is, their ability to control the viral infections by killing the
virus infected cells. Research also shows that increasing Glutathione
levels reduces Tumor Necrosis Factor (TNF). High TNF levels have
been linked to wasting syndrome and increased viral replication.
Taking Glutathione supplements may not be an effective way to
increase GSH levels due to poor assimilation.
Improvement
of immune functions in HIV infection by sulfur supplementation:
Two randomized trials.
Breitkreutz R, Pittack N and others. [J Mol Med 2000;78(1):55-62].
"Our findings suggest that the impairment of immunological functions
in HIV+ patients results at least partly from cysteine deficiency.
Because
immune reconstitution is a widely accepted aim of HIV treatment,
N-acetyl-cysteine [NAC] treatment may be recommended for patients
with and without antiretroviral therapy. Our previous report on
the massive
loss of sulfur in HIV-infected subjects and the present demonstration
of the immunoreconstituting effect of cysteine supplementation
indicate that the HIV-induced cysteine depletion is a novel mechanism
by which a virus destroys the immune defense of the host and escapes
immune elimination."
Whey
proteins as a food supplement in HIV-seropositive individuals.
Bounous G, Baruchel S, Falutz J, Gold P. [Clin Invest Med.
1993 Jun;16(3):204-9.] Preliminary data indicate that, in patients
who maintain an adequate total caloric intake, the addition of
"bioactive" whey protein concentrate as a significant portion
of total protein intake increases body weight and shows elevation
of glutathione (GSH) content of mononuclear cells toward normal
levels.
Stanford
NAC Study: Glutathione Level Predicts Survival
Author: John S. James [AIDS Treatment News; Issue: 266 03/07/97]
A small randomized controlled trial of oral N-acetylcysteine(NAC)
was run in San Francisco in 1993 and 1994. A report from this
study was published in the PROCEEDINGS
OF THE NATIONAL ACADEMY OF SCIENCES, USA (1); it was also
presented at a major immunology conference in San Francisco on
February 22, receiving television and newspaper coverage. For
persons with a CD4 count under 200, an abnormally low level of
glutathione -- inside CD4 T-cells in the blood --was remarkably
predictive of poor survival. (Glutathione is the major defense
of those cells against oxidative stress.) Oral NAC helped to replenish
low glutathione in blood cells. These findings alone do not prove
that NAC is beneficial...followup studies showed that persons
who were given or chose to take NAC during the trial had considerably
better survival than similar subjects who did not take NAC.
N-
acetylcysteine replenishes glutathione in HIV infection
De
Rosa SC, Zaretsky MD, Dubs JG, and others. [Eur J Clin Invest
2000 Oct;30(10):915-29.] Comment
in: Eur J Clin Invest. 2000 Oct;30(10):841-2. Studies here
test oral administration of NAC for safe and effective GSH replenishment
in HIV infection. NAC offers useful adjunct therapy to increase
protection against oxidative stress, improve immune system function
and increase detoxification of acetaminophen and other drugs.
These findings suggest that NAC therapy could be valuable in other
clinical situations in which GSH deficiency or oxidative stress
plays a role in disease pathology.
Publication Types: Clinical Trial
Randomized Controlled Trial
Glutathione
depletion in HIV-infected patients: role of cysteine deficiency
and effect of oral N-acetylcysteine
de Quay B, Malinverni R, Lauterburg BH. [AIDS 1992 Aug;6(8):815-9]
To determine whether a single oral dose of N-acetylcysteine corrects
the deficiency of cysteine and glutathione in plasma and mononuclear
cells of HIV-infected patients. A single oral dose of N-acetylcysteine
increased the concentration of cysteine in plasma and mononuclear
cells of HIV-infected patients. Oral N-acetylcysteine transiently
increases the concentrations of cysteine and glutathione in mononuclear
cells of patients with HIV infection. A sustained increase in
intracellular cysteine may be necessary to normalize intracellular
glutathione. This may be accomplished by repeat administration
of N-acetylcysteine.
Cysteine
and glutathione deficiency in HIV-infected patients. The basis
for treatment with N-acetyl-cysteine
Droge W. [Pharmacology. 1993;46(2):61-5.] Clinical studies
and complementary laboratory investigations suggest that the deterioration
of the immune system in HIV-infected patients may be the consequence
of a virus-induced cysteine deficiency. HIV-infected persons at
all stages of the disease have, on the average, decreased plasma
cystine and cysteine and decreased intracellular glutathione levels.
Cysteine levels also decrease in rhesus macaques within 1 to 2
weeks after infection with SIV(mac). HIV-infected persons and
SIV-infected macaques also have, on the average, markedly increased
plasma glutamate levels, which aggravate the cysteine deficiency
by inhibiting the membrane transport of cystine. Even moderately
increased extracellular glutamate levels as they are found in
HIV-infected persons cause a profound decrease of intracellular
cyst(e)ine levels. A correlation between individual T4+ cell counts
(but not T8+ cell counts) and individual cystine and glutamate
levels has been found not only in HIV-infected persons but also
in healthy individuals, indicating that the linkage between cysteine
supply and immune system is demonstrable even in the absence of
the virus. There is suggestive evidence that the HIV-induced cysteine
deficiency is not only responsible for the 'cellular dysfunction'
but also for the abnormal activation which is exemplified by the
lymphadenopathy syndrome and abnormal antibody production. We
have... suggested that N-acetyl-cysteine (NAC) may be considered
for the replenishment of cysteine and glutathione levels in HIV-infected
persons, since NAC is a well-established and safe drug with well-documented
pharmacokinetics.
HIV-induced
cysteine deficiency and T-cell dysfunction--a rationale for treatment
with N-acetylcysteine
Droge W, Eck HP, Mihm S. [Immunol Today. 1992 Jun;13(6):211-4.]
Markedly decreased plasma cystine and cysteine concentrations
have been found in HIV-infected patients at all stages of the
disease and in SIV-infected rhesus macaques. The elevated glutamate
levels found in the same patients aggravate the cysteine deficiency
by inhibiting the membrane transport activity for cystine. The
intact immune system appears to require a delicate balance between
pro-oxidant and antioxidant conditions, maintained by a limited
and well-regulated supply of cysteine. This balance is obviously
disturbed in HIV infection and may contribute to the pathogenesis
of AIDS.
Role of cysteine and glutathione in HIV infection and cancer cachexia:
therapeutic intervention with N-acetylcysteine
Droge W. et al. [Adv Pharm 38: 581-600, 1997.]
Nutrition
and HIV
Lichtenstein BS. [STEP Perspect. 1995 Spring;7(1):2-5.]
AIDS: Nutritional status directly affects immune competence; therefore,
dietary supplements can be beneficial. N-acetylcysteine (NAC),
a sulfur-containing amino acid, inhibits HIV replication by raising
serum glutathione levels through inhibition of TNF-a.
The
role of oxidative stress in disease progression in individuals
infected by the human immunodeficiency virus
Baruchel S, Wainberg MA. [J Leukoc Biol 1992 Jul;52(1):111-4]
This review describes the potential role of oxidative stress as
a cofactor of disease progression from asymptomatic human immunodeficiency
virus (HIV) infection to the acquired immunodeficiency syndrome
(AIDS). An indirect argument in favor of the role of oxidative
stress in HIV-associated disease progression is the consumption
of glutathione (GSH), a major intracellular antioxidant, during
HIV infection and progression. GSH is known to play a major role
in regulation of T cell immune functions. Oxidative stress may
also play an important role in the genesis of cellular DNA damage
and, in this context, may be related to HIV-associated malignancies
and disease progression. Finally, the role of antioxidants as
components of therapeutic strategies to combat HIV disease progression
is discussed.
Effects
of whey protein and resistance exercise on body composition and
muscle strength in women with HIV infection
Agin D, Kotler DP, Papandreou D, Liss M, Wang J, Thornton
J, Gallagher D, Pierson RN Jr. [Ann N Y Acad Sci. 2000 May;904:607-9.]
Glutathione
and cysteine in HIV-infected hemophiliacs
Lopez Galera RM, Juarez Gimenez JC, Montoro Ronsano
JB, Segura Cardona RM, Arbos Via MA, Altisent Roca C, Tusell Puigbert
JM. [Clin Chim Acta. 1996 Oct 15;254(1):63-72.]
Decreased
release of glutathione into the systemic circulation of patients
with HIV infection
Helbling B, von Overbeck J, Lauterburg BH. Department
of Clinical Pharmacology, University of Bern, Switzerland. [Eur
J Clin Invest 1996 Jan;26(1):38-44] Low glutathione (GSH) in patients
with HIV infection could contribute to their immune deficiency
since GSH plays an important role in the function of lymphocytes
and sulphydryls decrease the expression of HIV in vitro. During
infusion of GSH the concentration of cysteine in peripheral blood
mononuclear cells of the HIV-infected patients increased significantly.
Nevertheless, intracellular GSH did not increase. Thus, the consumption
of GSH is not increased in HIV infection. Rather, the present
data suggest that GSH in patients with HIV infection is low because
of a decreased systemic synthesis of GSH.
Correction
of glutathione deficiency in the lower respiratory tract of HIV
seropositive individuals by glutathione aerosol treatment
Holroyd KJ, Buhl R, Borok Z, Roum JH, Bokser AD, Grimes
GJ, Czerski D, Cantin AM, Crystal RG. [Thorax 1993 Oct;48(10):985-9]
Concentrations of glutathione, a ubiquitous tripeptide with immune
enhancing and antioxidant properties, are decreased in the blood
and lung epithelial lining fluid of human immunodeficiency virus
(HIV) seropositive individuals. Since the lung is the most common
site of infection in those who progress to AIDS it is rational
to consider whether it is possible to safely augment glutathione
levels in the epithelial lining fluid of HIV seropositive individuals,
thus potentially improving local host defence. It is feasible
and safe to use aerosolised reduced glutathione to augment the
deficient glutathione levels of the lower respiratory tract of
HIV seropositive individuals. It is rational to evaluate further
the efficacy of this tripeptide in improving host defence in HIV
seropositive individuals.
Erythrocyte
glutathione deficiency in symptom-free HIV infection is associated
with decreased synthesis rate
Jahoor F, Jackson A, and others. [Am J Physiol 1999 Jan;276(1
Pt 1):E205-11.] "Cysteine supplementation [by one week of NAC
given to HIV-infected volunteers] elicited significant increases
in both the absolute rate of synthesis and the concentration of
erythrocyte glutathione. These results suggest that the glutathione
deficiency of HIV infection is due in part to a reduced synthesis
rate secondary to a shortage of cysteine availability."
Can
HIV infection be treated with antioxidants?
Muller F. Medisinsk avdeling A, Rikshospitalet, Oslo. [Tidsskr
Nor Laegeforen 1995 Mar 10;115(7):835-7] Several recent reports
have indicated high levels of reactive oxygen species, causing
oxidative stress, in the pathogenesis of HIV infection. Oxidative
stress may lead to enhanced HIV replication in infected cells
and may also aggravate the immunodeficiency by reduction of cellular
immunity and possibly by increased programmed cell death of lymphocytes.
Moreover, reduced levels of antioxidants have been found in patients
with HIV infection. This raises the question of whether antioxidant
therapy might be beneficial in patients with HIV infection.
Role
of cysteine and glutathione in HIV infection and other diseases
associated with muscle wasting and immunological dysfunction
Droge W, Holm E. [FASEB J 1997 Nov;11(13):1077-89] Low
NK cell activity in most cases is not life-threatening, but may
be disastrous in HIV infection because it may compromise the initially
stable balance between the immune system and virus, and trigger
disease progression. This hypothesis is supported by the coincidence
observed between the decrease of CD4+ T cells and a decrease in
the plasma cystine level. In addition, recent studies revealed
important clues about the role of cysteine and glutathione in
the development of skeletal muscle wasting.... Cysteine supplementation
may be a useful therapy if combined with disease-specific treatments
such as antiviral therapy in HIV infection.
Role
of cysteine and glutathione in signal transduction, immunopathology
and cachexia
Droge W, Hack V, Breitkreutz R, Holm E, Shubinsky G,
Schmid E, Galter D. [Biofactors 1998;8(1-2):97-102] Abnormally
low plasma cystine levels have been found in the late asymptomatic
stage of HIV infection and several other diseases associated with
progressive loss of skeletal muscle mass. The phenomenon is commonly
associated with a low NK cell activity, skeletal muscle wasting
or muscle fatigue and increased rates of urea production. The
low NK cell activity is in most cases not life-threatening but
may be disasterous in HIV infection, because it may compromise
the initially stable balance between immune system and virus and
trigger disease progression.
Massive
loss of sulfur in HIV infection
Breitkreutz R, Holm S, and others. [AIDS Research and
Human Retroviruses. 2000; volume 16, number 3, pages 203-209]
We now confirm the peripheral tissue as a site of massive cysteine
catabolism in HIV infection and have determined the urinary loss
of sulfur per time unit.... The peripheral tissue of HIV+ patients
with or without highly active antiretroviral therapy (HAART) releases
large amounts of sulfate and plasma sulfate, thioredoxin, and
interleukin-6 levels are elevated in these patients. The abnormally
high sulfate/urea ratio suggests that this process drains largely
the glutathione pool."
Molecular
mechanism of decreased glutathione content in human immunodeficiency
virus type 1 Tat-transgenic mice
Choi
J, Leu RM, and others. [J Biol Chem 2000 Feb 4;275(5):3693-8.]
Glutathione
and HIV infection: reduced reduced, or increased oxidized?
Staal FJ. [Eur J Clin Invest. 1998 Mar;28(3):194-6.
Review]
Micronutrient
status in relationship to mortality in HIV-1 disease
Baum MK, Shor-Posner G. [Nutr Rev. 1998 Jan;56(1
Pt 2):S135-9. Review]
Antioxidant
supplementation in HIV/AIDS
Segal-Isaacson AE, Rand CJ. [Nurse Pract. 1995
Jul;20(7):8, 11-4. Review.]
The
role of oxidative imbalance in progression to AIDS: Effect of
the thiol supplier N-acetylcysteine
Malorni W, Rivabene R, and others. [AIDS Research
and Human Retroviruses. 1998; volume 14, number 17, pages 1589-1596]
"Our study suggests that the redox profile of patients may be
considered a predictive marker of AIDS progression and that the
acute infection and the asymptomatic phase of the disease may
represent a useful period in which the combined use of antiretroviral
and antioxidant drugs may be beneficial."
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Glutathione and un-denatured whey protein in HIV-AIDS
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