Re: Re: No scientific evidence — no scientific debate 31 December 2004
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James J Whitehead,
40A Josephine Avenue london SW2 2LA

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Re: Re: Re: No scientific evidence — no scientific debate

Dear All,

I have been wondering about one or two things for about 8 years now and would appreciate imput, views on this, first of all my observation with monotherapy AZT on diseases like KS is that they never got better, infact they always got much worse. My observation with dual therapy is also the same. However when P.I.'s where added and possibley 3TC I was pleased and impressed for the first time to see significant regression of KS and a sustained improvement in health and a decline in many of the diseases that can be called AIDS (but not all).

I think your all well aware that I agree with Eleni and The Perth Group about the importance of glutathione GSH and antioxidant levels in wasting ,KS,PCP ect in causation and treatment.

I am aware that most people think that the positive effects of triple ARV therapy is due to a decrease in viral load and associated rises in CD4 and of course vice versa that the cause of wasting, KS, PCP is thought to be an increase in viral load and decrease in CD4.

However I do not believe this theory. I agree that there is an association between low CD4's and these diseases however that association is not complete by any stretch of the imagination. Yes with the advent of triple ARV containing P.I.'s and 3TC there is an increase in CD4 often accompanied by an improvement in some of these diseases. However is it possible that the positive theraputic effects of triple ARV therapy is through a different mechanism besides increased CD4, like an increase in intracellular GSH and antioxidant levels ?

I found this paper interesting, references 52 and 53 are of interest in both explaining why I always saw KS get worse in people on AZT monotherapy but also because it provides some further evidence that side effects can be reduced and that the positive effects of triple ARV can be enhanced. and for the record I also believe that the occurance of Immune restoration disease is not becuase of low starting point CD4's but that it is due to lower starting levels of glutathione and antioxidant levels of protection. (references available.)

I would be interested in the views of all "sides" on this.

Morphine by the way creates oxidative stress and reduces glutathione.

"Saquinavir also protected HTrMCs against the proapoptotic effect of morphine. Moreover, saquinavir inhibited the production of superoxide by HTrMCs under both basal and MSS. Saquinavir also attenuated the morphine- induced expression of SOD and NADPH oxidase (Gp91phox) by HTrMCs. Interestingly, hemin exacerbated morphine-triggered HTrMC apoptosis. CONCLUSION: Oxidative stress seems to play a role in the accelerated rate of HTrMC apoptosis both under basal and MSS. Saquinavir may be inhibiting HTrMC apoptosis by mitigating oxidative stress." (2)

" At baseline, CD4+ T cells from HIV-infected patients were characterized by a decreased ratio of reduced glutathione to total glutathione, increased oxidized glutathione, and decreased levels of reduced glutathione (P < .01, for all parameters), with no significant changes in total levels of this thiol, compared with those in control subjects (figure 1). During HAART, there was a significant increase in this ratio, reflecting a decrease in oxidized glutathione and an increase in reduced glutathione (figure 1). In contrast to the rapid changes in virus load and T cell count, these changes in glutathione metabolism were first seen after 26 weeks, and, although several changes were observed, normalization was not observed, compared with what was observed in control subjects (figure 1). "(1)

"Before initiation of HAART, the HIV-infected patients had significantly decreased plasma levels of vitamin C, compared with those in control subjects (P < .001), and, notably, HAART induced a marked increase in this antioxidant vitamin, with the highest levels occurring at the end of the study period (figure 2). A similar pattern was also seen for vitamin E, although the increase was more modest (figure 2). Although levels of both vitamin C and vitamin E increased during HAART, the concentrations were not normalized, compared with those in control subjects (figure 2). In contrast to the rise in levels of vitamins, levels of MDA, as a parameter of lipid peroxidation, significantly decreased during HAART, but, as observed for the antioxidant vitamins, normalization was not observed during the study period (figure 2). Similar to what was observed for the glutathione parameters, the effects of HAART on levels of vitamin C, vitamin E, and MDA were first seen after 26 weeks of HAART (figure 2). For -carotene, concentrations were within normal limits throughout the study (figure 2). "(1)

" During HAART, the maximal change in virus load was negatively correlated with the maximal changes in both vitamin C (r = -0.67; P < .005) and the ratio of reduced glutathione to total glutathione in CD4+ T cells (r = -0.59; P < .01). After 1 year, 7 patients were classified as patients with virologic-treatment failures (HIV-RNA level, >200 copies/mL). Although, with regard to prior treatment regimen, baseline virus load, and CDC classification, these patients were comparable to those without virologic-treatment failure; the patients with virologic- treatment failure had significantly decreased vitamin C levels, compared with those in other patients (median [IQR], 7.19 [3.718.32] mol/L vs. 10.64 [9.2511.32] mol/L; P < .01), after 1 year.

The changes in intracellular thiol levels were also correlated with the changes in CD4+ T cell count during HAART. Thus, in these cells, the maximal increase in the number of CD4+ T cells was positively correlated with changes in both the ratio of reduced glutathione to total glutathione (r = 0.71; P < .001) and reduced glutathione (r = 0.62; P < .01).

To further study the relationship between glutathione and T cells, in HIV infection, we examined, in a separate experiment, whether glutathione supplementation in vitro could improve T cell proliferation in HIV- infected patients during HAART. In this in vitro experiment, we included only patients without virologic treatment failure, to examine the potential role that glutathione supplementation plays in addition to apparently successful HAART, since there is an increasing awareness that other therapeutic modalities may be of interest as supplementations to HAART [15]. In 6 patients (4 in CDC group A and 2 in CDC group B, before HAART) who were not included in the longitudinal HAART study (figures 1 and 2), whose median duration of HAART was 1 year (range, 816 months), and who had no signs of virologic treatment failure (as defined above), we found still-decreased T cell proliferation after anti-CD3 stimulation, compared with that in control subjects (figure 3A). More important, when glutathione-monoethyl ester, acting as glutathione precursor, was added to cell culture before stimulation, we found a dose-dependent increase in anti-CD3stimulated T cell proliferation, which, in all but 2 patients, reached levels within the normal range (figure 3A). Glutathione-monoethyl ester had no effect on spontaneous T cell proliferation. "(1)

"There are several studies of disturbed glutathione metabolism in HIV -infected patients [37], and a few studies also have reported decreased plasma levels of vitamin C [25]. In the present study, we have shown that, during HAART, the decrease in virus load and the increase in CD4+ T cell count are accompanied by both an improvement in the abnormal glutathione- redox status and an increase in the subnormal levels of antioxidant vitamins; however, HAART did not induce full normalization of these parameters, and, furthermore, in HIV-infected patients receiving HAART, glutathione supplementation in vitro increased anti-CD3stimulated T cell proliferation and suppressed the spontaneous release of TNF- from PBMCs. These findings lend further support to the idea that enhanced oxidative stress contributes to the pathogenesis of HIV infection, and our in vitro findings suggest that therapeutic intervention aimed at normalization of these oxidative disturbances could be of interest, even in the "HAART era." However, it remains to be proven that such effects of glutathione supplementation also are operative in vivo in HIV-infected patients receiving HAART. "(1)

" Although HAART markedly improves immunologic parameters, some immunodeficiency seems to persist to a variable degree. In the present study, we have shown that impaired T cell proliferation in HIV-infected patients receiving HAART and, notably, glutathione supplementation in vitro seem to correct this T cell defect. In previous studies, decreased levels of reduced glutathione in T cells have been shown to impair interleukin (IL)-2 production, IL-2 responses, and cytotoxic T cell activity and to favor T helper (Th) 2 responses over Th1 responses [9, 2932]. The importance of glutathione metabolism for T cell function is underscored by the fact that an 30% decrease in reduced glutathione in T cells almost completely blocks T cell proliferation, through T cellreceptor/CD3-activation [33]. The relevance of these findings to HIV infection has been shown by Cayota et al., who demonstrated that restoration of the glutathione-redox balance, by antioxidant supplementation in vitro, is able to restore the impaired CD4+ T cell proliferation in HIV-infected patients [34]. In the present study, we have shown that a similar phenomenon also may be seen in patients with a satisfactory response to HAART; and some recent studies have suggested that glutathione supplementation in vivo also may improve immunologic functions in patients receiving HAART [35]. "(1)

" Several mechanismssuch as low intake of antioxidants or their precursors, malabsorption, and, in peripheral tissue, enhanced cysteine metabolism with a consequent loss of sulfurmay account for glutathione and antioxidant deficiency during HIV infection [3, 9, 36]. Moreover, HIV may also, directly through a Tat-related mechanism, promote disturbed glutathione metabolism [37, 38], and it could be hypothesized that the improvement in glutathione-redox status during HAART could reflect decreased levels of HIV-Tat protein. However, disturbed glutathione metabolism and decreased antioxidant levels may also reflect enhanced consumption that is secondary to persistently enhanced inflammation in these patients. Thus, TNF- could impair glutathione-redox status by various mechanismssuch as consumption of reduced glutathione, secondary to enhanced production of reactive oxygen species, and impairment of the glutathione-reductase systemthereby leading to decreased regeneration of reduced glutathione from oxidized glutathione [3, 8, 39, 40]. Moreover, enhanced oxidative stress may increase TNF- production in various cells, and depletion of reduced glutathione may increase the inflammatory response to this cytokine [3, 8]. Thus, glutathione-redox disturbances and enhanced TNF- activation may represent a pathogenic loop, leading to enhanced inflammation and oxidative stress, and our findings suggest that this mechanism may also be operating, at least to some degree, during HAART. This inflammatory interaction not only may contribute to impaired T cell function (see above) but also may promote both HIV replication [4144] and T cell apoptosis [8, 45], thus contributing to CD4+ T cell depletion. The findings of the present study, demonstrate suppression of the spontaneous release of TNF- in PBMCs from HIV-infected patients during HAART, suggest that glutathione supplementation could represent a therapeutic approach to block the vicious circle involving oxidative stress and TNF-. This concept is also supported by some in vivo studies of HIV-infected patients, as well as by some murine models of AIDS [46, 47]. "(1)

"On the basis of recent findings implicating oxidative stress as playing a pathogenic role in atherogenesis [48, 49], our findings could also be of importance for an understanding of certain longtime side effects of HAART (e.g., hyperlipidemia potentially predisposing to atherosclerotic disorders). In fact, persistent TNF- activation appears to be involved in the pathogenesis of HAART-associated lipodystrophy syndrome [50]. Moreover, drug-associated dysfunction of mitochondria is believed to play a central role in the etiology of several of the various adverse symptoms that occur in HIV-infected patients treated with nucleoside reverse-transcriptase inhibitors [51], and, again, disturbed glutathione metabolism may enhance such toxic effects [52, 53]. Thus, although there is some improvement, disturbed glutathione-redox status and decreased antioxidant levels seem to persist even during HAART, and these effects not only may contribute to persistent immunodeficiency in these patients but also may potentially enhance the toxicity of such therapy"(1)

" The present study suggests that enhanced oxidative stress and disturbed glutathione metabolism exist, at least to some degree, during apparently successful HAART. These effects seem to be related to persistent TNF- activation in HIV-infected patients. As a supplement to HAART, combination therapy with glutathione-replenishing agents, antioxidants, and therapeutic modalities that down-regulate TNF- activity could be an interesting therapeutic approach in HIV-infected patients. Such therapy not only may contribute to both restoration of immune responses and down-regulation of HIV replication but also may attenuate the toxic effects of HAART. " (1)

On a personal note I have restarted combination therapy this time with antioxidants and I am not and have never been against the provision of these agents to anyone in the world. I am however concerned about side effects and I am concerned that people loving in poverty suffering from malnutrition might be more vulnerable to the side effects.

Last question does anyone have access to or a reference regards L glutamine supplementation and PCP prevention that I heard had been published in the Lancet ? I have looked but can not find it.

Best wishes

And a very happy New Year to all "sides".

James J Whitehead

Clinical trials volunteer memeber and


1)The Journal of Infectious Diseases 2003;188:232-238 © 2003 by the Infectious Diseases Society of America. All rights reserved.

Disturbed Glutathione Metabolism and Decreased Antioxidant Levels in Human Immunodeficiency VirusInfected Patients during Highly Active Antiretroviral TherapyPotential Immunomodulatory Effects of Antioxidants

Pål Aukrust,1,2 Fredrik Müller,2 Asbjørn M. Svardal,3 Thor Ueland,2 Rolf K. Berge,4 and Stig S. Frøland1,2

1Section of Clinical Immunology and Infectious Diseases, 2Research Institute for Internal Medicine, Medical Department, Rikshospitalet, Oslo, and Departments of 3Pharmacology and 4Clinical Biology, Division of Clinical Biochemistry, Haukeland Hospital, Bergen, Norway

(2)Kidney International Volume 65 Issue 3 Page 860 - March 2004 doi:10.1111/j.1523-1755.2004.00464.x

CELL BIOLOGY - IMMUNOLOGY - PATHOLOGY Protease inhibitors modulate apoptosis in mesangial cells derived from a mouse model of HIVAN1 http://www.blackwell- 2538&date=2004&volume=65&issue=3&spage=860

Competing interests: Clinical trials volunteer