Disclaimer: Some of these articles assume that AIDS is caused by HIV. While we disagree on this point, these articles explain important landmarks in the understanding of AIDS.
Last Modified: Jul 25, '06.
rumor viruses)"Mario Roederer of Stanford University describes the [1998] papers as the final nails in the coffin for the proliferation model of T cell dynamics. Roederer concludes that only by understanding how T cell numbers are regulated will we find the mechanism by which HIV destroys the immune system."
"First and foremost, we must always remember that the blood is an imperfect reflection of the immune system. It is not representative of the [entire body]...
The facts (1) that HIV uses CD4 as its primary receptor, and (2) that CD4+ T cell numbers decline during AIDS, are only an unfortunate coincidence that have led us astray from understanding the immunopathogenesis of this disease. HIV leads to the progressive destruction of all T cell subsets, irrespective of CD4 expression. Ultimately, AIDS is a disease of perturbed homeostasis. Only when we understand how the body regulates T cell numbers will we be able to find the mechanism(s) by which HIV destroys the immune system."
"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-acetylcysteine [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."
Data from three studies of HIV-infected patients show that these patients lose a massive amount of sulfur [whether they take HAART or not]. The loss can be life-threatening and may contribute to the wasting process.
Dr. Raoul Breitkreutz from Deutsches Krebsforschungszentrum [German Cancer Research Center], in Heidelberg, and colleagues conducted the studies in Germany. They determined that the mean sulfur loss was about 10 g per day, equivalent to "an alarming negative balance of approximately 2 kg of cysteine per year," as they report in the February 10th issue of AIDS Research and Human Retroviruses.
The researchers also determined that patients with HIV do not produce more sulfur than normal, so that the loss of sulfur could not be accounted for by excess production [ duh how can someone produce sulfur unless they are an alchemist?? ]. Highly active antiretroviral therapy did not affect this loss.
"The accumulating consequences of a steady loss of sulfur may eventually give rise to the wasting process," Dr. Breitkreutz's team speculates. "It is reasonable to assume that this massive loss of sulfur must lead to a life-threatening condition sooner or later." "The abnormally high sulfate/urea ratio suggests that this process drains largely the glutathione pool." [ literally pissing away the thiol pool! ]
In inherited disorders of mitochondrial function, 'thresholds' exist such that severe symptoms occur only when a certain percentage of mitochondria are affected. The precise threshold required varies among tissues, being lower in tissues with higher energy consumption, such as muscle and brain.6 HIV may cause mitochondrial dysfunction, either through mutations in, or depletion of, mtDNA. This could then render infected individuals at increased risk of reaching the 'threshold' for clinically relevant toxicities if exposed to further mitochondrial damage from NRTIs.
Both clinical and laboratory data point to the possibility of HIV-induced mitochondrial dysfunction. A series of seven cases of unexplained severe lactic acidosis in HIV-infected individuals was reported from San Francisco in the late 1980s, including three patients who were not taking antiretroviral agents when this syndrome developed.14 A mitochondrial myopathy has been reported in NRTI-naive patients with HIV infection.15 Increased astrocyte apoptosis (a process thought to be driven by mitochondrial dysfunction) has been associated with HIV dementia.16 Lymphocytes collected from individuals undergoing symptomatic HIV seroconversion have prominent mitochondrial alterations in addition to an increased tendency to undergo apoptosis compared with control cells.17 In vitro studies of lymphoblastoid and monocytoid cells acutely infected with various strains of HIV demonstrate prominent mitochondrial abnormalities.18
...Despite the fact that individuals with HIV infection may be particularly predisposed to their toxicities, NRTIs are currently an essential component of effective HIV therapy. The development of strategies for using NRTIs safely is therefore a priority. It is possible that mitochondrial toxicity might be treated or prevented through supplementation with micronutrients known to contribute to healthy mitochondrial function. Anecdotal reports of NRTI-induced neuropathy improving with L-acetyl carnitine administration,23 and a case report of coenzyme Q10 being used successfully to treat zidovudine-associated myopathy without zidovudine cessation (Franklin L. Rosenfeldt, Department of Cardiothoracic Surgery, Alfred Hospital, Melbourne, Victoria, Australia, personal communication), lend support to this possibility, but formal studies are lacking.
RESULTS: Studies of the NRTIs in enzyme assays and cell cultures demonstrate the following hierarchy of mitochondrial DNA polymerase gamma inhibition: zalcitabine > didanosine > stavudine > lamivudine > zidovudine > abacavir. In vitro investigations have also documented impairment of the mitochondrial enzymes adenylate kinase and the adenosine diphosphate/adenosine triphosphate translocator. Inhibition of DNA polymerase gamma and other mitochondrial enzymes can gradually lead to mitochondrial dysfunction and cellular toxicity. The clinical manifestations of NRTI-induced mitochondrial toxicity resemble those of inherited mitochondrial diseases (ie, hepatic steatosis, lactic acidosis, myopathy, nephrotoxicity, peripheral neuropathy, and pancreatitis). Fat redistribution syndrome, or HIV-associated lipodystrophy, is another side effect attributed in part to NRTI therapy. The morphologic and metabolic complications of this syndrome are similar to those of the mitochondrial disorder known as multiple symmetric lipomatosis: suggesting that this too may be related to mitochondrial toxicity. The pathophysiology of less common adverse effects of nucleoside analogue therapy, such as diabetes, ototoxicity, and retinal lesions, may be related to mitochondrial dysfunction but have not been adequately studied. CONCLUSION: NRTls can block both HIV reverse transcriptase and mitochondrial DNA polymerase gamma. Inhibition of the latter enzyme is the most likely cause of the adverse effects associated with these drugs.