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Can a Drug for Psoriasis and MS Help Protect the Brain From HIV's Toxicity?

November/December 2011

Researchers have found that a compound called dimethyl fumarate (DMF) can, in lab experiments with cells and HIV, suppress the production of HIV and cause HIV-infected cells to reduce production of compounds that harm brain cells. Before we detail these experiments, we first present some background information on antioxidants and HIV infection, followed by a brief history of DMF's application and recent therapeutic developments with this compound.


Antioxidants

Cells make a compound called GSH (glutathione) from the amino acids cysteine and glutamine. Then, using minerals such as selenium and zinc, they make GSH-containing enzymes. The purpose of these enzymes is to protect cells from the harmful effects of highly reactive molecules. Many such molecules are produced in the everyday activities that cells undergo.

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GSH is particularly important in protecting key organs such as the liver and kidneys when faced with toxicity from excess acetaminophen (Tylenol). A liquid formulation of N-acetyl-cysteine (NAC) is licensed for the treatment of acetaminophen toxicity (cysteine is converted into GSH) in Canada and other high-income countries.


Antioxidants and HIV

Since the mid-to-late 1980s, some researchers have theorized that antioxidants -- substances that protect the body from the harmful effects of highly reactive molecules -- may play a role in protecting the body from some of the effects of HIV infection. Researchers found that HIV-positive people have less-than-normal levels of GSH in many tissues and fluids such as blood, the lungs and many different types of the immune system's cells, including CD4+, CD8+, natural killer and monocytes/macrophages. In general, the greater the degree of HIV-related immune deficiency, the lower the concentration of GSH.


Clinical Trials

In the early 1990s, researchers at Stanford University in California conducted an eight-week randomized, placebo-controlled study of NAC in HIV-positive people. The dose of NAC used was about 4,400 mg daily. After the initial eight weeks, all participants were offered NAC for six months. Researchers collected data on the survival of participants for several years after they stopped using NAC. They found that this supplement significantly increased GSH levels within CD4+ cells. However, NAC did not significantly raise CD4+ cell counts. The data also suggested that people who used NAC were twice as likely to survive over the next two years compared to people who did not ever use NAC. At the time of the study, powerful anti-HIV drugs such as protease inhibitors were not available and most participants used AZT (zidovudine, Retrovir) with or without another nuke (nucleoside analogue). Due to the study design, firm conclusions about the effect of NAC on survival cannot be drawn and it is important to note that a large proportion of NAC users did eventually die. However, the trial did heighten interest in the use of antioxidants.

Researchers in Montreal also tested whey protein concentrates, which are rich in cysteine, in HIV-positive volunteers and found that they improved weight. In the time before ART was available, a sustained increase in weight was unusual in HIV-positive people.

Researchers in Toronto and Ottawa led a randomized, placebo-controlled study of mixed carotinoid supplementation in HIV-positive people who were also taking ART. Mixed carotinoids are often responsible for the colour of pink, red, orange and yellow vegetables and fruit and can function as antioxidants. An example of a carotinoid is beta-carotene; this particular carotinoid can be converted into vitamin A by the body. Mixed carotinoids contain the full range of carotinoids, not just beta-carotene. Researchers in this study found that participants who received the supplement of carotinoids survived longer than people who received placebo.

These and other studies suggest that some antioxidants and foods rich in the amino acid cysteine seem to have beneficial effects in people with HIV infection.

The Canadian HIV Trials Network is sponsoring a trial of micronutrients and antioxidants in people with HIV infection. It is still recruiting people.


Psoriasis

In the late 1950s, researchers in Germany found that compounds containing chemicals related to fumaric acid (mostly dimethyl fumarate, or DMF) were useful for the treatment of psoriasis. However, it was only decades later, in the late 1980s, that clinical trials were conducted to prove this beneficial effect. Subsequently, regulatory authorities in Germany approved a tablet formulation containing DMF and other compounds, sold as Fumaderm, for the treatment of psoriasis. Fumaderm has not been approved by regulatory authorities in Canada, the U.K., U.S. and many other high-income countries.

Now the Biogen Idec biotechnology company, whose headquarters are in the U.S., has completed two large Phase III trials of DMF (code named BG-12) for the treatment of multiple sclerosis (MS). Both trials, code-named Define and Confirm, found that BG-12 at a dose of 250 mg twice daily was effective at significantly preventing relapse of MS; and in Define, the drug significantly prevented worsening disability in some participants. The side effects were mainly diarrhea and flushing of the skin. German researchers who have used DMF for treating patients with psoriasis have stated that the drug's side effects are lessened after the first month of use.

Based on the promising results from Define and Confirm, Biogen Idec plans to seek regulatory approval of BG-12 in at least the U.S. in 2012.


Dimethyl Fumarate (DMF) and HIV

Researchers at the University of Pennsylvania have performed extensive laboratory experiments with HIV and a group of the immune system's cells called macrophages. As explained earlier in this issue of TreatmentUpdate, macrophages play an important role in helping HIV spread throughout the body, including to the brain. Moreover, macrophages likely play a critical role in HIV-related neurocognitive impairment.

The Philadelphia researchers found that DMF had the following impact:

  • HIV-infected macrophages produced fewer chemical signals that could harm brain cells.
  • It restored the ability of HIV-infected macrophages to produce their own antioxidants.
  • It reduced production of HIV.
  • It had an anti-inflammatory effect.

In part, DMF exerts its protective effect by activating genes within macrophages that carry instructions for making GSH.

The research team speculated that perhaps DMF treatment might also have suppressed the ability of macrophages to display co-receptors such as CXCR4 and CCR5. HIV uses one or sometimes both of these receptors, together with another receptor called CD4, to gain entry to and infect cells. Proof of this will require further experimentation.

Based on their results, the Philadelphia scientists propose that DMF (or BG-12), when used together with combination anti-HIV therapy, may protect brain cells and macrophages from the harmful effects of HIV and its proteins. DMF also has potential to help reduce the excess immune activation seen in HIV infection. This excess activation may play a role in some of the co-morbidities seen in HIV infection, such as cardiovascular disease, diabetes and bone thinning.

Clinical trials to explore these ideas in HIV-positive people, at least in North America, may have to wait until regulatory agencies such as the U.S. Food and Drug Administration and Health Canada approve DMF for the treatment of MS. The good news is that data collected over the past 14 years from patients in Germany suggest that DMF generally has not caused serious or permanent side effects.


References

  1. Eck HP, Gmünder H, Hartmann M, et al. Low concentrations of acid-soluble thiol (cysteine) in the blood plasma of HIV-1-infected patients. Biological Chemistry Hoppe-Seyler. 1989 Feb;370(2):101-8.
  2. Buhl R, Jaffe HA, Holroyd KJ, et al. Systemic glutathione deficiency in symptom-free HIV-seropositive individuals. Lancet. 1989 Dec 2;2(8675):1294-8.
  3. Roederer M, Staal FJ, Osada H, et al. CD4 and CD8 T cells with high intracellular glutathione levels are selectively lost as the HIV infection progresses. International Immunology. 1991 Sep;3(9):933-7.
  4. Roederer M, Raju PA, Staal FJ, et al. Cytokine-stimulated human immunodeficiency virus replication is inhibited by N-acetyl-L-cysteine. Proceedings of the National Academy of Sciences USA. 1990 Jun;87(12):4884-8.
  5. Kalebic T, Kinter A, Poli G, et al. Suppression of human immunodeficiency virus expression in chronically infected monocytic cells by glutathione, glutathione ester, and N-acetylcysteine. Proceedings of the National Academy of Sciences USA. 1991 Feb 1;88(3):986-90.
  6. Bounous G, Baruchel S, Falutz J, et al. Whey proteins as a food supplement in HIV-seropositive individuals. Clinical and Investigative Medicine. 1993 Jun;16(3):204-9.
  7. Fuchs J, Schöfer H, Milbradt R, et al. Studies on lipoate effects on blood redox state in human immunodeficiency virus infected patients. Arzneimittel-Forschung. 1993 Dec;43(12):1359-62.
  8. Walmsley SL, Winn LM, Harrison ML, et al. Oxidative stress and thiol depletion in plasma and peripheral blood lymphocytes from HIV-infected patients: toxicological and pathological implications. AIDS. 1997 Nov 15;11(14):1689-97.
  9. Herzenberg LA, De Rosa SC, Dubs JG, et al. Glutathione deficiency is associated with impaired survival in HIV disease. Proceedings of the National Academy of Sciences USA. 1997 Mar 4;94(5):1967-72.
  10. Austin J, Singhal N, Voigt R, et al. A community randomized controlled clinical trial of mixed carotenoids and micronutrient supplementation of patients with the acquired immunodeficiency syndrome. European Journal of Clinical Nutrition 2006 Nov;60(11):1266-76.
  11. Lehmann JC, Listopad JJ, Rentzsch CU, et al. Dimethylfumarate induces immunosuppression via glutathione depletion and subsequent induction of heme oxygenase 1. Journal of Investigative Dermatology. 2007 Apr;127(4):835-45.
  12. Killestein J, Rudick RA, Polman CH. Oral treatment for multiple sclerosis. Lancet Neurology. 2011 Nov;10(11):1026-34.
  13. Mullard A. Success of immunomodulators in MS shifts discovery focus to neuroprotection. Nature Reviews Drug Discovery. 2011 Dec 1;10(12):885-7.
  14. Cross SA, Cook DR, Chi AW, et al. Dimethyl Fumarate, an immune modulator and inducer of the antioxidant response, suppresses HIV replication and macrophage-mediated neurotoxicity: a novel candidate for HIV neuroprotection. Journal of Immunology. 2011 Nov 15;187(10):5015-25.
  15. Seu L, Burt TD, Witte JS, et al. Variations in the heme oxygenase-1 microsatellite polymorphism are associated with plasma CD14 and viral load in HIV-infected African-Americans. Genes and Immunity. 2012; in press.


  
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This article was provided by Canadian AIDS Treatment Information Exchange. It is a part of the publication Treatment Update. Visit CATIE's Web site to find out more about their activities, publications and services.
 
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