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Synergism Among Nutrient Deficiencies and Immune Dysfunction in Murine AIDS: Roles of Cocaine, Alcohol, and DHEA Supplementation


Ronald Ross Watson, Ph.D.
University of Arizona School of Medicine


Lecture Outline

  1. Definition of the murine AIDS model.

  2. Overview of methods to slow immune dysfunction and thus nutritional deficiencies during murine AIDS: T-cell receptor peptide, anti-IL-4, interferon-gamma replacement, DHEA vitamin E supplementation.

  3. Description of the effects of cocaine on retroviral immune dysfunction.

  4. Discussion of recent model study where DHEA therapy reduced immune dysfunction while ethanol consumption accentuated it. DHEA also reduced the toxic effects of alcohol on immune and nutritional parameters.

  5. Conclusions: Use of murine AIDS model rapidly defines studies and hypotheses for testing in HIV-infected humans. It shows the potential actions of drugs of abuse on immune and nutritional damage due to retroviral infection.

Abstract

Infection of female C57BL/6 mice with LP-BM5 murine retrovirus mixture is an economic model (1) that has most of the immune and nutritional changes seen in HIV-infected people. After 4.5 months of infection, severe loss of cytokine dysregulation, suppressed resistance to opportunistic pathogens, reduced antioxidant vitamin levels (2), and B-cell leukemia occur (1). Simultaneous cocaine injection at 40 mg/kg/day (3,4) or consumption of water containing 40% or food containing 30% (5) ethanol during murine AIDS accentuates these changes.

The murine AIDS model has rapidly defined several methods to maintain much of immune function and normal nutritional state using T-cell receptor peptide injection (6), vitamin E or A supplementation (7), melatonin or DHEA (dehydroepiandrosterone) consumption (8,9), replacement of suppressed production of interferon-gamma, and anti-IL-4 antibody suppression of excessive T helper 2 cell cytokine production (10). Our recent data show that DHEA supplementation helped overcome some of the immune and nutritional damage due to retrovirus infection (9) including their accentuation by ethanol consumption. Production of Th1 cytokines was suppressed by murine AIDS, with ethanol consumption accentuating this process. DHEA retarded this suppression while overcoming some of the excessive cytokine secretion by Th3 cells and their related suppression of B and T cell mitogenesis. Simultaneously, increased oxidation and loss of tissue vitamin E due to murine AIDS and accelerated by ethanol use were reduced. Similar synergistic effects would be expected from cocaine and murine retrovirus infection. Reduction of cytokine dysregulation by DHEA (9) as well as other agents (5-7) also reduces nutritional deficiencies.

Thus the murine AIDS model offers a rapid, economic, and immunologically relevant way to assert the effects of hormones and nutrient supplements on retroviral and drug-induced immune damage. Supported by NIH grant 59794.

References

Liang, B.; Wang, J.Y.; and Watson, R.R. Murine AIDS, a key to understanding retrovirus- induced immunodeficiency. Viral Immunol 98:225-239, 1998.

Zhang, Z.; Inserra, P.; Liang, B.; and Watson, R.R. Antioxidants and AIDS. In: Nutrients and Foods in AIDS. CRC Press, 1998. pp. 179-192.

Lopez, M.D.; Chen, G.J.; Huang, D.S.; and Watson, R.R. Modification of spleen cell subsets by chronic cocaine administration and murine retrovirus infection in normal and protein-malnourished mice. Int J Immunopharmacol 14:1153-1163, 1992.

Darban, H.; Watson, R.R.; Alak, J.; and Thomas, N. Cocaine facilitation of cryptosporidiosis by murine AIDS in male and female C57/BL6 mice. In: Drugs of Abuse, Immune and AIDS, 1993. pp. 143-151.

Wang, J.Y.; Liang, B.; and Watson, R.R. Alcohol consumption alters cytokine release during murine AIDS. Alcohol 14:155-159, 1997.

Liang, B.; Ardestani, S.; Chow, H.H.; Eskelson, C.; and Watson, R.R. Vitamin E deficiency and immune dysfunction are prevented in retrovirus-infected C57BL6 mice by T cell receptor peptide treatment. J Nutr 126:1389-1397, 1996.

Wang, Y.; Huang, D.S.; Liang, B.; and Watson, R.R. Nutritional status and immune responses in mice with murine AIDS are normalized by vitamin E supplementation. J Nutr 124:2024-2032, 1994.

Watson, R.R.; Chung, S.; Huls, A.; and Araghiniknam, M. Dehydroepiandrosterone (DHEA) and diseases of aging. Drugs Aging 9:274-291, 1996.

Arighiniknam, M.; Liang, B.; Zhang, Z.; Ardestani, S.; and Watson, R.R. Modulation of immune dysfunction during murine leukemia retrovirus infection of old mice by dehydroepiandrosterone sulfate (DHEAS). Immunology 90:344-349, 1997.

Wang, Y.; Ardestani, S.K.; Liang, B.; Beckham, C.; and Watson, R.R. Anti-interleukin-4 monoclonal antibody and interferon-gamma administration retards development of immune dysfunction and cytokine dysregulation during murine AIDS. Immunology 83:384-389, 1994.

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