Mechanism of Action of Micronutrients in HIV Infection and Drug Abuse
Ethan Will Taylor, Ph.D.
University of Georgia College of Pharmacy
Outline
The talk will focus on the roles of Se and Zinc, involving the following key points: (i) why injection drug use may place an increased oxidative stress on the body and the immune system; (ii) evidence that oxidative stress activates HIV replication and antioxidants inhibit it; (iii) brief review of clinical studies documenting correlations between Se and zinc status and HIV disease progression and mortality; (iv) evidence for the existence of HIV-encoded selenoproteins, including a glutathione peroxidase gene; (v) the identification of the same gene in Hepatitis C virus (HCV), a very common co-infection in HIV+ injection drug users; and (vi) the potential role of HIV-encoded selenoproteins in the clinical observations cited above.
Abstract
Injection drug users (IDUs) are a population known to be exceptionally prone to malnutrition. Nutritional deficiencies have been linked to compromised immune function even in drug users who are not infected with HIV, which is not surprising in light of the importance of nutrition for maintaining optimal immune function [1].
Of particular significance for HIV+ IDUs is the fact that injection drug use exerts an exceptional oxidant stress on the body and the immune system. In part because of tissue damage and cellular injury, drug abusers show increased lipid peroxidation products in blood, liver and urine [2-3], and low serum thiol levels indicative of increased oxidative stress are predictive of outcome in HIV+ IDUs [4]. This effect of drug abuse would lead to an increased requirement for nutritional antioxidants, which is very unlikely to be met in typical malnourished drug users. A study of heroin users showed significantly low urinary levels of the antioxidant trace mineral selenium (Se) [5], which suggests that Se intake is low and/or that absorption is impaired in IDUs.
Certain micronutrient deficiencies particularly Se and zinc have been associated with more rapid disease progression and increased mortality risk in various HIV+ populations [e.g., 6]. Because Se is known to be essential for cellular immunity [1,7], in addition to being an important antioxidant required to counter the increased lipid peroxidation caused by drug abuse, it could be especially critical for HIV disease progression in drug-abusing populations having malnutrition as a cofactor.
Significantly, a progressive deficit in serum Se has been consistently documented in HIV/AIDS [6,8,9], establishing powerful correlations between Se status and HIV disease progression and mortality in all HIV risk groups. In a recent longitudinal study, Se deficiency was associated with a 20-fold increase in AIDS-related mortality in HIV+ IDUs [6]. This proves the critical role of Se in HIV disease progression in IDUs, who have the dual risk factors of malnutrition and increased oxidative stress due to drug use.
It is now apparent that some viruses, including HIV-1 [9], a pox virus [10], and hepatitis C virus (HCV), encode homologues of glutathione peroxidase (GPx), the prototypical mammalian selenoprotein, in which selenocysteine is inserted at a UGA codon, which more commonly serves as a stop codon in the genetic code. Theoretical and in vitro data also support the possibility of selenoprotein coding potential associated with the nef gene region of HIV-1, due to the existence of highly conserved potential frameshift sequences in nef, and conserved UGA codons associated with the overlapping -1 reading frame and the 3'-terminal of nef [8]. We have demonstrated (Blumberg and Taylor, submitted for publication) that several of the predicted nef features are functional in vitro, including: (1) an active-1 frameshift site in nef, (2) Se-dependent readthrough of the 3'-terminal UGA of nef, and (3) incorporation of 75Se in a nef isoform during in vitro translation. These results are particularly significant because the nef gene has been widely implicated in HIV-1 pathogenesis.
A theoretical model will be presented whereby virally encoded selenoproteins serve to regulate HIV replication, e.g., relative to cellular redox status. By depleting Se in an infected cell, overexpression of HIV-encoded selenoproteins (e.g., nef isoforms) could actively contribute to an antioxidant defect and exacerbate the effects of Se deficiency or drug-induced oxidative stress, thus explaining the critical role of Se for survival in HlV-infected IDUs.
In principle, the situation is similar for the role of zinc in HIV infection, because HIV has several proteins that incorporate tightly bound zinc ions. Zinc is also essential for immune function, and zinc deficiency has also been correlated with increased mortality in HIV+ IDUs [6]. Thus, it is possible that HlV-related zinc incorporation could exacerbate the effects of zinc deficiency.
References
R.K. Chandra (1997) Nutation and the immune system: an introduction. Am. J. Clin. Nutr. 66: 460S463S.
A.M. Seledtsov (1995) Lipid peroxidation and status of the antioxidant system in opiate addiction, chronic alcoholism, or substance abuse caused by inhaling solvent vapors. Vopr. Med. Khim. 41: 50-53.
J.A. Knight, R.K. Pieper, S.E. Smith, H.H. Crockett(1988) Increased urinary lipoperoxides in drug abusers. Ann. Clin. Lab. Sci. 18: 374-377.
M. Marmor, P. Alcabes, S. Titus, K. Frenkel, K. Krasinski, A. Penn, R.W. Pero (1997) Low serum thiol levels predict shorter times-to-death among HlV-infected injecting drug users. AIDS 11: 1389-1393.
E.M. Rodriguez Rodriguez, M. Sanz Alaejos, C. Diaz Romero (1994) Urinary selenium concentrations in heroin abusers. Clin. Chim. Acta 231: 3946.
M.K. Baum, G. Shor-Posner, S. Lai, et al. (1997) High risk of mortality in HIV infection is associated with selenium deficiency. J. AIDS Human Retrovirol. 15: 370-374.
L. Kiremidjian-Schumacher, M. Roy, H.I. Wishe, M.W. Cohen, and G. Stotzky (1992): Regulation of cellular immune response by selenium. Biol. Trace Elem. Res. 33: 23-35.
E.W. Taylor, R.G. Nadimpalli and C.S. Ramanathan (1997): Genomic structures of viral agents in relation to the biosynthesis of selenoproteins. Biol. Trace Elem. Res., 56: 63-91.
E.W. Taylor, A. Bhat, R.G. Nadimpalli, W. Zhang, and J. Kececioglu (1997): HIV-1 encodes a sequence overlapping env gp41 with highly significant similarity to selenium-dependent glutathioneperoxidases. J. AIDS Human Retrovirol. 15: 393-394.
J.L. Shisler, T.G. Senkevich, M.J. Berry, B. Moss, Ultraviolet-induced cell death blocked by a selenoprotein from a human dermatotropic poxvirus. Science, 279: 102-105.
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