ABSTRACT

There is substantial evidence to support an important role for zinc in immune processes. Adequate zinc status is essential for T-cell division, maturation and differentiation; lymphocyte response to mitogens; programmed cell death of lymphoid and myeloid origins; gene transcription; and biomembrane function. Lymphocytes are one of the types of cells activated by zinc. Zinc is the structural component of a wide variety of proteins, neuropeptides, hormone receptors and polynucleotides. Among the best known zinc-dependent hormones/enzymes are Cu, Zn superoxide dismutase, an enzyme component of the antioxidant defense system, and thymulin, which is essential for the formation of T-lymphocytes. In animals and humans, zinc deficiency results in rapid and marked atrophy of the thymus, impaired cell-mediated cutaneous sensitivity and lymphopenia. Primary and secondary antibody responses are reduced in zinc deficiency, particularly for those antigens that require T-cell help, such as those in heterologous red blood cells. In addition, antibody response and the generation of splenic cytotoxic T cells after immunization are reduced. Zinc also inhibits the production of tumor necrosis factor, which is implicated in the pathophysiology of cachexia and wasting in acquired immune deficiency syndrome.

Deficiency of zinc is most frequently evaluated by measuring plasma levels. Even though plasma zinc is an acute phase reactant that may change in response to metabolic alterations, plasma zinc levels react to dietary intake in a rapid and measurable manner (Gershwin et al. 1985Keen 1990). Low plasma levels of zinc have been observed in congenital diseases such as sickle cell anemia (Ballester et al. 1986), Down’s syndrome (Licastro et al. 1992) and acrodermatitis enteropathica. Zinc deficiency also is characterized by decreased thymulin activity and impaired lymphocyte response to phytohemagglutinin (Chandra 19801997). Zinc deficiency has been observed in acquired conditions, including malabsorption syndrome (McClain 1985), malnutrition (Keen 1990), cancer (Mocchegiani et al. 1994), alcoholism (Zarski et al. 1987), end-stage liver disease (Pescovitz et al. 1996), uremia (Mahajan et al. 1982) and chronic and acute infectious diseases such as human immunodeficiency virus (HIV)3 type 1 (HIV-1) infection (Ripa and Ripa 1995). Similarly, altered zinc levels in plasma, enzymes and neurons have been demonstrated in a number of disorders of the central nervous system (Ebadi et al. 1995). Low plasma zinc levels, either congenital or acquired, are associated with immune abnormalities, impaired healing processes and increased susceptibility to infections.

Zinc status and HIV-1

The significance of zinc status in HIV-1 infection has not been fully elucidated. Zinc promotes multimerization and enhances enzymatic activity of viral integrase and its “zinc fingers” (Lee et al. 1997). Zinc also is a component of HIV-1 nucleocapsid proteins (Berthoux et al. 1997Darlix et al. 1995Zheng et al. 1996). In addition, HIV-1 transactivating protein (Tat) has a unique cysteine-rich region with zinc binding properties (Huang and Wang 1996) and has a high binding affinity for zinc (Frankel et al. 1988). Zinc utilization by the HIV-1 for gene expression, multimerization and integration characterizes HIV-1 as a zinc-dependent virus, which may at least in part explain the low plasma zinc levels frequently observed in HIV-1–infected patients (Mocchegiani et al. 1995).

Consistent with this characterization of the virus, Tang et al. (19931996) reported an association between elevated intakes of zinc and faster disease progression and death in HIV-1–infected homosexual/bisexual men. This cohort had a relatively high intake of zinc, and changes in zinc intake or plasma zinc status over time were not considered. It should also be noted that an excessive intake of zinc (300 mg/d, 20 times the recommended daily allowance) results in significant immune impairment in healthy adult men (Chandra 1985). In addition, excessive intake of zinc may interfere with copper and iron utilization and affect HDL cholesterol concentrations and monocyte function (Fosmire 1990Schlesinger et al. 1993), all of which may contribute to HIV-1 disease progression.

Zinc status and the immune system in HIV infection

Patients with acquired immune deficiency syndrome (AIDS) exhibit clinical symptoms similar to those associated with zinc deficiency, including immune deficiencies, impaired taste and appetite, decreased food intake, gastrointestinal malfunction with diarrhea, alopecia, epithelial lesions and hypogonadism and hypospermia (King and Keen 1994Odeh 1992).

Low concentrations of zinc are prevalent in HIV-1–infected male and female drug users as well as other HIV-1–infected cohorts (Baum et al. 1995 and 1997aBeach et al. 1992). Such low concentrations of plasma zinc have been linked with disease progression, independent of baseline CD4 cell count, lymphocyte concentrations and age- and calorie-adjusted dietary intake (Falutz et al. 1988Graham et al. 1991). Of particular importance, low plasma zinc levels have been associated with a threefold increased risk of HIV-1–related death in HIV-1–seropositive drug users (Baum et al. 1997b).

Zinc has an important role in inhibiting tumor necrosis factor (TNF) (Flieger et al. 1989), which has been implicated in the pathophysiology of AIDS, including wasting (Beutler and Cerami 1987). An increase in TNF levels has been reported as the disease advances to AIDS (Reddy et al. 1988Rosenberg and Fauci 1989). In addition, zinc deficiency reduces the secretion by T cells of interleukin-4 (IL-4), a growth factor for T-cell helpers (Dowd et al. 1986). In turn, IL-4 may significantly inhibit the production of TNF by monocytes (Hart et al. 1989), which reinforces the potential role of adequate zinc status in preventing disease progression in HIV-1 infection (Rosenberg and Fauci 1990).

Cu, Zn superoxide dismutase (Cu-Zn SOD) is a zinc-dependent enzyme that is essential for the antioxidant defense system. Zinc deficiency in HIV-1 infection may compromise the production of Cu-Zn SOD and adversely affect the antioxidant response to the overproduction of free radicals and lipid peroxides observed early in the disease (Favier et al. 1994). In vitro, Cu-Zn SOD has been demonstrated to reduce HIV-1 replication (Edeas et al. 1996), whereas oxidative stress stimulates the replication of HIV-1 (Favier et al. 1994).

Zinc supplementation and the immune system

Zinc supplementation has been demonstrated to increase the efficiency of the immune system in a number of study populations, including marasmic infants (Castillo-Duran et al. 1987), children recovering from malnutrition (Golden and Golden 1981), patients with sickle cell anemia (Prasad and Cossack 1984) and children with Down’s syndrome (Chiriciolo et al. 1993Licastro et al. 1992). In addition, improvement in immunologic responses has been demonstrated with zinc treatment in obese children and adolescents (Chandra and Kutty 1980). An advantageous effect of the use of zinc in individuals with cold symptoms has been reported by some (Al-Nakib et al. 1987Eby et al. 1984Godfrey et al. 1992Mossad et al.1996), but not all (Douglas et al. 1987Farr et al. 1987Smith et al. 1989Weismann et al. 1990), investigations. Zinc supplementation in elderly subjects produced the restoration, at least partially, of nutritional and thymic status with no adverse effects (Boukaiba et al. 1993). An improvement in immune response has also been demonstrated with zinc therapy in zinc-deficient elderly individuals (Cossack 1989), although not in healthy elderly individuals (Bogden et al. 1988Swanson et al. 1988).

Few zinc supplementation studies have been conducted in HIV/AIDS patients. Zinc administration in HIV-1 infection stage III and IV adult patients treated with zidovudine has been demonstrated to stabilize weight and to increase CD4 cell count as well as plasma levels of zinc-bound thymulin. A marked reduction in opportunistic infections in the zinc-treated group was also demonstrated in this study, especially in Pneumocystis carinii and Candida infections (Mocchegiani et al. 1995). This is in accord with our findings demonstrating a zidovudine-induced effect on nutritional parameters with zinc-adequate, but not zinc-deficient, subjects exhibiting a significant increase in the response of peripheral blood lymphocytes to mitogens (Baum et al. 1991).

In summary, evidence to date indicates that adequate amounts of zinc are essential to maintain the integrity of the immune system and that HIV-1–infected individuals are a population particularly susceptible to zinc deficiency. On the other hand, excessive zinc may stimulate HIV-1. The association between zinc deficiency and decreased survival in HIV-1–infected individuals indicates the need to carefully consider therapeutic options. Moreover, with the advent of new antiretroviral therapies that may significantly alter the natural history of HIV/AIDS, the prevalence of zinc deficiency and the potential of interventions in HIV-infected individuals may change dramatically, generating new challenges.

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Abbreviations

 

    • AIDS

      acquired immune deficiency syndrome

 

    • HIV

      human immunodeficiency virus

 

    • TNF

      tissue necrosis factor

 

  • Cu-Zn SOD

    Cu, Zn superoxide dismutase

Footnotes

1
Presented at the international workshop “Zinc and Health: Current Status and Future Directions,” held at the National Institutes of Health in Bethesda, MD, on November 4–5, 1998. This workshop was organized by the Office of Dietary Supplements, NIH and cosponsored with the American Dietetic Association, the American Society for Clinical Nutrition, the Centers for Disease Control and Prevention, Department of Defense, Food and Drug Administration/Center for Food Safety and Applied Nutrition and seven Institutes, Centers and Offices of the NIH (Fogarty International Center, National Institute on Aging, National Institute of Dental and Craniofacial Research, National Institute of Diabetes and Digestive and Kidney Diseases, National Institute on Drug Abuse, National Institute of General Medical Sciences and the Office of Research on Women’s Health). Published as a supplement to The Journal of Nutrition. Guest editors for this publication were Michael Hambidge, University of Colorado Health Sciences Center, Denver; Robert Cousins, University of Florida, Gainesville; Rebecca Costello, Office of Dietary Supplements, NIH, Bethesda, MD; and session chair, Craig McClain, University of Kentucky, Lexington.