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Center for Disease Prevention, Department of Psychiatry and Behavioral Medicine, University of Miami School of Medicine, Miami, FL 33136
2To whom correspondence should be addressed.
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ABSTRACT |
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 TOP ABSTRACT INTRODUCTIONZinc status and HIV-1Zinc status and the...Zinc supplementation and the...REFERENCES |
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KEY WORDS: • zinc • human immunodeficiency virus • nutrition • disease progression • supplementation
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INTRODUCTION |
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TOPABSTRACTINTRODUCTIONZinc status and HIV-1Zinc status and the...Zinc supplementation and the...REFERENCES |
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, Keen 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 1980
, 1997
). 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 |
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TOPABSTRACTINTRODUCTIONZinc status and HIV-1Zinc status and the...Zinc supplementation and the...REFERENCES |
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). Zinc also is a component of HIV-1 nucleocapsid
proteins (Berthoux et al. 1997
, Darlix et al. 1995
, Zheng 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. (1993
, 1996
) 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 1990
, Schlesinger et al. 1993
), all of which may
contribute to HIV-1 disease progression.
|
Zinc status and the immune system in HIV infection |
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TOPABSTRACTINTRODUCTIONZinc status and HIV-1Zinc status and the...Zinc supplementation and the...REFERENCES |
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, Odeh 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 1997a
, Beach 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. 1988
, Graham 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. 1988
,
Rosenberg 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 |
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TOPABSTRACTINTRODUCTIONZinc status and HIV-1Zinc status and the...Zinc supplementation and the...REFERENCES |
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),
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. 1993
, Licastro 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. 1987
, Eby et al. 1984
,
Godfrey et al. 1992
, Mossad et al.1996
),
but not all (Douglas et al. 1987
, Farr et al. 1987
, Smith et al. 1989
, Weismann 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. 1988
, Swanson 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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FOOTNOTES |
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3 Abbreviations: AIDS, acquired immune deficiency syndrome; HIV, human immunodeficiency virus; TNF, tissue necrosis factor; Cu-Zn SOD, Cu, Zn superoxide dismutase.
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REFERENCES |
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