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Immunology Centre, Research Department, Italian National Research Centres on Aging, 60121 Ancona, Italy
3To whom correspondence should be addressed.
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ABSTRACT |
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 TOP ABSTRACT INTRODUCTIONZinc, immune system and...Zinc and HIVSupplementation with zinc in...Future remarksREFERENCES |
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KEY WORDS: • zinc • thymulin • CD4+ • risk factors • opportunistic infections • viral load • HIV
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INTRODUCTION |
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TOPABSTRACTINTRODUCTIONZinc, immune system and...Zinc and HIVSupplementation with zinc in...Future remarksREFERENCES |
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). Among the most relevant findings are the listing of zinc
as a catalytic component of >200 enzymes, its requirement as a
structural constituent of many proteins and, likely, its function in
preventing free radical formation. The ensuing relevance for cell
division and differentiation, as well as for programmed cell death, for
gene transcription, for biomembrane functioning, and obviously for many
enzymatic activities, has led to the consideration of zinc as a leading
element in ensuring correct functioning of various tissues, organs and
systems (Fabris and Mocchegiani 1995
). Experimental
evidence in humans and animals has demonstrated that zinc deficiency
leads to a plethora of body homeostatic mechanism dysfunctions with
consequent slowed growth, susceptibility to many diseases and decreased
survival rates that can be corrected with zinc supplementation
(Mocchegiani et al. 1998
, Prasad 1991
). A
central clinical feature of zinc deficiency is the increased
susceptibility to infectious diseases. This led researchers to
speculate that zinc must be important for host immunity. Indeed, the
past two decades have witnessed a rapid growth in knowledge of the
underlying mechanisms whereby zinc exerts its ubiquitous effects on
immune function, disease resistance and general health (Walsh et al. 1994
, Zalewski 1996
). In particular, zinc is
essential for thymic functions by means of a zinc-dependent thymic
hormone called thymulin
(ZnFTS)4
(Dardenne et al. 1982
), which is indispensable for the
differentiation and maturation of T cells (Goldstein 1984
). In the course of infection, derangements of the immune
functions at both central and peripheral levels are usual and constant
events associated with more or less marked zinc deficiency
(Shankar and Prasad 1998
).
The aim of the present article was to summarize data from our
laboratory regarding the role of zinc in stage IV of human
immunodeficiency virus (HIV) infection according to the Centers for
Disease Control and Prevention classification (Centers for Disease Control AIDS Program 1987
) because marked zinc
deficiency and strong compromised immune functions are present with the
consequent appearance of opportunistic infections by various pathogens
leading to death of the infected individual (Fabris et al. 1988
, Levy 1989
). Supplementation with zinc
associated with zidovudine (AZT) therapy (retrospective study) is
discussed in comparison with new HAART therapy.
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Zinc, immune system and infections |
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TOPABSTRACTINTRODUCTIONZinc, immune system and...Zinc and HIVSupplementation with zinc in...Future remarksREFERENCES |
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, Wellinghausen et al. 1997
). The major
abnormalities during zinc deficiency in immune responses are in
T-lymphocyte and neutrophil functions. Zinc deficiency in animals
causes thymic and lymph node atrophy, impaired
cell-mediated cutaneous hypersensitivity reactions, decreased
response to mitogen [phytohemagglutinin (PHA)] and depression of
T-cell–dependent antibody production. Furthermore, a
zinc-deficient diet in experimental animals causes impaired
T-helper and T-suppressor functions and decreased T-killer
and natural killer activity (Iwata et al. 1979
)
(Table 1
). Assessment of the role of zinc in the development and function of
different lymphoid cell populations indicates that this element has an
effect predominantly on T-lymphocytes(Miller and Strittmatter 1992
) and macrophages (Wirth et al. 1989
), and less on B-lymphocytes (Cook-Mills and Fraker 1993
), although for this latter lymphocyte population,
an effect of zinc deficiency was documented on IgG production but
secondary to T-dependent antibody response (Forbes et al. 1991
). In humans from more or less zinc deficiency,
depressed immune functions both at central and peripheral levels,
particularly decreased thymic endocrine activity, reduced T-helper
functions and impaired natural killer activity, are constant events
(Chandra 1983
,Wellinghausen et al.
1997
), confirming, as such, the predominant role of zinc
deficiency in affecting cell-mediated immunity.
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). The effect of zinc
deficiency is mainly addressed, other than regarding the growth and
development of CD4+ cells (Miller and Strittmatter 1992
), regarding cytokine production relevant for
T-lymphocyte and macrophage functions. In particular, the
production of interleukin (IL)-2, IL-12, interferon (IFN)-
, and
IFN-
is decreased (Dowd et al. 1986
,Sala and
Kirchner 1987
) and the production of tumor necrosis factor
(TNF)-, IL-1, and IL-6 is increased during zinc deficiency
(Beck et al. 1996, Cui et al. 1998
)
(Table 1)
. In this context, a relevant point is related to findings
showing that zinc affects more than Th1 (cell-mediated immunity)
believed necessary for IL-2 and IFN- release rather than Th2 cells
(antibody-mediated immunity) believed necessary for IL-4, IL-6, IL-10,
and IL-13 release (Prasad et al. 1997
). With regard to
macrophages, the cytokine production (IL- 1ß, IL-6, TNF-, IL-12)
altered in zinc deficiency is normalized by in vitro zinc addition
(Driessen et al. 1994
). Recently, it was shown that zinc
also affects the major histocompatibility complex (MHC) class II
molecules with opposite effects, preventing or making easier the
antigen presentation from superantigen noxae, such as
Mycoplasma or toxins, respectively (Driessen et al. 1995
).
These findings clearly suggest the relevance of zinc deficiency for
immune depression with the onset of many pathologies, among which
infectious episodes are the most frequent (Clegg et al. 1989
). Indeed, numerous animal and human studies indicate that
zinc deficiency decreases resistance to infection diseases.
Zinc-deficient animals and humans have depressed immune
response (Chandra 1983
, Iwata et al. 1979
, Wellinghausen et al. 1997
) (Table 1)
, and
they are more susceptible to a diverse range of infectious pathogens,
including viruses, bacteria, fungi and protozoa (Table 1)
. The role of
zinc deficiency during infection is broad: from a delay in production
of protective IgG antibodies to decreased T-lymphocyte activation
and in some cases (e.g., for infections by Plasmodium
yoelii) to death (for a review, see Shankar and Prasad 1998
). An adequate zinc diet in animals is able to correct the
impaired resistance to infections with a reduction in infectious
episodes (Table 2
).
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) and in Down syndrome subjects (Licastro et al. 1994
). Significant reductions in infectious episodes by
supplementation with zinc are also observed in leprosy, malaria,
chronic diarrhea, congenital herpes, malnutrition and acrodermatitis
enteropathica (Table 2)
, in that it occurs for the latter in natural
bovine acrodermatitis enteropathica, where the impaired resistance to
viruses, fungi and bacteria is corrected by increased dietary zinc
intake (Good 1989
).
All of this findings support the idea of a key role played by zinc in
the efficiency of immune responses against infectious episodes. To
confirm this role of zinc, we used an HIV model (stage IV of disease,
Centers for Disease Control and Prevention classification,
Centers for Disease Control AIDS Program 1987
) because
zinc deficiency, deranged immune functions and occurrence or recidivism
of opportunistic infections are usual and constant events with an
unfavorable prognosis (Fabris et al. 1988
, Levy 1989
).
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Zinc and HIV |
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TOPABSTRACTINTRODUCTIONZinc, immune system and...Zinc and HIVSupplementation with zinc in...Future remarksREFERENCES |
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), as well as in the first phases of HIV infection
(Baum et al. 1995
). Therefore, zinc deficiency may be a
cofactor for the progression of the disease (Falutz et al. 1988
), despite the report that zinc deficiency is not a common
contributory factor for HIV infection or clinical expression and that
HIV infection does not induces zinc deficiency (Walter et al. 1990
). However, a general consensus exists on the presence of
malnutrition, intestinal absorption, changes in metabolic handling of
nutrients and increased energy expenditure in the setting of HIV
infection (Beisel 1995
, Kotler 1989
,
Sauerwein 1993
), with all of these characteristics
causing zinc deficiency in both humans and animals (Fabris and Mocchegiani 1998, Mills 1989
). On the other
hand, reduced appetite and decreased dietary intake are prominent
features of HIV infection, so it is therefore not surprising to find
zinc deficiency in HIV-positive patients, particularly those with
advanced stages of the disease (Odeh 1992
). Several
other factors may also contribute to zinc deficiency. HIV infection is
associated with acute and chronic infections with various types of
viral, bacterial, fungal or parasitic pathogens (Fauci et al. 1984
). These infections may cause zinc deficiency, and this can
last for a long period of time, depending on the cause (Sugarman 1983
).
Taking into account the pivotal role of zinc in the efficiency of the
immune system (Chandra 1983
, Prasad et al. 1988
, Wellinghausen et al. 1997
), in particular
for CD4+ cell growth and function (Miller and Strittmatter 1992
), the strong depletion of
CD4+ cells in the setting of HIV infection
leading to the appearance or recidivism of opportunistic infections,
followed by an unfavorable prognosis (Fauci et al.
), may
be in large part due to the low zinc bioavailability. Such an
assumption may be supported by the discovery that zinc is also required
for the biological activity of the thymic hormone ZnFTS
(Dardenne et al. 1982
) that is indispensable for the
differentiation and maturation of CD4+ cells
(Goldstein 1984
). The zinc-unbound form of thymulin
(FTS) is inactive with an inhibitory effect on the zinc-bound
active form (ZnFTS) (Fabris et al. 1984
). The in vitro
zinc addition to plasma samples unmasks the inactive form (FTS),
showing the total amount of thymulin molecules produced (ZnFTS + FTS)
(Fabris et al. 1984
). The ratio between total thymulin
(TT) and active thymulin (AT) represents the thymulin-unsaturable
fraction by zinc ions and, as such, is a good marker with which to test
real zinc deficiency (TT/AT > 2 = marked zinc deficiency;
TT/AT < 2 = mild zinc deficiency; TT/AT = 1n
zinc values) (Fabris et al. 1984
). This phenomenon
(TT/AT > 2) occurs in many zinc deficiencies, including HIV stage
IV, suggesting that the thymic defect in thymulin production is not
intrinsic but is in large part dependent on the low peripheral
zinc bioavailability to saturate all thymulin molecules produced
(Fabris et al. 1984
, 1988
, Fabris and Mocchegiani 1995
). In this context, discrepancies exist in
older literature regarding decrements in thymic hormone production in
HIV infection. Thymosin -1 is increased (Naylor et al. 1983
), whereas thymulin is decreased (Dardenne et al. 1983
, Incefy et al. 1986
). In agreement with
Dardenne et al. 1983
and Incefy et al. 1986
, in a retrospective study where only AZT was available, AT
is strongly reduced in stage IV (10 young patients), whereas inactive
thymulin (FTS) is strongly increased compared with young healthy
control subjects. The in vitro zinc addition to plasma samples unmasks
FTS-inactive molecules, showing that the total amount of thymulin
(ZnFTS + FTS) is near the young normal subject range
(Mocchegiani et al 1995
). The TT/AT ratio is > 2
(4–5 log-2) in stage IV, suggesting that the
severe zinc deficiency present in this stage of disease (70–75
µg/dL) is real (Fabris et al. 1988
, Mocchegiani et al. 1995
). Concomitantly, very strong CD4+
depletion is observed at individual level increments of 70% of
recidivistic opportunistic infections by various pathogens on d
120 of observation are also present (Mocchegiani et al. 1995
). These findings suggest that the marked zinc deficiency
in stage IV may be the cause of deranged immune functions with the
consequent increased appearance of recidivistic opportunistic
infections. On the other hand, the thymus gland is also atrophic in the
first phases of HIV infection (Gaulton et al. 1997
) due
to increased apoptosis of thymocytes (Meyaard et al. 1992
). Zinc prevents apoptosis (Fraker and Telford 1997
). The same mechanisms that involve apoptosis in atrophic
thymus have been recently proposed in aging because zinc in vitro
prevents old thymocyte apoptosis (Provinciali et al. 1998
), and supplementation with zinc in old mice restores
thymic functions and the number of thymocyte CD4+
cells (Mocchegiani et al. 1995
). These last findings
clearly suggest the key role played by zinc in thymic functions with
the consequent differentiation and maturation of
CD4+ cells. Because the analysis of risk factors
(Cox hazard regression) for infection incidence in stage IV confirms
zinc deficiency and CD4+ depletion as risk
factors with significant scores (Table 3
), this is further support that the low zinc bioavailability is crucial
for CD4+ depletion and, consequently, for HIV
progression, suggesting supplementation with zinc in this stage of
disease.
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). Second, during the acute phase response, zinc is
redistributed from plasma to liver and to lymphocytes (Beisel 1995
), being an adaptive response intended to deprive invading
pathogens of zinc (Clohessy and Golden 1996
). Because
the liver is a site of the extrathymic T-cell pathway prominent
during infections (Abo 1993
) and because zinc is also
relevant for this pathway (Mocchegiani et al. 1997
),
supplementation with zinc might not be necessary as previously
suggested (Walter et al. 1990
). However, the main reason
zinc supplementation is not suggested is related to the discovery that
HIV-Tat protein and HIV-nucleocapsid protein NCp7 are strongly
zinc dependent with high binding affinity (Frankel et al. 1988
, Melly et al. 1996
) and both proteins are
relevant for HIV replication (Fisher et al. 1986
,
Frankel et al. 1988
, Mely et al. 1996
).
Thus, major zinc bioavailability by supplementation with zinc might
induce a major activation of Tat and NCp7 proteins with consequent
quick viral HIV replication and rapid HIV progression. However, recent
discoveries showing zinc finger motifs required for inactivation of HIV
replication by means of gag precursors (Mizuno et al. 1996
, Turpin et al. 1996
), as well as a novel
zinc finger protein (KOX 1) as a protective agent against HIV
replication at intracellular level (Thiesen 199661
) and,
finally, the capability of zinc to prevent the loss of
CD4+ lymphocytes in an in vitro HIV feline model
(Johnson et al. 1996
), suggest that the low zinc
bioavailability in HIV infection may have more of a harmful rather than
a beneficial role for disease progression. Supplementation with zinc
may be useful to block and, as such, to stabilize the disease with
possibly no recidivism opportunistic infections.
A further support for the beneficial effect of zinc supplementation
comes from the findings showing a zinc-binding protein, such as
2-macroglobulin with high zinc binding
affinity (Fabris and Mocchegiani 1995
), to strongly
increase during infections with Pseudomonas aeruginosa
(Fitzgerald and Pastan 1993
) and, as such, may be a
marker for the appearance of acute phase infections (Roberts et al. 1982
). Impaired immune functions are also present during
infections with P. aeruginosa in patients affected by burns
(Berger et al. 1998
) and cystic fibrosis
(Mocchegiani et al. 1995
). Despite
2-macroglobulin having been suggested as
protective against bacteria endotoxins with a killing mechanism
(Fitzgerald and Pastan 1993
), its abnormal increments
may become deleterious for the efficiency of the immune system through
continuous sequestering of zinc (Mocchegiani et al. 1999
). Physiological supplementation with zinc in burned men
(Berger et al. 1998
) recovers immune efficiency with a
significant decrease in the number of bronchopneumonia infections
(Berger et al. 1998
). These last findings clearly
suggest that supplementation with zinc does not induce a possible
further deleterious role of 2-macroglobulin
because this zinc-binding protein may be completely saturated by
preexisting zinc ions, as occurs in cancer (Mocchegiani et al. 1999
). Indeed, the increased
2-macroglobulins in cancer are not affected by
supplementation with zinc, which induces, by contrast, a beneficial
effect on immune functions (Fabris and Mocchegiani 1995
)
with an 2-macroglobulin protective role
(Mocchegiani et al. 1999
). The same mechanism might also
occur in HIV infection, where physiological supplementation with zinc
might not induce a further viral replication because both Tat and NCp7
zinc-binding proteins might be completely saturated by preexisting
zinc ions. Thereby, zinc may be available for inhibitory action by gag
precursors (Mizuno et al. 1996
, Turpin et al. 1996
) and for immune efficiency recovery with consequent
opportunistic infection reduction. Such an hypothesis is supported by
the fact that up-physiological supplementation with zinc at
stage III of the disease, at the borderline for the appearance of the
first opportunistic infections (Fauci et al. 1984
) also
showing, in many cases, a high viral load (Mellors et al. 1996
), is able to prevent the onset of a first
opportunistic infection for a long period of time (~2 y), postponing
HIV progression (Mocchegiani et al. 1995
).
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Supplementation with zinc in HIV stage IV |
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TOPABSTRACTINTRODUCTIONZinc, immune system and...Zinc and HIVSupplementation with zinc in...Future remarksREFERENCES |
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) concomitant with AZT therapy in
stage IV (12 young patients) carried out from the time of recruitment
(time 0) for 1 mo induced an increment of CD4+
cells (from 80 ± 10 mm3 at time 0 to 121
± 9 mm3 at d 120 of observation from time
0), a restoration of both TT/AT ratio (2–2.5
log-2) and zincemia value; reductions (50%) in
recidivistic opportunistic infections at time 120 are also observed
(Mocchegiani et al. 1995
). The more relevant point is
related to complete disappearance of recidivistic opportunistic
infections by C. aesophagea and P. carinii in a
zinc-treated group (Mocchegiani et al. 1995
). These
findings suggest that the dose of zinc (three times the recommended
daily allowance) is not toxic because no side effects are observed
(Mocchegiani et al. 1995
), but it is beneficial against
the appearance of recidivistic opportunistic infections that involve
the extracellular matrix (Singh et al. 1992
). Prolonged
survival compared with the untreated group also occurs
(Mocchegiani et al. 1995
). Such an assumption is
confirmed by an analysis of risk factors (CD4+
depletion and zinc deficiency) in stage IV for recidivistic
opportunistic infections after supplementation with zinc showing
significant reductions in scores (Table 3)
. Although the number of
CD4+ cells is still strongly reduced (121 ± 9 mm3) after zinc supplementation, its score as a
relative risk factor is not significant. This latter fact may suggest
the possible presence of a low viral load in zinc-treated group
compared with the zinc-untreated group (viral load was not tested
due to the lack of availability of an HIV RNA technical procedure in
this retrospective study). Although these findings further confirm the
measure of CD4+ as misleading to predict HIV
progression compared with viral load (Mellors et al. 1996
), they may suggest a role of zinc HIV replication by means
of gag precursors (Frankel et al. 1988
, Mely et al. 1996
), despite the strong CD4+
depletion remaining very evident after supplementation with zinc
compared with values of young healthy control subjects (965 ± 68
mm3). Few zinc trials have been carried out in
HIV infection in the 1990s. Some articles have, however, reported a
beneficial effect of supplementation with zinc (135 mg zinc gluconate/d
for 15 d corresponding to 40 mg Zn2+/d) on
the recovery of immune efficiency (CD4+ cells and
PHA-mitogen responsiveness) in stage IV of HIV infection
(Zazzo et al. 1989
). General good health as revealed by
increments of body weights (Isa et al. 1992
) and
increased survival (Baum et al. 1995
) are also
associated. Although these studies have been carried out in small
cohorts of HIV subjects, they are suggestive to give a pivotal role to
zinc in HIV infection to thwart the appearance of
opportunistic infections.
Further indirect support for this assumption comes from the new HAART
therapy. Other HIV subjects (10 subjects in stage IV with
CD4+ cells of 
100
mm3) treated with new HAART showed significant
increments of CD4+ cells and zincemia values
associated with significant decrements of the viral load (HIV RNA)
(tested with reverse transcription—polymerase chain reaction technical
procedure, Mellors et al. 1996
). No appearance
occurred of recidivistic opportunistic infections during 4 mo of
observation (Table 4
). Furthermore, significant inverse correlations exist between
CD4+ and HIV RNA (r = -0.79,
P < 0.01) but also between zincemia and HIV RNA
(r = - 0.73, P < 0.01) in
HAART-treated subjects. This suggests that in addition to
increasing CD4+ cells (Chaisson and Moore 1997
), the new HAART therapy may thwart the appearance
of recidivistic opportunistic infections (Chaisson and Moore 1997
), also through major zinc bioavailability. As such, zinc
is crucial against infections in both stage III (Mocchegiani et al. 1995
) and stage IV, which is critical for an unfavorable
prognosis (Fabris et al. 1988
, Fauci et al. 1984,
Levy 1989
). The same relative risk factors
also show significant reduction of scores in HAART-treated patients
compared with AZT-treated patients (Tables 3 and
5). Because HIV RNA has been show as a real predictor for HIV progression
and, consequently, the development of new HAART therapy
(Chaisson and Moore 1997
, Mellors et al. 1996
), the presence of a nonsignificant score for HIV RNA in
HAART-treated subjects is confirmation (Table 5)
. Zinc is absent in
HAART drugs (protease inhibitors) (S. Veccia, personal communication).
Thus, the mechanism or mechanisms via which HAART may induce zinc
increments are still unknown. Decreased acute inflammation
(Chandra 1992
) or major zinc intestinal absorption may
occur as revealed by significant increments in body weight in
HAART-treated subjects (Table 4)
.
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), they also further suggest the key role played by
zinc in resistance against infections, as recently proposed
(Shankar and Prasad 1998
). Such a key role may be
independent of the HIV and the pathogens involved. |
Future remarks |
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TOPABSTRACTINTRODUCTIONZinc, immune system and...Zinc and HIVSupplementation with zinc in...Future remarksREFERENCES |
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1) Severe zinc deficiency is present in stage IV of HIV infection associated with a strongly compromised immune system with the appearance of many recidivistic opportunistic infections that lead to death of the individual. Such severe zinc deficiency and CD4+ depletion have significant scores as relative risks for recidivistic opportunistic infections, suggesting that such an appearance may be also due to zinc deficiency.
2) Supplementation with zinc (three times the recommended daily
allowance) for 1 mo induces at individual levels significant reductions
(50%) in recidivistic opportunistic infections with complete
disappearance of recidivism by C. aesophagea and P.
carinii with a role for zinc more involved in extracellular
matrix. The significant reduction in scores in relative risk factors
(CD4+ depletion and zinc deficiency) after
supplementation with zinc is in line with the proposed pivotal role of
zinc in resistance to infection (Chandra 1989
,
Shankar and Prasad 1998
). Because of the significant
inverse correlation between zincemia and HIV RNA in HAART-treated
subjects with no appearance of opportunistic infections, it is further
indirect evidence of that. Thus, zinc is important to induce resistance
to infections. However, supplementation with zinc must be carried out
with caution and for short periods because high doses of zinc are
dangerous due to toxic effects on immune functions as a result of
competition phenomenon with copper (Chandra 1984
,
Fosmire 1990
). Such an aspect is relevant in stage IV,
where the immune system is strongly compromised. In addition, high
doses of zinc might also effectively induce a quick viral replication
by means of Tat or NCp7 proteins and, as such, justify the lack of
benefit of high doses of zinc in HIV infection reported by others
(Tang et al. 1996
). By contrast, physiological or
up-physiological supplementation with zinc for short periods
may be beneficial, as demonstrated in stage III with postponement of
HIV progression (Isa et al. 1992
, Mocchegiani et al. 1995
, Zazzo et al. 1989
).
Taking into account the relevant role of zinc in thymic functions
(Dardenne et al. 1982
) and peripheral immune efficiency
(Chandra 1983
, Fabris and Mocchegiani 1995
), recidivistic opportunistic infection reductions after
zinc supplementation may occur by means of thymic endocrine activity
restoration, which, in turn, promote a major homing of stem cells from
the bone marrow (Fabris et al. 1997
) and might induce
recovery of CD4+ cell number. The restoration of
thymic endocrine activity followed by CD4+
increments and relative risk factor reductions after supplementation
with zinc is in line with this interpretation.
Alternatively, other direct or indirect mechanisms for
CD4+ recovery may be taken into account. A direct
effect of zinc in preventing apoptosis of CD4+
cells by means of endonuclease enzymes with a cleavage mechanism or by
means of c-myc may be involved, although such a prevention
may be dependent on intracellular zinc concentrations (Fraker and Telford 1997
). Indirectly, zinc might reduce
CD4+ apoptosis by means of its influence on
immune cells to produce various cytokines, such as IFN-, which in
turn may prevent CD4+ apoptosis induced by
bacteria endotoxins by means of its transcription factors IRF-1 and
IRF-2 (Lopez-Collazzo et al. 1998
). Zinc, by means of
the inhibition of nuclear factor
B (Shumilla et al. 1998
), which is under the control of TNF- (Beg and Baltimore 1996
), might prevent CD4+
apoptosis induced by TNF- (Beg and Baltimore 1996
).
Indeed, TNF- is strongly increased in HIV infection and, as such, is
suggested as a prognostic factor for HIV progression (Odeh 1992
). Moreover, zinc may have also a direct action as an
antioxidant by means of nitric oxide, which in turn induces zinc
release from metallothioneins and so may limit free radical membrane
damage during inflammation (Shankar and Prasad 1998
).
All these possible mechanisms require further study.
3) Because zinc is important to induce resistance to infections,
perhaps, independent of HIV and pathogens involved, the study of the
existence of a parallelism between HIV and aging for infection
recidivism represents an interesting tool for future research because
recidivistic infections lead to death under both conditions
(Pawlec and Solana 1997
). Indeed, although the use of
HAART may have resolved the problem of possible reduction in
recidivistic opportunistic infections in stage IV through
possible major zinc bioavailability, zinc deficiency is present in
aging (Fabris and Mocchegiani 1995
) and severe
recidivistic infections at the bronchoalveolar level lead often to
death in old individuals because of the poor efficacy of conventional
antibiotic therapy (Lewis and Reeves 1994
). Thus,
supplementation with zinc may also be beneficial in aging as resistance
against severe recidivistic infections.
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ACKNOWLEDGMENTS |
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FOOTNOTES |
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2 Supported by Italian National Research Centres on Aging and Italian Heath Ministry.
4 Abbreviations used: AZT, zidovudine; HIV, human immunodeficiency virus; IFN, interferon; IL, interleukin; PHA, phytohemagglutinin; TNF, tumor necrosis factor.
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