Nutrients and HIV: Part 2
Vitamins A and E, Zinc,
B-Vitamins, and Magnesium

This section is compiled by Frank M. Painter, D.C.
Send all comments or additions to:    Frankp@chiro.org

FROM:   Alternative Medicine Review 2000 (Feb); 5 (1): 39–51 ~ FULL TEXT

Lyn Patrick, ND

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Vitamin A and HIV/AIDS

Vitamin A deficiency is a common occurrence in HIV infection, and serum levels appear to decrease as the disease progresses. [1] Low serum levels of vitamin A were found in 12-19 percent of HIV-positive, asymptomatic subjects in the United States. [1, 2] Vitamin A deficiency was found in an increasingly higher proportion of women than men (p< .01) in an HIV-infected, intravenous drug-using population. [3]

Low serum vitamin A levels were seen in 63 percent of 474 pregnant women in Malawi. Infant mortality was directly associated with maternal serum vitamin A levels. [4] In a cohort of 133 HIV-infected mothers in the Baltimore area, the risk of perinatal transmission of HIV was associated with maternal vitamin A deficiency. Sixteen percent of transmitters and 5 percent of non-transmitters were severely vitamin A deficient. Vitamin A-deficient mothers were 3.69 times more likely to transmit the virus to their children. [5] Research at Memorial Sloan Kettering Cancer Center in New York has confirmed maternal vitamin A deficiency as a risk factor for transmission of HIV. Seventy percent of children born to HIV+ mothers were vitamin A-deficient compared to age-matched controls as early as the first few months of life, regardless of the child's HIV status. [6] Approximately 25 percent of this pediatric population was found to have growth or developmental delays.

HIV-positive children also develop vitamin A deficiencies prior to AIDS diagnosis. [7] The development of this deficiency does not appear to depend on dietary intake; in an HIV-positive population judged to have "adequate dietary intake" of vitamin A, 27 percent of the children had low retinol levels. [8] Dietary and supplemental intake of 9,000-20,000 IU appears to delay progression to AIDS, reducing the relative risk of progression by approximately 50 percent. [9]

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Trials with Vitamin A in HIV/AIDS

A randomized, double-blinded trial in Durban, South Africa, evaluated the effect of 5,000 IU retinyl palmitate and 30 mg beta carotene daily during the third trimester of pregnancy, and 200,000 IU at birth in HIV-positive mothers. Women receiving the supplements were less likely to have a pre-term birth (11.4% with vitamin A and 17.4% with placebo; p=0.03). Of the 80 pre-term deliveries, those who received vitamin A were less likely to transmit the virus (17.9% on vitamin A vs. 33.8% on placebo). [10] A randomized, placebo-controlled trial of vitamin A in children of HIV-positive mothers in Durban evaluated the use of age-adjusted doses of vitamin A. [11] Children received a single dose at one and three months (50,000 IU), six and nine months (100,000 IU), and 12 and 15 months (200,000 IU). At follow-up (16 months), the supplemented group had 28 percent less diarrhea, 40 percent less prolonged bouts of diarrhea, and a 77-percent reduction in hospitalization for diarrhea. A multivariate analysis at the end of the trial suggested the therapeutic benefit was actually seen in the children who had contracted HIV and were later diagnosed HIV seropositive.

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Zinc

Zinc is a component of more than 200 mammalian metallo-enzymes. [12] In humans, zinc deficiency can manifest as T-cell lymphopenia, decreased lymphocyte response to mitogens, depressed thymic hormone activity, a specific CD4+ T-cell population depression, decreased natural killer cell activity, [13] and depressed serum concentrations of albumin, prealbumin, and transferrin. [14] Zinc has a modulating role in blood sugar regulation, thyroid and gonadal function, adrenal hormone and prolactin production, and calcium/phosphorus metabolism, all of which are disturbed in a state of zinc deficiency. [15] Zinc salts have been shown to have anti-viral activity, either directly or through immune-modulation, against more than 40 viruses. [16]

Zinc and HIV/AIDS

In HIV infection, zinc plays specific roles as an anti-oxidant, immune-modulator, [17] and a possible direct anti-viral agent. [18,19] Zinc, in vitro, has been found to inhibit cell death mediated by tumor necrosis factor (TNF), a cytokine linked to cellular apoptosis and wasting syndrome in HIV. [20]

The HIV protease enzyme, currently the topic of much research and one of the central focuses of pharmaceutical HIV suppression, is necessary to potentiate the production of new HIV-1 viruses. [21] The HIV virus binds to zinc ions in T-cells in order to produce pro-viral peptides which form the basis of new infectious viral particles. The HIV-1 protease enzyme then cuts the viral chains to form new infectious viral particles, which are released into the circulation and infect new immune cells. As with other proteases, including collagenase, angiotensin-converting enzyme (ACE), carboxypeptidase A, and neutral endopeptidases, zinc has both an enhancing and inhibiting activity, depending on the concentration of zinc in the surrounding tissues. [22] Multiple studies have shown if sufficient zinc ions are bound to the protease it will remain inactive. [23]

In HIV replication, viral RNA is transformed into viral DNA via the enzyme reverse transcriptase. Then the enzyme integrase allows for the integration of viral DNA with host DNA. Zinc binds to the integrase enzyme via "zinc finger protein" structures and allows for optimal activity of the integrase enzyme. Inhibitors of zinc finger proteins are currently the subject of research in HIV pharmacology. [24, 25]

Although the net effect of in vivo tissue zinc concentrations on HIV replication has yet to be determined, there is evidence that adding zinc to antiviral medications enhances the medication's effect. Comparable to the in vitro anti-viral activity of zidovudine (AZT), the peptide T22 is four-times stronger when bound to zinc ions via cysteine. [26]

Baum demonstrated a need for zinc in an AZT-treated population in which 64 percent of the treated patients were zinc deficient, while only 24 percent of the untreated population had low zinc levels. [27] AZT metabolism necessitates a zinc-dependent thymidine kinase for conversion to its active form. The medication may contribute to zinc deficiency, which could lead to decreased effectiveness of the drug in a zinc-deficient patient. Baum also found AZT-treated patients with adequate zinc levels had a significantly greater mitogen response, which was not demonstrated in those who were zinc-deficient. [27]

Zinc Deficiency in HIV/AIDS

The incidence of zinc deficiency in HIV infection has been documented in multiple studies. [28] In a survey of 228 in-patients with AIDS, 29 percent had low and 21 percent had marginally low serum zinc levels. [29] The presence of zinc deficiency in these patients significantly increased the chance of bacterial infection. While frank zinc deficiencies occur in AIDS patients as a result of malabsorption, medications, altered metabolic states, and fluid loss from nausea, vomiting, and diarrhea, [30] zinc deficiency in both plasma and serum has been observed in HIV+ patients in the asymptomatic state as well. [2, 31, 32]

Low or marginally low plasma zinc levels were found in 50 percent of 100 healthy, asymptomatic HIV-1 seropositive patients without a history of alcoholism or clinical evidence of nutritional deficiencies. [2] Although some studies have not seen alterations in HIV patients' serum zinc levels, [33-35] others have documented declining plasma and serum levels as the disease progresses, and have found lower zinc levels in more advanced stages of the disease. [32,36] Depressions in blood zinc levels in HIV/AIDS may reflect the presence of acute infections; serum zinc levels decrease as hepatic zinc uptake increases, reflecting zinc's role as an acute-phase reactant. [37] Opportunistic infections have been shown to lower serum zinc levels, with depressed serum levels lasting long after the infection is resolved. [38]

Because of zinc's role in acute infection and its subsequent altered metabolism in chronic infection, it has been argued that serum levels may not be an accurate reflection of immune impairment related to zinc body stores and zinc availability in HIV. [39] Thymulin, a thymic hormone which becomes biologically active only after binding with zinc ions, has been proposed as a more sensitive marker. [40] Zinc-binding by thymulin allows recognition by T-lymphocytes and enables T-lymphocyte differentiation; thymulin activity is decreased in cases of zinc deficiency. Low levels of thymulin are found in Down's and Duchenne's syndrome, type 1 diabetes, and HIV/AIDS. [41, 42] Thymulin levels in ARC (AIDS-Related Complex, an obsolete term which was used to describe AIDS at the beginning of symptom appearance) patients were demonstrated to be low, while serum zinc levels in the same subjects were within normal limits. [43]

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Trials With Zinc in HIV/AIDS

Regardless of the methodological issues of measuring zinc bioavailability, studies looking at zinc supplementation in HIV/AIDS have proven useful. Isa [44] evaluated 11 men with AIDS who were classified as Stage 5 according to Walter Reed classification (see Table 1). Before zinc supplementation, serum and blood cell zinc levels did not differ significantly from controls. After 10 weeks' supplementation with oral zinc sulfate, providing 0.45mg/kg/day of elemental zinc, there was a significant (p<0.05) increase in mean CD4+ cells (from 280 to 390/mm3). Absolute counts of CD3+ lymphocytes also rose significantly. During supplementation, all patients exhibited progressive weight gain, with a mean increase of seven pounds(p<0.001), which could not be accounted for by increased calorie intake.

Mocchegiani [45] followed 18 HIV+ patients with CD4+ of 250-400/mm3 on anti-viral medication (AZT alone) who were supplemented with 12 mg elemental zinc daily for 30 days, and found the relative risk for opportunistic infection was significantly higher in the unsupplemented group on AZT. In 28 HIV+ patients on HAART (two nucleoside analogues and a protease inhibitor) who were supplemented with the same zinc protocol, no significant risk for opportunistic infections was found in the zinc-unsupplemented HAART group. There was an inverse correlation between serum zinc levels and HIV-RNA (viral load) in both groups. This researcher also observed that triple anti-viral therapy improved zinc absorption and serum zinc levels. Theoretically, zinc absorption might have improved as a result of the anti-inflammatory effect on the gut of a lowered viral load.

Zinc supplementation has also been investigated in pediatric HIV. Thirteen stable HIV-infected children (mean, six years of age) were given oral zinc, 1.8-2.2 mg/kg/day. [46] Prior to supplementation, nine subjects had low serum zinc levels. After supplementation, six of the nine had normal serum zinc levels. After 3-4 weeks, two patients had significant increases in CD4+ count, and clinical scores improved in four patients. In another small trial of pediatric patients treated with 2 mg zinc/day for three weeks, significant increases were seen in total lymphocyte count, and a doubling of the CD4/CD8 ratio was observed, indicating a relative rise in CD4+ cell numbers. [47]

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