A beneficial reduction of watery diarrhoea-related morbidity induced by zinc supplementation in HIV-1-infected children has recently been demonstrated . In the past few years zinc has emerged as a major therapeutic and preventive strategy against diarrhoea [2–4]. These data now open new perspectives for its use, suggesting that zinc could be a safe, simple and cost-effective tool to reduce morbidity and mortality in HIV-1-infected children . Even though zinc is recommended for the treatment of childhood diarrhoea by WHO/UNICEF , several important questions remain to be answered, in particular in the HIV-1-infected child, because the study by Bobat et al.  did not provide evidence on the mechanisms elicited by zinc to limit diarrhoea in these particular patients.
The aetiology of HIV-1-related severe watery diarrhoea is certainly multifactorial and still largely unknown . We have recently provided evidence for a primary role of Tat (the transactivating peptide produced by HIV-1 and essential for its replication) in the pathogenesis of diarrhoea in AIDS patients. Functioning as an enterotoxin, like Vibrio cholerae toxin, Tat stimulates active fluid secretion from the serosal to the luminal side of human enterocytes in the classical Ussing chamber in-vitro model used to investigate transepithelial ion transport [6,7]. A similar mechanism has been reported  for Cryptosporidium parvum, the most frequent and dangerous opportunistic enteric pathogen in AIDS patients. These findings suggest that HIV-1-infected children are at a high risk of secretory diarrhoea. In addition, we have demonstrated that Tat is able to inhibit sodium ion/glucose symporter activity, a major mechanism to absorb fluid at the intestinal level, further determining the occurrence of diarrhoea . Interestingly, the Tat effects on intestinal ion transport were dose dependent, with a maximal effective dose of 0.1 nmol, which is well within the range of what is generally measured in the sera of patients with HIV-1 infection, suggesting that effective Tat concentrations may well be reached in vivo[9,10]. On the other hand, zinc is directly active on transepithelial ion transport at the intestinal level, as direct zinc–enterocyte interaction results in net ion absorption, thereby counteracting active secretion, such as that induced by V. cholerae toxin in the same experimental model . To determine whether zinc was effective in inhibiting Tat-induced ion secretion, we incubated human derived Caco-2 intestinal cells with chemical synthesized, high-pressure liquid chromatography 96% pure, HIV-1 Tat, (Tecnogen, Piana di Monteverna, Italy), in the presence or absence of zinc (ZnSO4; Sigma Chemical Co., St Louis, Missouri, USA), using the Ussing chamber experimental model . As shown in Figure 1, the pre-incubation of human enterocytes with zinc (35 μmol) resulted in the almost total inhibition of Tat-induced ion secretion, as reflected by the intensity of the short circuit current. These results suggest that zinc is able to prevent intestinal fluid secretion induced by Tat, and is able to interact directly with a specific mechanism of HIV-1-related diarrhoea, explaining well the results obtained in South Africa by Bobat and co-workers , and supporting the usefulness of the ‘zinc approach’ in adjunct to specific antiretroviral therapy in HIV-1-infected children.
An emphasis on the costs and economic benefits of an alternative therapy is an important aspect of health services research. The cost savings and the attractive cost-effectiveness, disposability and thermostability of zinc indicates the need to assess further the role of these micronutrients in the prevention and treatment of diarrhoea in AIDS patients.
1. Bobat R, Coovadia H, Stephen C, Naidoo KL, McKerrow N, Black RE, Moss WJ. Safety and efficacy of zinc supplementation for children with HIV-1 infection in South Africa: a randomized double-blind placebo-controlled trial. Lancet 2005; 366:1862–1867.
2. Bhutta ZA, Bird SM, Black RE, Brown KH, Meeks Gardner J, Hidayat A, et al
. Therapeutic effects of oral zinc in acute and persistent diarrhoea in children in developing countries: pooled analysis of randomised controlled trial. Am J Clin Nutr 2000; 72:1516–1522.
3. Brooks WA, Santosham M, Naheed A, Goswami D, Wahed MA, Diener-West M, et al
. Effect of weekly zinc supplements on incidence of pneumonia and diarrhoea in children younger than 2 years in an urban, low-income population in Bangladesh: randomized controlled trial. Lancet 2005; 366:999–1004.
4. Berni Canani R, Ruotolo S. The dawning of the ‘zinc era’ in the treatment of pediatric acute gastroenteritis worldwide? J Pediatr Gastroenterol Nutr 2006; 42:253–255.
5. Janoff EN, Smith PD. Emerging concepts in gastrointestinal aspects of HIV-1 pathogenesis and management. Gastroenterology 2001; 120:607–621.
6. Berni Canani R, Cirillo P, Mallardo G, Buccigrossi V, Secondo A, Annunziato L, et al
. Effects of HIV-1 Tat protein on ion secretion and on cell proliferation in human intestinal epithelial cells. Gastroenterology 2003; 124:368–376.
7. Berni Canani R, De Marco G, Passariello A, Buccigrossi V, Ruotolo S, Bracale I, et al
. Inhibitory effect of HIV-1 Tat protein on the sodium-D-glucose symporter of human intestinal epithelial cells. AIDS 2006; 20:5–10.
8. Guarino A, Berni Canani R, Casola A, Pozio E, Russo R, Bruzzese E, et al
. Human intestinal cryptosporidiosis: secretory diarrhea and enterotoxic activity in Caco-2 cells. J Infect Dis 1995; 171:976–983.
9. Guarino A, Berni Canani R. Enterotoxic and cytotoxic effects of HIV-1 virus in human enterocytes. In: Naim HY, Zimmer KP, editors. The brush border membrane – from molecular cell biology to clinical pathology. Heilbronn, Germany: SPS Veragsgesellschaft mbH; 2006. pp. 348–360.
10. Albini A, Soldi R, Giunciuglio D, Giraudo E, Benelli R, Primo L, et al
. The angiogenesis induced by HIV-1 Tat protein is mediated by the flk-1/KDR receptor on vascular endothelial cells. Nat Med 1996; 2:1371–1375.
11. Berni Canani R, Cirillo P, Buccigrossi V, Ruotolo S, Passariello A, De Luca P, et al
. Zinc inhibits cholera toxin-induced, but not Escherichiacoli
heat-stable enterotoxin-induced, ion secretion in human enterocytes. J Infect Dis 2005; 191:1072–1077.