Abstract
BackgroundHighly effective antiviral treatment can suppress HIV-1 infection, but the chronic effects of HIV-1-related viral proteins, including gp120 and Tat, on organs such as the lungs can be damaging. HIV-1 transgenic rodent models are useful for studying the systemic effects of these proteins independently of viral infection. We have previously shown that HIV-1 transgene expression (and therefore, HIV-1-related protein expression) in rats decreases alveolar macrophage zinc levels and phagocytic capacity by unknown mechanisms. We hypothesized that HIV-1 transgene expression induces chronic inflammation and zinc sequestration within the liver and thereby decreases zinc bioavailability in the lung. We examined the expression of the pro-inflammatory cytokine, tumor necrosis factor alpha (TNFα), the zinc storage protein, metallothionein (MT1), and the zinc exporter, ZNT1 in the livers and the lungs of wild type and HIV-1 transgenic rats ± dietary zinc supplementation. In addition, we measured zinc levels, the zinc importing protein ZIP1, and the phagocytic capacity in the alveolar macrophages.ResultsHIV-1 transgene expression increased the liver-specific expression of TNFα, suggesting a chronic inflammatory response within the liver in response to HIV-1-related protein expression. In parallel, HIV-1 transgene expression significantly increased MT1 and ZNT1 expression in the liver as compared to the lung, a pattern that is consistent with zinc sequestration in the liver as occurs during systemic inflammation. Further, HIV-1 transgene expression decreased intracellular zinc levels and increased expression of ZIP1 in the alveolar macrophages, a pattern consistent with zinc deficiency, and decreased their bacterial phagocytic capacity. Interestingly, dietary zinc supplementation in HIV-1 transgenic rats decreased gene expression of TNFα, MT1, and ZNT1 in the liver while simultaneously increasing their expression in the lung. In parallel, zinc supplementation increased alveolar macrophage intracellular zinc levels and bacterial phagocytic capacity in HIV-1 transgenic rats.ConclusionTaken together, these findings suggest that chronic HIV-1-related protein expression causes liver inflammation and zinc sequestration, which in turn limits zinc bioavailability in the lung and thereby impairs alveolar macrophage phagocytic function. Importantly, dietary zinc supplementation decreases liver inflammation and zinc sequestration and restores alveolar macrophage phagocytic function in HIV-1 transgenic rats, a result with potential clinical implications for improving lung health in HIV-1-infected individuals.
Highlights
Effective antiviral treatment can suppress HIV-1 infection, but the chronic effects of HIV-1related viral proteins, including gp120 and Tat, on organs such as the lungs can be damaging
Consistent with the conclusion that not all of the systemic manifestations of AIDS can be attributed directly to viral infection and replication within target tissues, by the age of 7 months the HIV-1 transgenic rats begin to display modestly decreased body weights compared to wild type littermates
HIV-1 transgene expression increased gene expression of ZIP4 and decreased the expression of ZNT4 in the alveolar macrophages, and these effects can be reproduced by treating a macrophage cell line with a zinc chelator in vitro As HIV-1 transgene expression significantly lowers zinc levels in the alveolar space, we examined its effects on the expression of zinc transporters in the alveolar macrophages
Summary
Effective antiviral treatment can suppress HIV-1 infection, but the chronic effects of HIV-1related viral proteins, including gp120 and Tat, on organs such as the lungs can be damaging. HIV-1 infection decreases phagocytosis and increases the severity of lung infection from diverse organisms including Streptococcus pneumoniae, Klebsiella pneumoniae, Mycobacterium tuberculosis, and Pneumocystis carinii [1,2,6]. These observations raise the novel possibility that unrecognized macrophage dysfunction in HIV-1-infected individuals could contribute to the morbidity and mortality of lung infections in these vulnerable patients. It is important to identify the mechanisms by which alveolar macrophage immune function is compromised in chronic HIV-1 infection so that new complementary therapies aimed at improving pulmonary host defenses can be developed
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