Background: Highly effective antiviral treatment can suppress HIV-1 infection, but the chronic effects of HIV-1-\r\nrelated viral proteins, including gp120 and Tat, on organs such as the lungs can be damaging. HIV-1 transgenic\r\nrodent models are useful for studying the systemic effects of these proteins independently of viral infection. We\r\nhave previously shown that HIV-1 transgene expression (and therefore, HIV-1-related protein expression) in rats\r\ndecreases alveolar macrophage zinc levels and phagocytic capacity by unknown mechanisms. We hypothesized\r\nthat HIV-1 transgene expression induces chronic inflammation and zinc sequestration within the liver and thereby\r\ndecreases zinc bioavailability in the lung. We examined the expression of the pro-inflammatory cytokine, tumor\r\nnecrosis factor alpha (TNFa), the zinc storage protein, metallothionein (MT1), and the zinc exporter, ZNT1 in the\r\nlivers and the lungs of wild type and HIV-1 transgenic rats �± dietary zinc supplementation. In addition, we\r\nmeasured zinc levels, the zinc importing protein ZIP1, and the phagocytic capacity in the alveolar macrophages.\r\nResults: HIV-1 transgene expression increased the liver-specific expression of TNFa, suggesting a chronic\r\ninflammatory response within the liver in response to HIV-1-related protein expression. In parallel, HIV-1 transgene\r\nexpression significantly increased MT1 and ZNT1 expression in the liver as compared to the lung, a pattern that is\r\nconsistent with zinc sequestration in the liver as occurs during systemic inflammation. Further, HIV-1 transgene\r\nexpression decreased intracellular zinc levels and increased expression of ZIP1 in the alveolar macrophages, a\r\npattern consistent with zinc deficiency, and decreased their bacterial phagocytic capacity. Interestingly, dietary zinc\r\nsupplementation in HIV-1 transgenic rats decreased gene expression of TNFa, MT1, and ZNT1 in the liver while\r\nsimultaneously increasing their expression in the lung. In parallel, zinc supplementation increased alveolar\r\nmacrophage intracellular zinc levels and bacterial phagocytic capacity in HIV-1 transgenic rats.\r\nConclusion: Taken together, these findings suggest that chronic HIV-1-related protein expression causes liver\r\ninflammation and zinc sequestration, which in turn limits zinc bioavailability in the lung and thereby impairs\r\nalveolar macrophage phagocytic function. Importantly, dietary zinc supplementation decreases liver inflammation\r\nand zinc sequestration and restores alveolar macrophage phagocytic function in HIV-1 transgenic rats, a result with\r\npotential clinical implications for improving lung health in HIV-1-infected individuals.
Loading....