Research Article: HIV-1 transgene expression in rats induces differential expression of tumor necrosis factor alpha and zinc transporters in the liver and the lung

Date Published: October 6, 2011

Publisher: BioMed Central

Author(s): Pratibha C Joshi, David M Guidot.


Highly 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.

HIV-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.

Taken 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.

Partial Text

Despite significant advances in HIV-1 treatment including the development of highly active anti-retroviral therapy (HAART), infected individuals are prone to pneumonias by multiple pathogens including Klebsiella pneumoniae and Mycobacterium tuberculosis [1,2]. In addition, HIV-1-infected individuals are at increased risk for more typical community-acquired pneumonias from Pneumococcal pneumoniae and influenza [3,4]. Although the precise mechanisms are being investigated, HIV-1 can infect alveolar macrophages [5], and there is considerable evidence that phagocytosis and other innate immune functions are impaired in monocytes/macrophages from HIV-1 infected individuals [6,7]. For example, in immunocompetent individuals Klebsiella pneumoniae usually produces a mild respiratory illness. However, in alcoholics and in HIV-1-infected individuals, Klebsiella evades the normal innate immune defenses within the lower airways and can produce an overwhelming and frequently fatal pneumonia. In experimental models, 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. Therefore, 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.

In this study we determined that chronic HIV-1 transgene expression in rats, which causes a progressive systemic illness that recapitulates many of the manifestations of AIDS in humans, increases the expression of the pro-inflammatory cytokine TNFα in the liver but not in the lung. In parallel, this chronic and systemic expression of HIV-1-related proteins alters the expression of zinc transporters and storage proteins within the liver in a pattern that is consistent with hepatic zinc sequestration. In contrast, zinc bioavailability in the lung and the alveolar space is markedly decreased, and alveolar macrophages become zinc-deficient despite altering their cell-specific expression of zinc transporters in a pattern that promotes cellular zinc import and retention. This apparent hepatic zinc sequestration, and consequent relative zinc deficiency within the alveolar space, has profound consequences on alveolar macrophage bacterial phagocytic capacity. In contrast, HIV-1 transgenic rats whose diets were supplemented with zinc had no evidence of liver inflammation or zinc sequestration and, in parallel, had the same alveolar macrophage phagocytic function as their wild type littermates. Taken together, these results suggest a novel mechanism by which chronic HIV infection may cause alveolar macrophage immune dysfunction and raise the possibility that dietary zinc supplementation could enhance pulmonary host defenses in these vulnerable individuals.

In summary, we report that HIV-1 transgene expression, and therefore the chronic expression and systemic circulation of HIV-1-related proteins, induces an acute phase-like response resulting in a differential expression of TNFα in the liver as compared to the lung. In parallel, alterations in the expression of zinc storage and transport proteins suggest zinc sequestration in the liver and as a consequence, zinc deprivation and alveolar macrophage dysfunction in the lung. In contrast, dietary zinc supplementation decreases TNFα expression and apparent zinc sequestration in the liver, replenishes intracellular levels of zinc in the alveolar macrophages, and improves alveolar macrophage bacterial phagocytic function.

GM-CSF: granulocyte-macrophage colony stimulating factor; HAART: highly active anti-retroviral therapy; MT1: metallothionein 1; TNFα: tumor necrosis factor alpha; TPEN: N,N,N’,N’-tetrakis-(2-pyridyl-methyl) ethylenediamine; ZIP: ZRT/IRT-related proteins

The authors declare that they have no competing interests.

PCJ: conception and design, data collection and analysis, figure and manuscript preparation; DMG: design, intellectual content, and editorial support All authors have read and approved the final manuscript.




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