Infection with human immunodeficiency type 1 (HIV-1) virus is an enormous challenge worldwide as this highly mutable virus causes widespread immune dysfunction and opportunistic infections that can lead to respiratory failure and death. Within the lung, although the effects of HIV-1 on alveolar macrophage function have been studied extensively, very little attention has focused on the effects of HIV-1 expression on alveolar epithelial function. We hypothesized that expression of the HIV-1 genome causes oxidative stress within the alveolar space and impairs alveolar epithelial barrier function. To test our hypothesis, we used an HIV-1 transgenic rat model that expresses the HIV-1-related proteins but is not infected with virus. We first determined that HIV-1 expression decreased lung lavage levels of the antioxidant glutathione by more than 80% (p < .05). To evaluate epithelial barrier function, we assessed both alveolar epithelial monolayer integrity using radiolabeled sucrose permeability in vitro and lung liquid clearance of an intratracheal saline challenge in vivo. We determined that epithelial monolayers from HIV-1 transgenic rats were more than twice as permeable (p < .05) as epithelial monolayers from wild-type rats. Consistent with these findings, HIV-1 transgenic rats had a ≈ 30% decrease (p = .07) in liquid clearance in vivo compared with wild-type rats. Finally, we have begun to survey the lungs of these HIV-1 transgenic rats for HIV-1-related protein expression as the observed oxidative stress and barrier dysfunction cannot be explained by viral infection or replication in this model. We found that although the HIV-1-related protein gp120 is present in the alveolar lavage fluid, there was no evidence of gp120 expression in the alveolar epithelial cells. In parallel, although the HIV-1 Tat gene is expressed (as determined by quantitative PCR) in the whole lung, there was no detectable Tat expression in the alveolar epithelium. In conclusion, transgenic expression of the HIV-1 genome in rats causes significant oxidative stress in the lung and impairs alveolar epithelial barrier function. We speculate that HIV-1-related proteins such as gp120 and Tat, which are known to cause oxidative stress in other tissues, induce oxidative stress and epithelial dysfunction within the alveolar space. To our knowledge, this is the first experimental evidence that HIV-1-related protein expression affects the alveolar epithelium. We speculate further that previously unrecognized alveolar epithelial barrier dysfunction could contribute to respiratory failure in HIV-1-infected individuals when they develop serious pulmonary infections.
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