Anti-Retroviral Therapy Is Associated with Decreased Alveolar Glutathione Levels Even in Healthy HIV-Infected Individuals

Abstract

ObjectiveLung infections are a leading cause of death in HIV-infected individuals. Measuring redox in HIV-infected individuals may identify those with chronic oxidative stress who are at increased risk for lung infection. We sought to estimate the association between HIV infection and oxidative stress in the lung, as reflected by decreased levels of glutathione and cysteine in the epithelial lining fluid.MethodsBronchoalveolar lavage (BAL) fluid was collected from healthy HIV-infected subjects and controls. Individuals were excluded if they had evidence of major medical co-morbidities, were malnourished or smoked cigarettes.ResultsWe enrolled 22 otherwise healthy HIV and 21 non-HIV subjects. Among the HIV-infected subjects, 72.7% were on anti-retroviral therapy (ART) with a median CD4 count of 438 (279.8–599) and viral load of 0 (0–1.0) log copies/mL. There were no significant differences in median BAL fluid glutathione and cysteine levels between HIV and HIV-uninfected subjects. However, BAL glutathione was significantly higher in HIV-infected subjects on anti-retroviral therapy (ART) compared to those not on ART [367.4 (102–965.3) nM vs. 30.8 (1.0–112.1) nM, p = 0.008]. Further, HIV infection with ART was associated with an OR of 2.02 for increased BAL glutathione when adjusted for age and body mass index, whereas HIV infection without ART was associated with an OR of 2.17 for decreased BAL glutathione.ConclusionHIV infection without ART was associated with increased oxidative stress, as reflected by decreased alveolar glutathione levels, in otherwise healthy HIV-infected individuals. Further study needs to be done identify predictors of lung health in HIV and to address the role of ART in improving lung immunity.

HIV-1 decreases Nrf2/ARE activity and phagocytic function in alveolar macrophages

“…Impaired AM function is likely responsible for the increased risk of infection seen in these patients. We recently reported [16,19] a significant decrease in glutathione level in bronchoalveolar lavage fluid, as well as attenuated phagocytosis in AMs derived from HIV-1 transgenic rats, which has been shown in the individuals with HIV/AIDS [6,[22][23][24]. In present study, we investigated Nrf2, a master transcription factor that has a critical role in maintenance of redox homeostasis, to understand the mechanisms of the impairment in AMs.…”

Pulmonary Innate Immune Dysfunction in Human Immunodeficiency Virus

“…Evidence from our group and others suggests that the alveolar space is significantly more oxidized in HIV infection (43). We have shown that the expression and function nuclear factor (erythroid-derived 2)-like 2, the master transcription factor that regulates antioxidant defenses, is compromised in the lung of HIV transgenic rats (44), likely due to the effects of viral proteins in the alveolar space.…”

The Complexity of HIV Persistence and Pathogenesis in the Lung Under Antiretroviral Therapy: Challenges Beyond AIDS

“…However, other studies report that HIV impairs TLR-mediated TNF-a production in the alveolar compartment, decreases in TLR-1 and TLR-4, leading to deficiencies in innate immune response in the presence of ART (124). In addition, measurements of glutathione and cysteine levels in BAL as surrogate markers of oxidative stress in the lung showed no significant differences between HIV-infected and uninfected subjects and that HIV-infected patients without ART had significantly decreased alveolar glutathione levels, suggesting increased oxidative stress in that population (33).…”

“…Further studies by Fan et al pointed to inhibition of the nuclear factor (erythroidderived 2)-like 2/antioxidant response element (Nrf2/ARE) pathway as mechanistic insights into HIV-mediated barrier functions and oxidative status (51). HIV-associated COPD also features low levels of glutathione in the lungs and in the peripheral blood (33). Together, this suggests that the presence of infectious pathogens such as HIV, coupled with abnormal inflammatory responses and oxidative stress, all contribute mechanistically to HIV-COPD.…”