How HIV-related proteins increase the susceptibility to lung injury despite anti-retroviral therapy

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Infection by the human immunodeficiency virus (HIV) remains a major global threat with ~34 million individuals living with HIV worldwide. Although combination antiretroviral therapy is effective at slowing disease progression, it fails to eradicate latent viral reservoirs. In parallel, HIV integrates into target tissues and the chronic expression of HIV-related proteins, including gp120 and Tat, can induce alveolar macrophage and epithelial dysfunction even when ART limits viral replication to undetectably low levels. Consequently, individuals living with HIV are remarkably susceptible (perhaps 10-fold or greater) to serious pneumonias, such as from Pseudomonas aeruginosa, and lung injury. Using clinically relevant HIV-1 transgenic rodent models and cell culture systems we discovered that HIV-related proteins induce oxidative stress by inhibiting Nrf2 (Nuclear factor (erythroid-derived 2)-like 2), the master transcription factor that activates anti-oxidant and immune defenses. Our preliminary studies for the first time show that HIV-1 transgenic mice have an impaired clearance of P. aeruginosa with exacerbated lung injury and inflammation compared to wild type mice. Additionally, the relative loss of Nrf2 signaling results in unrestrained inflammatory signaling in macrophages including the activation of Triggering Receptor Expressed on Myeloid cells-1 (TREM-1), a member of the super immunoglobulin family expressed on myeloid cells. These intriguing findings led us to hypothesize that chronic exposure to HIV-related viral proteins dysregulates the normal balance between Nrf2 and TREM-1 signaling. This imbalance, in which Nrf2 is suppressed and TREM-1 is induced, promotes a pathophysiological environment that impairs innate immune responses to bacterial invasion and renders the lung susceptible to infection and injury. We further hypothesize that targeting the balance between Nrf2 and TREM-1 signaling is a novel therapeutic approach to enhance lung health in individuals living with HIV. We propose to test these hypotheses in three integrated aims: 1) Investigate the molecular basis for the dysfunctional signaling of Nrf2 and TREM-1 in macrophages in response to HIV-related viral proteins. 2) Define the functional consequences of TREM-1 induction in alveolar macrophages by HIV-related proteins on both epithelial barrier integrity and macrophage-epithelial interactive innate immunity against Pseudomonas aeruginosa. 3) Determine the impact of modulating Nrf2-TREM-1 signaling in vivo on lung bacterial clearance in HIV-1 transgenic mice challenged with Pseudomonas aeruginosa. It is imperative that we elucidate the mechanisms by which HIV-related proteins impair innate immunity within the lung, including how they promote an environment in which latent viral reservoirs may be established within the alveolar macrophage pool. In parallel, understanding the discrete molecular and cellular mechanisms by which HIV-related proteins impair alveolar macrophage immune responses and the associated integrity of the alveolar epithelial barrier will provide novel findings that can guide the development of therapeutic strategies to enhance lung health in individuals living with HIV.