Pioglitazone Modulates p65-Mediated Mitochondrial Bioenergetics: Implications for Acetaldehyde-Induced HIV Replication in Alveolar Macrophages

Alcohol misuse is twice as prevalent among people living with HIV (PWH), and this increases the risk of pulmonary complications even in those receiving antiretroviral therapy. Our prior work showed that the alcohol metabolite, acetaldehyde, activates nuclear factor kappa B p65 (p65), leading to HIV replication and interleukin (IL)-1β activation in alveolar macrophages (AMs). Since the aforementioned processes are energy-demanding, which conversely impair mitochondrial functions, we hypothesized that acetaldehyde-induced p65 drives AMs to a mitochondrial hyperactive state to promote HIV replication and IL-1β release and induces oxidative stress and mitochondrial dysfunction. Since we found pioglitazone (PIO) to be a negative regulator of p65, we postulate that PIO suppresses HIV replication and IL-1β activation in AMs by restricting p65-induced mitochondrial hyperactivation. Murine AMs were exposed to acetaldehyde via the acetaldehyde generating system (AGS) and infected in vitro with EcoHIV, a chimeric ecotropic HIV construct. AGS + EcoHIV activated p65, resulting in enhanced ATP-linked mitochondrial respiration, proton leak, non-mitochondrial respiration and the generation of Reactive Oxygen Species (ROS) in AMs. Inhibition of mitochondrial ATP synthesis with low-dose oligomycin attenuated AGS-induced HIV replication and AGS + EcoHIV-induced IL-1β release from AMs. PIO treatment, which attenuated AGS-induced p65 activation, suppressed proton leak, non-mitochondrial oxygen consumption, ROS, and IL-1β and p24 release. While p65-induced mitochondrial hyperactivation represents AMs' adaptive response to the energy demands imposed by HIV replication and proinflammatory activation when exposed to acetaldehyde, PIO treatment may offer a novel therapeutic strategy to restore adequate mitochondrial bioenergetics in the AMs of PWH who misuse alcohol.

EcoHIV; acetaldehyde generating system; alcohol; alveolar macrophages; inflammation; mitochondrial hyperactivation; nuclear factor kappa B p65; pioglitazone.