The role of Pannexin-1 channels in HIV and Alzheimer’s disease: the development of an early biomarker of cognitive decline
Human immunodeficiency virus-1 (HIV) infection of the CNS can have devastating neurological consequences, but the cellular and molecular basis of HIV CNS dysfunction are still poorly understood. Only recently, my laboratory using electrophysiological, imaging, pharmacological/molecular approaches, patient data, and animal model experiments, identified a novel host protein involved in acute and chronic HIV infection and NeuroHIV, Pannexin-1 (Panx-1). Panx-1 channels are large ionic channels that remain in a close stage in healthy conditions. In pathological conditions, such as acute and chronic HIV infection, Panx-1 channels open, releasing large signaling molecules between the cytoplasm and the extracellular space, including ATP. Upon ATP release through the channel, ATP activates autocrine and paracrine purinergic receptors to induce intracellular signaling to promote damage. Thus, Panx-1 channels could be a unique pharmacological target to reduce/prevent the devastating consequences of NeuroHIV and other neurodegenerative diseases including Alzheimer’s disease.
Our laboratory demonstrated that during acute HIV infection, HIV induces Panx-1 opening by binding to CD4 and CCR5 or CXCR4 to accelerate their clustering and mediate actin rearrangement to enable efficient viral entry and subsequent events of replication. Surprisingly, we identify that Panx-1 channels are extremely active in long-term HIV infection, even in the absence of systemic replication due to ART. We identified that all chronic HIV-infected individuals analyzed had uncontrolled Panx-1 channel opening resulting in high circulating ATP levels despite effective ART. Increased serum ATP levels perfectly correlated with cognitive decline, suggesting that ATP in circulation can be used as a biomarker of cognitive impairment in the HIV-infected and Alzheimer’s disease population.
We identified that ATP in the HIV-infected population induces accelerated leukocyte differentiation into a migratory phenotype characterized by higher expression of key adhesion and tight junction proteins required for adhesion and transmigration across the Blood Brain Barrier (BBB). High ATP compromised the BBB integrity and promoted the transmigration of uninfected and HIV-infected cells across the BBB by a Panx-1, ATP, and purinergic-dependent mechanism. Also, we identified that the uncontrolled Panx-1 opening in the HIV-infected population was nef dependent even in individuals with undetectable replication. Nef binds to the intracellular portion of the Panx-1 channel resulting in channel and plasma membrane depolarization, aberrant pore permeability and incomplete channel closing. The role of these mechanisms was analyzed in macaques infected with SIV, supporting our in vivo and in vitro data that SIV infection resulted in Panx-1 opening, ATP secretion, leukocyte activation, BBB compromise, and synaptic pruning. Blocking these steps prevented CNS damage. Together, our research has led us to formulate the hypothesis that “HIV uses the axis Pannexin-1/ATP/purinergic receptor to induce brain damage even in the absence of viral replication”. Overall, we propose to identify innovative approaches to prevent and revert CNS damage.