The Role of Pannexin-1 Channels in HIV and NeuroHIV Pathogenesis

Abstract

The human immunodeficiency virus-1 (HIV) enters the brain shortly after infection, leading to long-term neurological complications in half of the HIV-infected population, even in the current anti-retroviral therapy (ART) era. Despite decades of research, no biomarkers can objectively measure and, more importantly, predict the onset of HIV-associated neurocognitive disorders. Several biomarkers have been proposed; however, most of them only reflect late events of neuronal damage. Our laboratory recently identified that ATP and PGE₂, inflammatory molecules released through Pannexin-1 channels, are elevated in the serum of HIV-infected individuals compared to uninfected individuals and other inflammatory diseases. More importantly, high circulating ATP levels, but not PGE₂, can predict a decline in cognition, suggesting that HIV-infected individuals have impaired ATP metabolism and associated signaling. We identified that Pannexin-1 channel opening contributes to the high serological ATP levels, and ATP in the circulation could be used as a biomarker of HIV-associated cognitive impairment. In addition, we believe that ATP is a major contributor to chronic inflammation in the HIV-infected population, even in the anti-retroviral era. Here, we discuss the mechanisms associated with Pannexin-1 channel opening within the circulation, as well as within the resident viral reservoirs, ATP dysregulation, and cognitive disease observed in the HIV-infected population.

Keywords: biomarker; comorbidities; cure; dementia; purinergic.

Figure 1

Mechanisms of Panx-1 opening during HIV infection. (a) Mechanism of Panx-1 opening during acute infection. (1) Upon binding to CD4 and CCR5 (or CXCR4), (2) signaling through this binding leads to Panx-1 becoming open, (3) releasing ATP. (4) The ATP released then binds to purinergic receptors, (5) allowing HIV entry. Inhibition of Panx-1 ATP release or P2 receptors inhibits HIV entry. (b) Mechanisms of Panx-1 opening during chronic infection. Peripheral blood mononuclear cells (PBMCs) isolated from HIV-infected patients show Panx-1 in a spontaneously open state, despite a lack of viral replication, but the mechanism is unknown.

Figure 2

ATP release and metabolism. ATP is released through hemichannels, such as Panx-1. ATP (and ADP) are degraded into AMP by CD39. AMP is catabolized into adenosine by CD73. Adenosine is deaminated into inosine by adenosine deaminase (ADA), which is associated with CD26. Concentrative and equilibrated nucleoside transporters (CNT, ENT) facilitate nucleoside uptake and transport. Intracellular adenosine can be deaminated by ADA or converted to AMP by soluble adenosine kinase (ADK). Intracellular AMP is converted to adenosine by soluble CD73 (sCD73).