Circulating levels of ATP is a biomarker of HIV cognitive impairment

Abstract

Background: In developed countries, Human Immunodeficiency Virus type-1 (HIV-1) infection has become a chronic disease despite the positive effects of anti-retroviral therapies (ART), but still at least half of the HIV infected population shown signs of cognitive impairment. Therefore, biomarkers of HIV cognitive decline are urgently needed. Methods: We analyze the opening of one of the larger channels expressed by humans, pannexin-1 (Panx-1) channels, in the uninfected and HIV infected population ( n = 175). We determined channel opening and secretion of intracellular second messengers released through the channel such as PGE 2 and ATP. Also, we correlated the opening of Panx-1 channels with the circulating levels of PGE 2 and ATP as well as cogntive status of the individuals analyzed. Findings: Here, we demonstrate that Panx-1 channels on fresh PBMCs obtained from uninfected individuals are closed and no significant amounts of PGE 2 and ATP are detected in the circulation. In contrast, in all HIV-infected individuals analyzed, even the ones under effective ART, a spontaneous opening of Panx-1 channels and increased circulating levels of PGE 2 and ATP were detected. Circulating levels of ATP were correlated with cognitive decline in the HIV-infected population supporting that ATP is a biomarker of cognitive disease in the HIV-infected population. Interpretation: We propose that circulating levels of ATP could predict CNS compromise and lead to the breakthroughs necessary to detect and prevent brain compromise in the HIV-infected population.

HIV gp120 Protein Increases the Function of Connexin 43 Hemichannels and Pannexin-1 Channels in Astrocytes: Repercussions on Astroglial Function

“…Prior data indicate that gp120 may induce the release of several "danger" signals from glial cells, including ATP [81], the latter molecule being recently proposed as a biomarker of HIV-1-mediated cognitive impairment [82]. With this in mind, two significant elements underscore the importance of ATP signaling on the gp120-induced astrocyte changes in our system.…”

Astrocytes are HIV reservoirs in the brain: A cell type with poor HIV infectivity and replication but efficient cell‐to‐cell viral transfer

“…Our data indicate that HIV infection of astrocyte is not only important because it could be a viral reservoir but can amplify apoptosis, inflammation, and cellular dysfunction into neighboring uninfected cells, including neurons, endothelial cells, and other uninfected astrocytes (Eugenin et al, 2011;Orellana et al, 2014). We have previously demonstrated that HIV infection but not replication regulates expression of Connexin-43containing channels resulting in the maintenance of gap junctional communication between the few HIV-infected astrocytes and neighboring cells as well as the opening of hemichannels that contribute to the release of intracellular inflammatory mediators such as ATP and prostacyclin further contributing to the chronic inflammation observed in at least half of the HIV-infected population (Velasquez et al, 2020). Also, in vivo studies from our laboratory indicate that infected astrocytes can amplify CNS damage up to 300-500 µm away from the infected astrocytes clusters Malik et al, 2017).…”

The Glutamate System as a Crucial Regulator of CNS Toxicity and Survival of HIV Reservoirs

“…However, upon inflammation and damage, hemichannels become open and have been associated with several neurodegenerative disorders (Xing et al, 2019) including NeuroHIV (Eugenin et al, 2011a;Orellana et al, 2014;Berman et al, 2016;Eugenin, 2016, 2019). Only recently, we identified that circulating levels of ATP can be used to provide an early detection of cognitive impairment in HIV-infected individuals (Velasquez et al, 2020).…”