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 channels, in the uninfected and HIV infected population (n=175). Upon opening several intracellular second messengers are released into the extracellular space including PGE2 and ATP in serum/plasma. We correlated the cognitive status of the patients with circulating levels of both factors upon a visit to the clinic. Findings: Here, we demonstrate that pannexin channels on fresh PBMCs from uninfected individuals are closed. In contrast, all HIV-infected individuals analyzed, even the ones under effective ART, had a spontaneous opening of pannexin-1 channels and increased circulating levels of PGE2 and ATP. These results suggest that even low or undetectable levels of HIV result in chronic inflammation and opening of pannexin-1 channels. Furthermore, we found that circulating levels of ATP, but not PGE2, correlated with the cognitive status of people living with HIV. 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. Funding Statement: This work was funded by The National Institute of Mental Health grant, MH096625, the National Institute of Neurological Disorders and Stroke, NS105584, and UTMB internal funding (to E.A.E). Research in the Geiger (J.D.G.) laboratory was supported by the National Institute of General Medical Sciences under award numbers P30GM100329 and U54GM115458, the National Institute of Mental Health under award numbers R01MH100972 and R01MH105329, the National Institute of Neurological Diseases and Stroke under award number R01NS065957, and the National Institute of Drug Abuse under award number 2R01DA032444. The NNTC is made possible through funding from the NIMH and NINDS by the following grants: Manhattan HIV Brain Bank (MHBB): U24MH100931; Texas NeuroAIDS Research Center (TNRC): U24MH100930; National Neurological AIDS Bank (NNAB): U24MH100929; California NeuroAIDS Tissue Network (CNTN): U24MH100928; and Data Coordinating Center (DCC): U24MH100925. The authors also acknowledge the New Jersey and New York Blood Center, the Alfred P. Sloan Foundation Minority fellowship (to S.V.) and Mount Sinai NeuroAIDS Disparities Summer Institute, R25 MH080663 (to S.V. trainee). Declaration of Interests: The authors stated: None. Ethics Approval Statement: Patients gave written, informed consent for the provision of blood for the purposes of HIV research before inclusion in the current CHARTER pilot study. The protocol for blood collection and analysis was approved by the Mount Sinai, Rutgers University and University of Texas Medical Branch Institutional Review Board (Protocol Numbers, Pro20140000794, Pro2012001303, 18-0136, 18-0135, 18-0134).