Abstract
Polyamines (PAs) are polycationic biomolecules containing multiple amino groups. Patients with HIV-associated neurocognitive disorder (HAND) have high concentrations of the polyamine N-acetylated spermine in their brain and cerebral spinal fluid (CSF) and have increased PA release from astrocytes. These effects are due to the exposure to HIV-Tat. In healthy adult brain, PAs are accumulated but not synthesized in astrocytes, suggesting that PAs must enter astrocytes to be N-acetylated and released. Therefore, we tested if Cx43 hemichannels (Cx43-HCs) are pathways for PA flux in control and HIV-Tat-treated astrocytes. We used biotinylated spermine (b-SPM) to examine polyamine uptake. We found that control astrocytes and those treated with siRNA-Cx43 took up b-SPM, similarly suggesting that PA uptake is via a transporter/channel other than Cx43-HCs. Surprisingly, astrocytes pretreated with both HIV-Tat and siRNA-Cx43 showed increased accumulation of b-SPM. Using a novel polyamine transport inhibitor (PTI), trimer 44NMe, we blocked b-SPM uptake, showing that PA uptake is via a PTI-sensitive transport mechanism such as organic cation transporter. Our data suggest that Cx43 HCs are not a major pathway for b-SPM uptake in the condition of normal extracellular calcium concentration but may be involved in the release of PAs to the extracellular space during viral infection.
Highlights
The human immunodeficiency virus (HIV), identified in 1980, is a lentivirus that attacks the immune system and brain of humans and other primate species [1], known as simian immunodeficiency virus (SIV)
PA levels in brain have been associated with the severity of aging, dementia, neurological syndromes, and HIV-associated neurocognitive disorders (HAND), little is known about PA flux in the brain [52,53]
We found that astrocytes took up biotinylated spermine (b-SPM), but there was no difference between the uptake/accumulation of b-SPM between control astrocytes and astrocytes treated with HIV-1 trans-activator of transcription (HIV-Tat)
Summary
The human immunodeficiency virus (HIV), identified in 1980, is a lentivirus that attacks the immune system and brain of humans and other primate species [1], known as simian immunodeficiency virus (SIV). HIV-1 is highly virulent and infective [2] and is responsible for the AIDS pandemic [3]. The initial steps of HIV infection are binding of the virions to the CD4 cell receptor and co-receptor on the cell surface. These co-receptors are called CCR5 and CXCR4 [4] and play an important role in the initiation and spread of the HIV infection. In addition to affecting the immune system, HIV infection is responsible for causing cognitive, behavioral, and
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