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

Abstract

At least half of human immunodeficiency virus (HIV)-infected individuals suffer from a wide range of cognitive, behavioral and motor deficits, collectively known as HIV-associated neurocognitive disorders (HAND). The molecular mechanisms that amplify damage within the brain of HIV-infected individuals are unknown. Recently, we described that HIV augments the opening of connexin-43 (Cx43) hemichannels in cultured human astrocytes, which result in the collapse of neuronal processes. Whether HIV soluble viral proteins such as gp120, can regulate hemichannel opening in astrocytes is still ignored. These channels communicate the cytosol with the extracellular space during pathological conditions. We found that gp120 enhances the function of both Cx43 hemichannels and pannexin-1 channels in mouse cortical astrocytes. These effects depended on the activation of IL-1β/TNF-α, p38 MAP kinase, iNOS, cytoplasmic Ca2+ and purinergic signaling. The gp120-induced channel opening resulted in alterations in Ca2+ dynamics, nitric oxide production and ATP release. Although the channel opening evoked by gp120 in astrocytes was reproduced in ex vivo brain preparations, these responses were heterogeneous depending on the CA1 region analyzed. We speculate that soluble gp120-induced activation of astroglial Cx43 hemichannels and pannexin-1 channels could be crucial for the pathogenesis of HAND.

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

“…This observation clearly shows that cell-to-cell contact is essential to the effective spread of viral infection from astrocytes and further proves that the most efficient model of HIV infection is via cell-to-cell contact. This is in agreement with multiple studies from our laboratory and others that have all demonstrated that HIV infection utilizes cell-to-cell communications to enhance the spread of the infection, suggesting that in patients under ART, where there are very limited virus replication and mostly inactivated viral reservoirs (Gajardo-Gomez et al, 2020;Hazleton et al, 2010Hazleton et al, , 2012Okafo et al, 2020b;Orellana et al, 2013), after reactivation, the reservoirs do not just undergo only epigenetic and genetic changes that affect viral gene expression but also changes that affects cell-to-cell communication systems that could shield the produced virions from the immune system.…”

Human immunodeficiency virus‐1/simian immunodeficiency virus infection induces opening of pannexin‐1 channels resulting in neuronal synaptic compromise: A novel therapeutic opportunity to prevent NeuroHIV

“…Even that these viral strains used in vitro were not the same as the dual inoculation of our macaques, the result on Panx-1 channel opening was comparable. Overall, the data indicate, like in HIV(Gajardo-Gomez et al, 2020;Orellana et al, 2013;Velasquez et al, 2020), that infection induces the opening of Panx-1 channels. Strikingly, SIV infection of the macaques, in vivo, resulted in the constant opening of Panx-1 channels even in the circulation of the animals.…”

“…A critical question is how Panx‐1 channels participate in SIV CNS disease. We recently demonstrated that Panx‐1 channels become open in response to HIV‐gp120 to CD4 and CCR5/CXCR4 (Gajardo‐Gomez et al., 2020; Orellana et al., 2013) and also demonstrated that chronic HIV infection, even in individuals under ART without significant viral replication, had a spontaneous opening of Panx‐1 channels by an unknown mechanism (Velasquez et al., 2020). In agreement, we identified that upon Panx‐1 channel opening, the serum/plasma levels of ATP and PGE 2 were elevated (Velasquez et al., 2020).…”

“…Our laboratory demonstrated that latently HIV‐infected immune and CNS cells could use connexin and pannexin (Panx) containing channels, gap junctions, and hemichannels to enhance and amplify damage/inflammation into neighboring uninfected cells even in the absence of active replication (Berman et al., 2016; Castellano & Eugenin, 2014; Castellano et al., 2016; Eugenin & Berman, 2007; Eugenin et al., 2011; Gajardo‐Gomez et al., 2020; Hazleton et al., 2010; Malik & Eugenin, 2016, 2019; Malik et al., 2017).…”

Astroglial Hemichannels and Pannexons: The Hidden Link between Maternal Inflammation and Neurological Disorders

“…In the last decade, other research groups and we have described that hemichannels and pannexons, two families of plasma membrane channels, may alter different aspects of astroglial function with potentially significant consequences for neuronal function during pathological conditions [111,112,[114][115][116][117][118][119][120][121][122]. Hemichannels result from the oligomerization of six protein subunits called connexins around a central pore [123] (Figure 2).…”