THE ROLE OF CONNEXIN43 CHANNELS IN BRAIN DAMAGE AMPLIFICATION ELICITED BY VIRUSES AND NEURODEGENERATIVE DISEASES
HIV infection compromises the central nervous system (CNS) in a significant number of infected individuals, resulting in neurological dysfunction that ranges from minor cognitive deficits to frank dementia. As HIV-infected individuals live longer due to the success of antiretroviral therapies (ART), HIV-associated neurological disorders have become a major public health issue. While macrophages/microglia are the predominant CNS cells infected by HIV, my laboratory and others have shown that HIV-infected astrocytes, despite being low in numbers, play key roles in NeuroHIV pathogenesis. Only recently, due to the development of new techniques to detect and quantify HIV-reservoirs, we show that ART decreased the numbers of HIV-infected myeloid cells, and microglia/macrophages. However, HIV-infected astrocyte numbers are not altered by ART. Moreover, we demonstrated that few astrocytes could repopulate the entire body indicating the significance of this reservoir. These data underscore the importance of astrocytes as a viral reservoir.
Gap junctions (GJ) connect the cytoplasm of two adjoining cells enabling the direct exchange of cytoplasmic products. Each GJ channel is formed for the docking of two hemichannels (HC), and each channel is mainly formed by Connexin43 (Cx43), the main connexin in astrocytes.Recently, our lab discovered that HC could also be open under non-HIV replicating conditions, enabling the release of intracellular factors into the extracellular environment. Both types of connexin channels, GJ and uHC, can pass molecules up to 1.2 kDa in size, including second messengers, ions, ATP, prostaglandins, small peptides, and RNA. During the previous funding period, we demonstrated that HIV-infected astrocytes “hijack” GJ and HC to spread toxic, pro-apoptotic, and pro-inflammatory molecules - such as IP3, Ca+2, glutamate, ATP, and PGE2 - to vast areas of the CNS, and into uninfected cells eliciting neuronal and glial compromise. We have identified that HIV astrocytic and myeloid reservoirs within the brain have altered inter-organelle interactions that result in the survival or cell death based on the low-level expression of two viral proteins: HIV-tat to maintain Cx43 expression at the promoter level, and HIV-Nef that binds to the IP3 receptor 1/3, preventing its activation. Surprisingly, we identified a novel mechanism of cell survival/death based on compromised interactions among the mitochondria, lipid vesicles, ER, and the plasma membrane (a priority field for the NIH, inter-organelle interactions). We identified several “linkers” between these different organelles, including bim at the mitochondria and IP3R at the ER. More importantly, these organelle interactions induced by HIV provide a unique metabolic signature in astrocytes and macrophage/microglia that can be exploited to kill CNS viral reservoirs. This is unique! We demonstrated that most of these mechanisms also operate in vivo (i.e., in human/monkey/hu-mice brain tissues), underscoring the importance of glial cells and Cx43-containing channels in the pathogenesis of NeuroHIV. Our central hypothesis is that “”. We propose that the role of astrocytes and the function of Cx43-containing channels in the pathogenesis of NeuroHIV is unique and provides a novel explanation for the occurrence of CNS damage under conditions of low to undetectable HIV replication, which is highly relevant to the current ART era.