HIV infection of astrocytes a novel brain viral reservoir that uses gap junction channels to amplify toxicity and facilitate viral rebound.
An article written by Eliseo A. Eugenin. Ph.D, Assistant Professor of Pathology Center for AIDS Research (CFAR) Investigator, Dept. of Pathology. F727, Albert Einstein College of Medicine, 1300 Morris Park Avenue, Bronx, NY, 10461, USA
HIV-1 enters the brain approximately 2 weeks after primary infection and despite successful antiretroviral therapy (ART), central nervous system (CNS) infection and HIV associated neurologic disorders (HAND) still persist in 50 % of infected individuals. This CNS compromise has been associated with amplification of damage rather that the virus itself, especially in the current ART era that effectively reduces viral load to undetectable or low levels (Gannon et al., 2011). The amplification mechanisms that result in neurological disorders in HIV-1 infected individuals are not completely understood.
It was known for many years that HIV can infect few astrocytes and viral replication in these cells is extremely restricted (Conant et al., 1994; Tornatore et al., 1994; Brack-Werner, 1999; Ohagen et al., 1999; Schweighardt and Atwood, 2001). Thus, the scientific community did not continue to examine the importance of this cell type in the pathogenesis of AIDS and its role as a viral reservoir. In the last few years we began re-examining the role of these cells in the context of AIDS and NeuroAIDS. We demonstrated in agreement with previous reports, that HIV infects only few astrocytes in vitro and in vivo, and that viral replication is extremely low to undetectable (Eugenin and Berman, 2007; Eugenin et al., 2011). However and even thought only 5 % of the cells are infected, this cell type is the more abundant cell type in the brain, thus, the total number of infected cells correspond to a large number. Experiments to determine whether the virus alters cell death indicated that these infected cells in vivo and in vitro are protected from apoptosis, resulting in a perfect reservoir for the virus.
In addition, we detected that despite low to undetectable viral replication and numbers of infected cells, bystander killing of uninfected CNS cells surrounding these HIV infected astrocytes resulted in astrocyte, neuronal and endothelial apoptosis. This damage results in CNS dysfunction and BBB disruption even in the absence of viral replication. This is representative of the current ART era where viral replication and presence of highly infected cells is minimal.
We showed that gap junction channels, the only type of channel that connects directly the cytoplasm of two or more apposed cells (Saez et al., 2003), enable coordination of intercellular signals that are amplified from few HIV infected cells into uninfected cells. These channels normally coordinate different function such as metabolism, electrical signals, migration and intercellular signaling. In pathological conditions, gap junction channels in astrocytes are usually down regulated, but HIV infection by an unknown mechanism, hijacks this communication system to spread toxicity and inflammation. Thus, HIV infection maintains the viability of these few infected cells, inducing bystander killing of uninfected surrounding cells and enhancing inflammation, resulting in CNS damage by a gap junction dependent mechanism.
propose that astrocytes are an important viral reservoir within the brain, and also that gap junction channels are key mediators of amplification of damage from these few infected cells to uninfected cells even in non replicating viral conditions.
We propose that astrocytes are an important viral reservoir within the brain, and also that gap junction channels are key mediators of amplification of damage from these few infected cells to uninfected cells even in non replicating viral conditions. Our data suggest that elimination of the toxic effect of these viral reservoirs requires the elimination of both, the HIV immortalized astrocytes and the toxic signals generated by the HIV infected cells and amplified by gap junctions. Thus, both systems contribute to the pathogenesis of HAND and AIDS.
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Key words: HIV astrocytes, HIV brain, HIV reservoirs