The Role of Astrocytes in HIV Neuropathogenesis

A new study suggests that HIV infection of astrocytes may be extensive in individuals that suffer from HIV-associated dementia (HAD). Until now, it was thought that astrocyte infection in HIV was rare. Previous studies had shown that only 1-3% of astrocytes were infected in individuals with HAD. The new data suggest that infection may be greater than earlier thought; specifically, 16-19% of the perivascular astrocyte population may be infected (1). Astrocytes make up a large amount of the cells in the brain and are important in maintaining normal functioning neurons. Some of these functions include neurotransmitter uptake, ion concentration maintenance, neurovascular coupling, structural support, and the formation of the blood brain barrier among other things. As such, a reduction in the proper functioning of the astrocyte may result in dramatic changes in brain function. Such is the case in HAD and HIVE (HIV encephalitis).

HIV does not directly damage neurons in the brain, rather it does so indirectly through nearby cells: astrocytes, macrophages and microglia. Some mechanisms have been described. Specifically, the release of neurotoxic mediators by activated macrophages/microglia (M/M). To enter the central nervous system, HIV must cross the blood brain barrier (BBB). It does this via infected monocytes. Infected monocytes cross into the central nervous system, activating astrocytes and the M/M response in the neuronal tissue. Once there, the macrophages and microglia not only damage surrounding neurons, but help to induce a greater monocyte response. The release of chemotactic substances attracts additional monocytes, effectively amplifying the overall response (2). Again, neuronal damage is indirect, resulting from the activation of local macrophages and microglia in addition to the breakdown of normal astrocyte function.

Interestingly, astrocytes do not actively make new virus when infected with HIV. Rather, they are latently infected as the transcription and translation processes are altered and no new viral proteins are produced. It is unknown how latent infection results in the compromise of astrocyte function and ultimately HAD. However, one study suggested the role of cytokine release from HIV infected brain macrophages and microglia. In this particular model, astrocytes infected with HIV have altered gene expression, specifically the Fas is upregulated, making them particularly susceptible to apoptosis. Astrocytes become stimulated by surrounding macrophages and microglia via cytokines and other factors. This stimulation is said to result in apoptosis (3). The details of these specific pathways in this form of astrocyte death, and ultimately HAD, remain to be elucidated.

Of particular significance, with regards to this new study, is that astrocyte infection frequency correlated with HIVE severity, particularly in the perivascular regions (1). This is thought to occur through increased movement of infected monocytes into the brain. With the aforementioned mechanisms of central nervous system HIV infection in mind, this makes sense. The upregulation of chemokines released by infected monocytes and microglia results in subsequent amplification of the pro-inflammatory response resulting in HIVE. Interestingly though, this study also suggests that there is a release of cytokines from infected astrocytes as well. Accordingly, the greater the number of astrocytes infected, the greater the severity of HIVE. Applying these findings may hold particular significance for how the treatment for HAD should be approached. Current therapy, highly active antiretroviral therapy (HAART), only targets replicating virus. As such, only infected macrophages are targeted in the brain. Infected astrocytes, which do not have actively replicating virus, are not targeted by HAART. Knowing that astrocyte infection may now be more extensive than earlier thought, it may be important to consider its role carefully when treating HIV individuals for HAD and HIVE.


Churchill, Melissa J., Steven L. Wesselingh, Daniel Cowley, Justin C. McArthur, and Bruce J. Brew. "Extensive Astrocyte Infection Is Prominent In Human Immunodeficiency Virus-Associated Dementia." Annals of Neurology 66.2 (2009): 253-58.

Gorry, Paul R., Chi Ong, Janine Thorpe, Sylvie Bannwarth, Katherine A. Thompson, Anne Gatignol, Steven L. Wesselingh, and Damian FJ Purcell. "Astrocyte Infection by HIV-1: Mechanisms of Restricted Virus Replication, and Role in Pathogenesis of HIV-1 Associated Dementia." Current HIV Research 1.4 (2003): 463-74.

Yadav, A., and R. G. Collman. "CNS Inflammation and Macrophage/Microglial Biology Associated with HIV-1 Infection." Nal of Neuroimmune Pharmacology 4.4 (2009): 430-47 http://www.ncbi.nlm.nih.gov/pubmed/19768553