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Chloroquine mediated molecular tuning of astrocytes for enhanced permissiveness to HIV infection
Theophilus S Vijaykumar1, Avindra Nath, Ashok Chauhan
1Department of Neurology, Johns Hopkins University (JHU), Baltimore, MD, USA.
Abstract:
We report in this study that minimum productive HIV infection in astrocytes (a predominant cell type in brain and persists for the entire life) occurs through endocytosis. The lysosomotropic agent chloroquine enhanced permissiveness of astrocytes to HIV infection possibly by circumventing degradation of endosome-entrapped viral particles. In particular, chloroquine may promote establishment of a stable long term viral reservoir in astrocytes and may eventually facilitate early onset of neurological complications.
Insights
Human immunodeficiency virus (HIV) infects brain astrocytes via endocytosis. The drug chloroquine may increase astrocyte susceptibility to HIV, potentially creating a viral reservoir and leading to neurological issues.
Area of Science:
- Neuroscience
- Virology
- Cell Biology
Background:
- Astrocytes are the most abundant glial cells in the brain and play crucial roles in neuronal support and brain homeostasis.
- Persistent infection of astrocytes by human immunodeficiency virus (HIV) is implicated in HIV-associated neurological disorders.
- Understanding the mechanisms of HIV entry and persistence in astrocytes is critical for developing therapeutic strategies.
Purpose of the Study:
- To investigate the cellular mechanisms of productive HIV infection in human astrocytes.
- To determine the effect of chloroquine, a lysosomotropic agent, on astrocyte permissiveness to HIV infection.
- To explore the potential of chloroquine in establishing long-term HIV reservoirs within astrocytes.
Main Methods:
- Primary human astrocyte cultures were used to model HIV infection.
- HIV infection dynamics in astrocytes were analyzed with and without chloroquine treatment.
- Endocytosis pathways involved in HIV entry were investigated.
- Viral particle fate within endosomes was assessed.
Main Results:
- Productive HIV infection in astrocytes is primarily mediated by the endocytic pathway.
- Chloroquine significantly enhanced astrocyte permissiveness to HIV infection.
- Chloroquine treatment appeared to circumvent the degradation of endosome-entrapped HIV particles.
- These findings suggest chloroquine may promote the establishment of a stable, long-term HIV reservoir in astrocytes.
Conclusions:
- HIV utilizes endocytosis for productive infection in astrocytes, highlighting a key cellular entry mechanism.
- Chloroquine's ability to enhance astrocyte permissiveness suggests a role in facilitating persistent HIV reservoirs.
- The findings raise concerns about potential acceleration of HIV-related neurological complications due to chloroquine's effects on astrocyte infection.
