Everall I, Trillo-Pazos G, Kandanearatchi A, Vyakarnam A, Eyeson J; International Conference on AIDS.
Int Conf AIDS. 2000 Jul 9-14; 13: abstract no. TuOrA407.
I. Everall, Institute of Psychiatry, Kings College London, DeCrespigny Park, London, SE5 8AF, United Kingdom, Tel.: +44 171 848 04 41, E-mail: i.everall@iop.kcl.ac.uk
Background: Antiretroviral drug efficacy in HIV infected human brain has been scarcely tested. Clinical studies indicate that HAART can improve cognitive function, but it is unknown which antiretrovirals ameliorate HIV brain damage. Methods: To assess this we established an innovative human brain aggregate system. Each aggregate contains all relevant cells: neurons, astrocytes, microglia/macrophages and oligodendrocytes, relevant neurotransmitter profile, and is the nearest model to the in vivo human brain. Aggregates were infected with lymphotrophic strain IIIB, or macrophage trophic strain SF162 (at 0.01 MOI). After 9 days infection, aggregates were exposed to either 20pM or 2nM of zidovudine (ZDV) or 3nM or 300 nM of abacavir (ABC), the expected brain tissue drug doses. At 21 days in culture, cellular damage was estimated by stereological and flow activated cell sorting methods. Results: Control aggregates consisted of 41% neurons (MAP2 positive cells), 35% astrocytes (GFAP positive cells), 2% microglia/macrophages (pgm-1 positive cells), and 16% oligodendrocytes (MOG positive cells). Infection with SF162 caused a significant 35% decrease in neuronal number (c2 = 7.4, p = 0.01) which was prevented by addition of either 20pM ZDV, 2nM ZDV, or 300nM ABC. By contrast, infection with IIIB was not associated with neuronal loss, but with a statistically significant 400% increase in microglial cells (predominant cell type infected with HIV in the brain). Moreover, both ZDV and ABC significantly prevented this increase in microglial proliferation. Conclusion: This demonstrates for the first time that NRTIs can prevent neuronal loss and microglial cell proliferation in this HIV infected aggregate model. Such protection indicates that these agents will be efficacious in the treatment of HIV associated cognitive impairments. Importantly, this model is being used to test which other drugs prevent HIV associated brain damage.
Publication Types:
Keywords:
- AIDS Vaccines
- Acquired Immunodeficiency Syndrome
- Animals
- Antiretroviral Therapy, Highly Active
- Brain
- Brain Injuries
- Dideoxynucleosides
- HIV Infections
- HIV Seropositivity
- Humans
- Microglia
- Zidovudine
- abacavir
Other ID:
UI: 102238804
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