|NeuroAids Vol. 3, Issue 3 (May 2000)|
Protector, Prey, or Perpetrator:
What are the Possible Portals of Entry for HIV into the CNS?
How Does HIV Cross Brain Endothelial Cells?
Does HIV Have to Enter the CNS to Produce CNS Effects?
Viral products, rather than whole virus or infected immune cells, could cross the BBB. The viral coat gp120 crosses the BBB at a modest rate by the mechanism of adsorptive endocytosis (15). Since gp120 is very neurotoxic, its entry could induce CNS effects. Circulating gp120 has not been demonstrated in the blood, even though it is readily shed from virus. The ability of Tat and other viral products to cross the BBB has not been investigated. However, brain endothelial cells respond to tat treatment (17) suggesting that binding of tat and possibly internalization occurs.
The levels of many of the proinflammatory cytokines are elevated in the blood of patients with AIDS (18, 19) and their decrease with antiretroviral therapy is associated with cognitive improvement (20). TNF, IL-1, and IL-6 are all transported across the BBB and so could directly affect CNS function (21). These cytokines also have direct effects on BBB function, including disrupting it. In addition, cytokines have more subtle effects, which would likely be more important in AIDS dementia. Altered transport of glucose, amino acids, vitamins, or regulatory substances contributes to CNS dysfunction in other disease states and could do so in AIDS (22).
Much work has focused on the release of neurotoxins from microglia and astrocytes. However, the brain endothelial cell is also a source of nitric oxide, cytokines, and other substances with neurotoxic effects (23, 24). Circulating substances associated with HIV infection, such as Tat and the cytokines themselves, can induce the brain endothelial cells to release these substances. The endothelial cell does not require that HIV be within the CNS to produce these effects, as half of the endothelial cell surface faces the circulation and half the CNS. Endothelial cells have the potential to react to blood-borne substances at their luminal surface and to release neurotoxic substances at their abluminal surface.
Why Do Anti-viral Drugs Concentrate in the Brain so Poorly?
How Does Virus Reenter the Circulation?
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