HIV causes dementia by inhibiting neurogenesis

A significant proportion of people with HIV/ AIDS develop neurological symptoms, such as impaired co-ordination, personality changes, deficits in learning and memory, and mania and depression.

HIV-associated dementia is difficult to treat; although highly active anti-retroviral therapy (HAART) has led to improved prognoses for patients, these drugs do not effectively penetrate the blood brain barrier. So, the brain can act as a "silent reservoir" for HIV, which can therefore cause lasting and irreparable damage.

Exactly how HIV causes dementia was unknown. But a new study by researchers from the University of California, San Diego at La Jolla, now shows that, as well as causing the death of neurons, the virus also inhibits formation of new cells of new brain cells involved in learning and memory. So, as well as damaging the brain, the AIDS virus prevents the organ from repairing itself.

Soon after anti-HIV antibodies are detectable in the blood, some HIV patients develop various neurological symptoms, such as encephalitis (inflammation of the brain), meningitis (inflammation of the meninges, the three membranes that line the brain) and neuropathy (nerve damage).

A recent neuroimaging study showed that various parts of the cerebral cortex (the primary sensory and motor cortices, and premotor cortex) are about 15% thinner in AIDS patients than in healthy subjects. HIV is also known to cause damage to subcortical regions of the brain such as the limbic system.

But it is known that HIV does not infect nerve cells. The virus is believed to enter the brain within infected monocytes or lymphocytes (immune system cells); once inside, it primarily infects microglial cells, as well as astrocytes, which consequently secrete toxins such as tumour necrosis factor, free radicals and quinolinic acid, that induce programmed cell death (apoptosis) in neurons.

In the new study, Shu-Ichi Okamoto and his colleagues isolated neural progenitor cells from the dentate gyrus of the hippocampus of adult rats. The hippocampus is a part of the limbic system involved in memory and learning. The progenitor cells are stem cells which normally divide to give rise to neurons; the newly-generated cells become incorporated into the existing hippocampal circuitry and so are involved in memory and learning.

An HIV protein called gp120 was then added to the cell cultures. gp120 is a glycoprotein expressed on the surface of HIV particles, which is essential for the virus to enter the cells it infects. It was found that the protein prevented the proliferation of the progenitors, and determined that gp120 inhibits the proliferation of neural progenitors by activating an enzyme called p38 mitogen-activated protein kinase 2 (MAPK).

The researchers then created genetically engineered mice that express gp120. When examined, these animals were also found to have reduced numbers of dividing progenitor cells in the dentate gyrus of the hippocampus. The progenitors were also found to synthesize and secrete more MAPK than control mice.

Finally, it was found that compounds that inhibit MAPK function also reduce the ability of gp120 to inhibit progenitor proliferation. Because MAPK is involved in both the death of mature cells and the inhibition of progenitors induced by gp120, this pathway could be a target for new therapies for the treatment of HIV-associated dementia.

Reference:

Okamoto, S., et al. (2007). HIV/gp120 decreases adult neural progenitor cell proliferation via checkpoint kinase-mediated cell-cyle withdrawal and G1 arrest. Cell Stem Cell 1: 230-236. [Full text]

Thompson, P. M., et al. (2005). Thinning of the cerebral cortex visualized in HIV/AIDS reflects CD4+ T lymphocyte decline. Proc. Nat. Acad. Sci. 102: 15647-15652. [Full text]