Study Suggests Possible Mechanism of HIV-induced Dementia

Article

How does HIV infection induce dementia? One mechanism may involve viral interference with neuron generation in the brain, and this mechanism might one day be targeted by a newly developed class of drugs, according to a study published in the July 15, 2004 issue of The Journal of Infectious Diseases.

 

Researchers Mitchell D. Krathwohl and Jodi L. Kaiser, of the University of Minnesota, report that HIV uses proteins on its outer coat to bind to receptors on the cellular precursors of neurons, called neural progenitor cells, which then receive an off signal from the virus that prevents them from differentiating into neurons. The resulting increase in the number of resting progenitor cells and decrease in the number of newly differentiated neurons may underlie the impaired cognition and memory loss of AIDS dementia complex.

 

The Minnesota investigators study was based on recent findings showing that neural progenitor cells capable of differentiating into neurons proliferate in adults, not just in fetuses as previously thought; that the area of the brain known as the hippocampus is rich in neural progenitor cells; and that such cells can be forced into quiescence by chemokines, molecules that deliver signals to cells by attaching themselves to specific cell-surface receptors. Because HIV is known to bind to chemokine receptors and send signals through them, the investigators hypothesized that the virus may use chemokines to cripple neuron generation.

 

Krathwohl and Kaiser first demonstrated that certain HIV coat proteins using certain chemokine receptors inhibited neural progenitor cells in culture, and that the effect was mediated by the receptors. They then showed that the coat proteins inhibited a metabolic step necessary for neural progenitor cell proliferation; indirect evidence suggested that this occurred via signaling through chemokine receptors. The investigators next found that cerebral spinal fluid from patients with AIDS dementia also inhibited neural progenitor cell proliferation. They then showed that progenitor cell numbers were reduced in hippocampal tissue obtained at autopsy from demented patients with HIV infection compared to that from non-demented patients with or without the infection.

 

Finally, the researchers examined a certain class of proteins, called apolipoproteins, that help transport fat in the bloodstream. The study found that apolipoprotein E3 blocked HIV coat protein inhibition of neural progenitor cell proliferation but the E4 protein did not, suggesting a possible explanation for the association between AIDS dementia and the E4 genotype.

 

The investigators noted that the ability of HIV to inhibit neuron proliferation by chemokine signaling at the cell surface represented a phenomenon distinct from entry into cell, the mechanism by which viruses are conventionally thought to exert pathogenic effects.

 

Commenting on the Minnesota study in an accompanying editorial, Aimee Kao and Richard Price, of the University of California, San Francisco, characterized the work as intriguing but cautioned that more experimental work with cell and animal models is needed to confirm these findings and define their molecular basis with precision. They pointed out, however, that the recent development of drugs that interfere with HIV-chemokine receptor binding may afford a special opportunity to test hypotheses of chemoreceptor-mediated brain injury, and that such agents may even have potential for mitigating AIDS dementia complex.

 

Source: Infectious Diseases Society of America (IDSA)

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