AIDS Interferes With Stem Cells In The Brain
A prominent problem in AIDS is a form of dementia that robs one’s ability to concentrate and perform normal movements. Scientists at the Burnham Institute for Medical Research (Burnham) have discovered how HIV/AIDS disrupts the normal replication of stem cells in the adult brain, preventing new nerve cells from forming.
Drs. Stuart Lipton, Marcus Kaul, Shu-ichi Okamoto and their colleagues uncovered a novel molecular mechanism that inhibits stem cell proliferation and that could possibly be triggered in other neurodegenerative diseases as well.
A normally functioning adult human brain has the ability to partially replenish or repair itself through neurogenesis, the proliferation and development of adult neural progenitor/stem cells (aNPCs) into new nerve cells. Neurogenesis can take place only within specific regions of the brain, such as the dentate gyrus of the hippocampus.
The hippocampus is the brain’s central processing unit, critical to learning and memory. aNPCs differentiate, adapt, and assimilate into existing neural circuits and mature with guidance from neurotransmitters, the chemical substances that nerve cells use to communicate with one another. The brain’s self-renewal through neurogenesis is impaired in AIDS dementia, Alzheimer’s, Huntington’s, and other neurodegenerative diseases, as evidenced by a greatly reduced number of aNPCs in brain tissue from individuals suffering from these diseases. The Burnham team focused on the determining the effect of a protein associated with AIDS, called HIV/gp120, which plays a key role in the pathogenesis of AIDS dementia.
In initial work with cell cultures in Petri dishes, the researchers methodically ruled out the possibility that HIV/gp120 would be inducing the death of stem cells and determined instead that HIV/gp120 was acting by inhibiting stem cell proliferation. Next, they confirmed these results in a special mouse strain bred to express HIV/gp120 in its brain. This mouse model for AIDS dementia mimics several features of the disease process found in humans. They observed a significant decrease in the number of proliferating stem cells in the brains of HIV/gp120-mice compared with similar tissue from normal, wild-type mice.
HIV/gp120 is known to interact with two receptors, called chemokine receptors, which are expressed on aNPCs. The researchers discovered that the same two receptors were targeted by HIV/gp120 sourced from either mouse or human brain tissue.
In search of a mechanism behind the finding that HIV/gp120 reduced proliferation of aNPCs, the scientists studied the effect of the protein on the cell cycle. Cells undergo seasons or cycles, known as G1, S, G2, and M (for mitosis, or cell division). They found that cells exposed to HIV/gp120 got stuck in the G1 or resting phase, and that the cell cycle was arrested.
Cell cycle is studied intensively by cancer researchers who have delineated certain “checkpoint” pathways that can jam cell proliferation, one of the key behaviors of cancer. Checkpoint pathways are overcome by cancers when they fool the body’s normal machinery into producing more cancerous cells. With dementia, it turns out that the opposite is true: the Burnham team discovered that HIV/AIDS could co-opt the checkpoint pathway to prevent stem cells in the brain from dividing and multiplying.
One such checkpoint pathway is modulated by an enzyme called p38 mitogen-activated protein kinase (MAPK), whose activity is known to disrupt the cell cycle. In mature nerve cells, the Burnham team had previously shown that HIV/gp120 activates the p38 MAPK pathway to contribute to cell death. Lipton and colleagues now report that the p38 MAPK pathway is also the mechanism underlying decreased stem cell proliferation in the brain associated with HIV/AIDS. Under experimental conditions, they were able to neutralize the p38 MAPK pathway and restore stem cell proliferation.
“We show for the first time how HIV/AIDS inhibits proliferation of neural stem cells and prevents the formation of new nerve cells in the adult brain,” said Dr. Stuart Lipton, Director of Burnham’s Del E. Webb Center for Neuroscience, Aging, and Stem Cell Research.
“The fact that the mechanism of action involves the p38 MAPK enzyme is fortuitous because drugs to combat that pathway are being tested for other diseases. If they prove effective, they might also work to protect the brain. Thus, this study offers real hope for combating the bad effects of HIV/AIDS on stem cells in the brain.” Lipton went on to state, “It will be important to see if HIV/AIDS acts similarly on stem cells for other organs in the human body, as this may impact on the disease process as a whole.”
Cell Stem Cell, Vol 1, 230-236, 16 August 2007
HIV/gp120 Decreases Adult Neural Progenitor Cell Proliferation via Checkpoint Kinase-Mediated Cell-Cycle Withdrawal and G1 Arrest
1 Center for Neuroscience, Stem Cells, and Aging, Burnham Institute for Medical Research, La Jolla, CA 92037, USA
2 Department of Neurosciences, University of California, San Diego, La Jolla, CA 92093, USA
3 Department of Psychiatry University of California, San Diego, La Jolla, CA 92093, USA
Impaired adult neurogenesis has been observed in several neurodegenerative diseases, including human immunodeficiency virus (HIV-1)-associated dementia (HAD). Here we report that the HIV-envelope glycoprotein gp120, which is associated with HAD pathogenesis, inhibits proliferation of adult neural progenitor cells (aNPCs) in vitro and in vivo in the dentate gyrus of the hippocampus of HIV/gp120-transgenic mice. We demonstrate that HIV/gp120 arrests cell-cycle progression of aNPCs at the G1 phase via a cascade consisting of p38 mitogen-activated protein kinase (MAPK) → MAPK-activated protein kinase 2 (a cell-cycle checkpoint kinase) → Cdc25B/C. Our findings define a molecular mechanism that compromises adult neurogenesis in this neurodegenerative disorder.