Study Details How AIDS Virus Kills Immune Cells
By Will Dunham
WASHINGTON (Reuters) - As it invades the body, the virus that causes AIDS (news - web sites) unleashes a domino effect of destruction at the molecular level within immune system cells, ultimately leading to cellular suicide, scientists said on Tuesday.
Researchers at the University of California at San Diego used cutting-edge technology to track with unprecedented precision the progression of cellular damage that follows infection with human immunodeficiency virus (HIV (news - web sites)).
They revealed the sequence of events and the mechanisms employed by the virus to slay the very cells charged with defending the body against such invaders -- immune cells called CD4+ T cells.
``They are like the conductor of the immune response,'' said Jacques Corbeil, assistant professor of medicine at the UCSD School of Medicine and the study's lead author, referring to the CD4+ T cells. Those cells previously were known as T helper cells.
``You lose those and you are done. It creates a profound immunodeficiency,'' Corbeil said in a telephone interview.
HIV invades and swiftly overpowers the immune cell's DNA, inserting its own viral blueprints into the cellular machinery, poisoning genes and altering the cellular energy source, the researchers said.
It then suppresses the immune cell's DNA repair mechanism, and induces the cell suicide process called apoptosis, they said in their study. ``When we looked at the data, we realized how much HIV packs a punch,'' Corbeil added..
``The virus is extremely clever,'' said Dr. Daniel Masys, a biomedical information technology expert at UCSD School of Medicine and co-author of the study. ``It doesn't just hit the cell randomly, kind of shooting holes in it. It actually initiates the process of programmed cell death.''
``HIV actually suppresses more genes than it turns on as the process unfolds. Basically, the cell perceives this invasion and shuts down and commits apoptosis. To me, it was somewhat surprising that it was at that scale.''
The destruction of the immune cells robs the body of its ability to defend itself, eventually leading to the collapse of the immune system and full-blown AIDS.
Corbeil said a better understanding of how the virus decimates immune system cells could help in the development of drugs or vaccines to block or prevent HIV infection. The study appears in the journal Genome Research.
Microarray ``gene chip'' technology, silicon chips coated with DNA fragments, and a software program designed by UCSD experts enabled the researchers simultaneously to monitor about 6,800 genes eight times over a period of three days to see whether they were active or inactive. It was the largest number of genes ever tracked by AIDS researchers.
``Historically this kind of research would measure one or two enzymes or one or two molecules of interest,'' Masys said.
``Now we can look across the entire blueprint of the cell, the entire genome, and watch how the orchestration of destruction by the virus occurs at a molecular level. That's really without precedent.''
The researchers took CD4+ T cells, infected them, and watched the process unfold over 72 hours. Healthy cells were analyzed at the same intervals for comparison.
The researchers found that within hours of infecting the immune cell, HIV suppressed genes that maintain a constant and healthy internal environment. HIV cripples enzymes vital for the function of the mitochondria, the cell's energy source.
HIV also deactivates the genes that normally fix altered cellular DNA, leaving the immune cell unable to repair ongoing damage caused by the virus, the researchers said.
Almost immediately after infection, HIV begins turning off some key genes while turning on others in the host cell.
The first observation by the researchers came 30 minutes after infection. HIV already had suppressed more than 500 genes in the infected cells, while activating nearly 200 other genes -- including ``suicide'' genes that generally stay dormant until being activated as part of the normal cycle of cell death.
the end of three days, HIV had turned off about half the genes that normally
would be active in a healthy immune cell, the researchers found.