New research targets HIV hiding in macrophages

[Cosmicdancer]

http://www.sciencedaily.com/releases/2011/01/110123085455.htm

Unexpected Find Opens Up New Front in Effort to Stop HIV:

ScienceDaily (Jan. 23, 2011) — HIV adapts in a surprising way to survive and thrive in its hiding spot within the human immune system, scientists have learned. While the finding helps explain why HIV remains such a formidable foe after three decades of research -- more than 30 million people worldwide are infected with HIV -- it also offers scientists a new, unexpected way to try to stop the virus.

The work by researchers at the University of Rochester Medical Center and Emory University was published Dec. 10 in the Journal of Biological Chemistry.

It's thanks largely to its ability to hide out in the body that HIV is able to survive for decades and ultimately win out against the body's relentless immune assault. One of the virus's favorite hiding spots is an immune cell called a macrophage, whose job is to chew up and destroy foreign invaders and cellular debris.

For more than 15 years, Baek Kim, Ph.D., has been fascinated by HIV's ability to take cover in a cell whose very job is to kill foreign cells. In the last couple of years Kim, professor of Microbiology and Immunology at the University of Rochester Medical Center, has teamed with Emory scientist Raymond F. Schinazi, Ph.D., D.Sc., director of the Laboratory of Biochemical Pharmacology at Emory's Center for AIDS Research, to test whether the virus is somehow able to sidestep its usual way of replicating when it's in the macrophage.

The pair found that when HIV faces a shortage of the molecular machinery needed to copy itself within the macrophage, the virus adapts by bypassing one of the molecules it usually uses and instead tapping another molecule that is available.

Normally, the virus uses dNTP (deoxynucleoside triphosphate, the building blocks for making the viral genetic machinery) to get the job done, but dNTP is hardly present in macrophages -- macrophages don't need it, since they don't replicate. But macrophages do have high levels of a closely related molecule called rNTP (ribonucleoside triphosphate), which is more versatile and is used in cells in a variety of ways. The team found that HIV uses primarily rNTP instead of dNTP to replicate inside macrophages.

"The virus would normally just use dNTP, but it's simply not available in great quantities in the macrophage. So HIV begins to use rNTP, which is quite similar from a chemical perspective. This is a surprise," said Kim. "The virus just wants to finish replicating, and it will utilize any resource it can to do so."

When the team blocked the ability of the virus to interact with rNTP, HIV's ability to replicate in macrophages was slashed by more than 90 percent.

The work opens up a new front in the battle against HIV. Current drugs generally target dNTP, not rNTP, and take aim at the infection in immune cells known at CD4+ T cells. The new research opens up the possibility of targeting the virus in macrophages -- where the virus is out of reach of most of today's drugs.

"The first cells that HIV infects in the genital tract are non-dividing target cell types such as macrophages and resting T cells" said Kim. "Current drugs were developed to be effective only when the infection has already moved beyond these cells. Perhaps we can use this information to help create a microbicide to stop the virus or limit its activity much earlier."

Kim notes that a compound that targets rNTP already exists. Cordycepin in an experimental compound, derived from wild mushrooms, that is currently being tested as an anti-cancer drug. The team plans to test similar compounds for anti-HIV activity.

"This significant breakthrough was unappreciated prior to our paper. We are now exploiting new anti-HIV drugs jointly based on this novel approach that are essentially not toxic and that can be used to treat and prevent HIV infections," said Schinazi, who has developed several of the drugs currently used to treat HIV patients.

The first authors of the paper, who contributed equally to the project, are graduate students Edward Kennedy of Rochester and Christina Gavegnano of Emory. Other authors include, from Rochester, graduate students Laura Nguyen, Rebecca Slater and Amanda Lucas; and from Emory, post-doctoral associate Emilie Fromentin.

The work was funded by the National Institute of Allergy and Infectious Diseases and the U.S. Department of Veterans Affairs, where Schinazi is also employed.

[xman]

interesting. the problem now is to wait the approval process. since we are in a preclinical phase the compound still needs to pass the three human trial phases prior to be launched on market. unfortunately as everyone knows this process is extremely long so i'm not sure how this could benefit us and if it poses any practical possibilities in the decade ahead.

[Cosmicdancer]

Agreed, but as the article states, "Kim notes that a compound that targets rNTP already exists. Cordycepin in an experimental compound, derived from wild mushrooms, that is currently being tested as an anti-cancer drug. The team plans to test similar compounds for anti-HIV activity."

I'll need to research what phase the clinical trials are in for Cordycepin.  It would be great if an already approved drug is active against rNTP. 

[Inchlingblue]

Wow, this is very interesting.

[MitchMiller]

Yartsa Gunbu is cordycepin.  A few web searches yielded some info.  It is a fungus that grows on catapillars in Tibet.  There are ways to the chemical equivalent synthetically.  There are a couple supplement sites hawking it, but after reading how expensive it is, I doubt their stuff contains much, if any, of it. 

One article implies it breaks down fast in the body, so don't really know if eating the fungus as is would be of much value, but if you're desperate, you can take a trip to Tibet and feast on it.  One guy had a picture of a meal of it on the web.

I also checked out a chemical web site that stated there are no legal restrictions on it, so if it really worked, I would expect the supplement industry would quickly enter the picture.

[Cosmicdancer]

Cordycepin is in a phase 1/2 clinical trial of leukemia patients that was supposed to be ending in December, 2010, according to the link below.  But it's not clear if it reached enrollment goals or if it's on schedule.

http://clinicaltrials.gov/ct2/show/NCT00709215

[kaamos]

There's tan article of a Ghana university where 300 HIV + pacients were treated with cordyceps sinensis( fungi original of cordycepin) and later they didnt show trace of the virus and cd4 count go high. Study is from 2004, cordyceps is secure, usted for hundred of year for chinese tradicional medicine