Corporate Banner
Satellite Banner
Immunology
Scientific Community
 
Become a Member | Sign in
Home>News>This Article
  News
Return

Stanford Chemists Synthesize Compound that Flushes Out Latent HIV

Published: Monday, July 23, 2012
Last Updated: Monday, July 23, 2012
Bookmark and Share
A new collection of compounds, called "bryologs" - derived from a tiny marine organism - activate hidden reservoirs of the virus that currently make the disease nearly impossible to eradicate.

Thanks to antiretrovirals, an AIDS diagnosis hasn't been a death sentence for nearly two decades. But highly active antiretroviral therapy, or HAART, is also not a cure.

Patients must adhere to a demandingly regular drug regimen that carries plenty of side effects. And while the therapy may be difficult to undergo in the United States, it is nearly impossible to scale to the AIDS crisis in the developing world.

The problem with HAART is that it doesn't address HIV's so-called proviral reservoirs - dormant forms of the virus that lurk within T-cells and other cell types.

Even after all of the body's active HIV has been eliminated, a missed dose of antiretroviral drugs can allow the hibernating virus to emerge and ravage its host all over again.

"It's really a two-target problem," said Stanford chemistry Professor Paul Wender, "and no one has successfully targeted the latent virus."

But Wender's lab is getting closer, exciting many HIV patients hoping for a cure.

The lab has created a collection of "bryologs" designed after a naturally occurring, but difficult to obtain, molecule. The new compounds have been shown to activate latent HIV reservoirs with equal or greater potency than the original substance. The lab's work may give doctors a practical way to flush out the dormant virus.

The findings were published on July 15 in the journal Nature Chemistry.

Nature's medicine
The first attempts to reactivate latent HIV were inspired by observations of Samoan healers. When ethnobotanists examined the bark of Samoa's mamala tree, traditionally used by healers to treat hepatitis, they found a compound known as prostratin.

Prostratin binds to and activates protein kinase C, an enzyme that forms part of the signaling pathway that reactivates latent viruses. The discovery sparked interest in the enzyme as a potential therapeutic target, especially as it was discovered that prostratin isn't the only biomolecule to bind to the kinase.

The bryozoan Bugula neritina - a mossy, colonial marine organism - produces a protein kinase C-activating compound that is many times more potent than prostratin. The molecule, named bryostatin 1, was deemed to hold promise as a treatment, not only for HIV but for cancer and Alzheimer's disease as well.

The National Cancer Institute initiated a Phase II clinical trial for the compound in 2009 for the treatment of non-Hodgkin lymphoma. But the substance had a number of side effects and proved prohibitively difficult to produce.

"It took 14 tons of bryozoans to make 18 grams of bryostatin," said Wender. "They've stopped accrual in trials because, even if the trials worked, the compound cannot be currently supplied."

Patient enrollment was suspended until more accessible compounds came out of the Wender Group's lab.

A synthetic approach
Wender, who published the first practical synthesis of prostratin and its analogs in 2008, had set out to make a simpler, more effective synthetic analog of bryostatin.

"We can copy the molecule," he said, "or we can learn how it works and use that knowledge to create something that has never existed in nature and might be superior to it."

The seven resulting compounds, called bryologs, share two fundamental features with the original bryostatin: the recognition domain, which directly contacts protein kinase C, and the spacer domain, which allows the bryolog-protein kinase C complex to be inserted into the cell membrane.

The researchers tested the new compounds' ability to reactivate viral reservoirs in J-Lat cell lines, which contain latent HIV and begin to fluoresce when they express the virus.

In the J-Lat line, bryologs induced virus in as many or more cells than bryostatin at a variety of concentrations, and ranged from 25 to 1,000 times more potent than prostratin. The compounds showed no toxic effects.

Bryolog testing remains in the early stages - the researchers are currently conducting in vivo studies in animal models. But practical bryostatin substitutes may be the first step toward true HIV-eradication therapy.

"I receive letters on a regular basis from people who are aware of our work - who are not, so far as I know, scientifically trained, but do have the disease," said Wender. "The enthusiasm they express is pretty remarkable. That's the thing that keeps me up late and gets me up early."

The research was supported by the National Institutes of Health.

Primary authors are Stanford chemistry graduate student Brian Loy and doctoral students Brian DeChristopher and Adam Schrier, in collaboration with Professor Jerry Zack, co-director of the UCLA AIDS Center, and Dr. Matthew Marsden from the UCLA School of Medicine.


Further Information

Join For Free

Access to this exclusive content is for Technology Networks Premium members only.

Join Technology Networks Premium for free access to:

  • Exclusive articles
  • Presentations from international conferences
  • Over 2,900+ scientific posters on ePosters
  • More than 4,200+ scientific videos on LabTube
  • 35 community eNewsletters


Sign In



Forgotten your details? Click Here
If you are not a member you can join here

*Please note: By logging into TechnologyNetworks.com you agree to accept the use of cookies. To find out more about the cookies we use and how to delete them, see our privacy policy.

Related Content

Mapping the Mechanical Properties of Living Cells
Researchers have developed a new way to use atomic force microscopy to rapidly measure the mechanical properties of cells at the nanometer scale, an advance that could pave the way for better understanding immune disorders and cancer.
Monday, December 21, 2015
Viral Infections Leave a Signature on the Immune System
A test that queries the body’s own cells can distinguish a viral infection from a bacterial infection and could help doctors know when to use antibiotics.
Thursday, December 17, 2015
Women’s Immune System Genes Operate Differently from Men’s
A new technology reveals that immune system genes switch on and off differently in women and men, and the source of that variation is not primarily in the DNA.
Friday, July 31, 2015
HIV Susceptibility Linked to Little-Understood Immune Cell Class
High levels of diversity among immune cells called natural killer cells may strongly predispose people to infection by HIV, and may be driven by prior viral exposures, according to a new study.
Thursday, July 30, 2015
Genetic Signature Enables Early, Accurate Sepsis Diagnosis
Systemic inflammation after injuries or surgery can dramatically alter the activity of thousands of genes, but a new study shows that changes in just 11 of them are enough to detect the presence or absence of accompanying infection.
Monday, May 18, 2015
Foreign Antibodies Mobilize Immune System to Fight Cancer
A mouse’s T cells can be primed to attack and eliminate a malignant tumor by injecting antibodies from another mouse with resistance to the tumor, as well as by activating certain signaling cells, a study has found.
Thursday, May 07, 2015
Stanford Research Leads to New Understanding of How Cells Grow and Shrink
Researchers use new techniques to document how cells can conceal growth and then suddenly swell up.
Saturday, May 17, 2014
Immune Response Triggered by Honeybee Venom Supports Hypothesis on the Origin of Allergies
Allergy-like immune reactions could represent a mechanism of the body that protects it against toxins.
Wednesday, November 27, 2013
DNA ‘Reverse’ Vaccine Reduces Levels of Immune Cells Believed Responsible For Type-1 Diabetes
A clinical trial of a vaccine has delivered initially promising results, suggesting that it may selectively counter the errant immune response that causes the diabetes.
Wednesday, July 03, 2013
Antibody Hinders Growth of Gleevec-Resistant Gastrointestinal Tumors in Lab Test
An antibody that binds to a molecule on the surface of a rare but deadly tumor of the gastrointestinal tract inhibits the growth of the cancer cells in mice.
Thursday, February 07, 2013
Lasker Award Goes to Biochemist James Spudich
Research helps to explain the molecular activity that enables heartbeats, makes muscles contract and powers immune cells.
Wednesday, September 12, 2012
Stanford Scientist Omics Profile used to Discover, Track his Diabetes Onset
Researchers also spied on Dr Snyder's immune system and watched it battle viral infections.
Monday, March 19, 2012
Scientific News
Tricked-Out Immune Cells Could Attack Cancer
New cell-engineering technique may lead to precision immunotherapies.
Neural Networks Adapt to the Presence of a Toxic HIV Protein
HIV-associated neurocognitive disorders (HAND) afflict approximately half of HIV infected patients.
HIV Protein Manipulates Hundreds of Human Genes
Findings search for new or improved treatments for patients with AIDS.
Breaking the Brain’s Garbage Disposal
The children’s ataxia gene problem turned out to be not such a big deal genetically — it was such a slight mutation that it barely changed the way the cells made the protein.
Flesh-Eating Bacteria Work Together
Scientists recently discovered different strains of deadly flesh-eating bacteria working together to spread infection and they now have a better understanding of the role of the toxins they produce. The discovery could change how the illness and other diseases are treated.
Utilizing Antibodies from Ebola Survivors
A collaborative team from The University of Texas Medical Branch at Galveston, Vanderbilt University, The Scripps Research Institute and Integral Molecular Inc. have learned that antibodies in the blood of people who have survived a strain of the Ebola virus can kill various types of Ebola.
Antibiotic Use in Early Life Disrupts Gut Microbiota
The use of antibiotics in early childhood interferes with normal development of the intestinal microbiota, shows research conducted at the University of Helsinki.
Easier Diagnosis for Fungal Infection of the Lungs
A new clinical imaging method developed in collaboration with a University of Exeter academic may enable doctors to tackle one of the main killers of patients with weakened immune systems sooner and more effectively.
Mitochondrial Troublemakers Unmasked in Lupus
Drivers of autoimmune disease inflammation discovered in the traps of pathogen-capturing white blood cells.
Important Regulator of Immune System Decoded
Plasma cells play a key role in our immune system. Now scientists at the Research Institute of Molecular Pathology (IMP) in Vienna, Austria, and at the Walter and Eliza Hall Institute (WEHI) in Melbourne, Australia, succeeded in characterizing a central regulator of plasma cell function.
SELECTBIO

Skyscraper Banner
Go to LabTube
Go to eposters
 
Access to the latest scientific news
Exclusive articles
Upload and share your posters on ePosters
Latest presentations and webinars
View a library of 1,800+ scientific and medical posters
2,900+ scientific and medical posters
A library of 2,500+ scientific videos on LabTube
4,200+ scientific videos
Close
Premium CrownJOIN TECHNOLOGY NETWORKS PREMIUM FOR FREE!