New non-drug fix for HIV?

Researchers are slowly establishing a connection between an extremely rare genetic disease and HIV -- and homing in on a safe, non-prescription compound that could treat both. Recently, linkurl:James Hildreth;http://www.mmc.edu/faculty/som-jhildreth.html at the Meharry Medical College School of Medicine in Nashville, Tenn., and his colleagues found that cells affected by Niemann-Pick Type C (NPC), which disrupts cholesterol trafficking, were unable to release HIV, suggesting these cells would

By | June 30, 2009

Researchers are slowly establishing a connection between an extremely rare genetic disease and HIV -- and homing in on a safe, non-prescription compound that could treat both. Recently, linkurl:James Hildreth;http://www.mmc.edu/faculty/som-jhildreth.html at the Meharry Medical College School of Medicine in Nashville, Tenn., and his colleagues found that cells affected by Niemann-Pick Type C (NPC), which disrupts cholesterol trafficking, were unable to release HIV, suggesting these cells would not spread the virus. These findings, published May 27 in the Journal of Virology, are rooted in a hypothesis Hildreth has explored for a long time: that "cholesterol is somehow essential" to HIV, he said. For instance, HIV-1 relies on specialized structures known as lipid rafts, which are rich in cholesterol, to infect new cells. That line of thinking has led him to investigate whether a compound widely employed by the food and chemical industries (and used as a drug solubilizer) which depletes cells of cholesterol could serve as a preventative agent -- or even a treatment -- for HIV. And his growing body of evidence is suggesting the compound, known as cyclodextrin, might do just that.
Cyclodextrin infusions
Image: Chris Hempel
"There are very few [compounds] that rival the safety profile" of cyclodextrin, said Hildreth. If further research confirms it has an effect on a disease that affects millions of people worldwide, that would be a major advance, he noted. "It's been exciting for me from the beginning." Cyclodextrin appears to also linkurl:show some benefit in NPC,;http://www.the-scientist.com/blog/display/55377/ pointing further to a connection between HIV and the rare genetic disease. Indeed, a family with identical 5-year-old twins with NPC recently received permission from the US Food and Drug Administration to give the girls regular infusions of cyclodextrin. NPC leads to marked abnormalities in the liver and brain and is invariably fatal. "You have no idea what a relief it is to have something to try," said Chris Hempel, mother to Addi and Cassi. The girls have so far received several infusions, starting with one continuous 4-day infusion, and are now getting a series of 8-hour weekly infusions of increasing doses. Hempel said the girls improved remarkably after the first 4-day infusion, showing better control of their head and neck and better balance, and were more affectionate and responsive to people. These improvements waned a bit once the girls switched to weekly doses, but seem to be returning as the doses increase.
Addi and Cassi getting their infusions
Image: Chris Hempel
In a linkurl:previous experiment,;http://www.ncbi.nlm.nih.gov/pubmed/11485618?ordinalpos=4&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_DefaultReportPanel.Pubmed_RVDocSum Hildreth and his colleagues found that adding cyclodextrin to uninfected cells to deplete cellular cholesterol warded off HIV infection. Restoring normal cholesterol levels removed that protection. In a linkurl:mouse model;http://www.ncbi.nlm.nih.gov/pubmed/11805132?ordinalpos=15&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_DefaultReportPanel.Pubmed_RVDocSum of HIV, cyclodextrin prevented vaginal transmission of the virus by infected cells. In a primate model, the data were somewhat less promising. When macaques received topical cyclodextrin before being exposed to the virus, the treatment appeared to prevent infection initially, but linkurl:offered little protection upon re-exposure;http://www.ncbi.nlm.nih.gov/pubmed/18434406?ordinalpos=&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.SmartSearch&log$=citationsensor to SIV, again following cyclodextrin prophylaxis. Hildreth said that may be because the animals received a massive dose of the virus -- "way more than you'd ever see in seminal fluid in a natural setting" -- and the batches of cyclodextrin used for the repeated doses were not of the same quality. He said he is now repeating the study using a "physiologically relevant" amount of the virus. "We're pretty confident." Hildreth explained that NPC is likely disrupting HIV transmission by affecting the trafficking of the viral protein Gag. "The very dramatic thing in NPC cells is the Gag protein seems to never make it to the plasma membrane." Currently, Hildreth is developing cyclodextrin as a microbicide against HIV. He has filed an investigational new drug application with the FDA, and is investigating whether the compound could serve as a therapeutic. Steven Walkley, who linkurl:studies lysosomal storage disorders;http://neuroscience.aecom.yu.edu/faculty/primary_faculty_pages/walkley.html such as NPC at Albert Einstein College of Medicine in New York, said his own data show cyclodextrin has a "remarkable" effect on mice with NPC. "They're living literally twice as long as they would otherwise, " he said. "We were very surprised, to say the least." (He and his colleagues have submitted their findings for publication.) Walkley noted that his mice receive 4000 milligrams per kilogram of cyclodextrin -- 10 times a recent dose the Hempel girls received -- and he hasn't noticed any side effects. However, it's still unclear how exactly cyclodextrin is warding off NPC, which means there could be some side effects scientists have not yet discovered, he added. "Maybe there's something going on and we just haven't found it yet." Peter Pentchev, a retired scientist who worked with NPC for decades at the National Institutes of Health, echoed Walkley's opinion about the promise of cyclodextrin in NPC, dubbing it the "perfect drug" for the disease. He cautioned, though, that "we know what [cyclodextrin] does, but we don't know why or how." But scientists are working on those questions, he added. "In the next year, I'd be really surprised if we don't get some answers." Hempel, too, has failed to notice a single side effect since her girls began cyclodextrin infusions. "We're proving the safety of this compound," she said. "I definitely feel like Addi and Cassi are leading the way here, not only for NPC kids, but potentially for AIDS patients."
**__Related stories:__***linkurl:Twin Disorders;http://www.the-scientist.com/article/display/55136/
[November 2008]*linkurl:Take drug additive, not drug?;http://www.the-scientist.com/blog/display/55377/
[26th January 2009]*linkurl:Cholesterol and NPC, circa 1997;http://www.the-scientist.com/article/display/55129/
[November 2008]

Comments

Avatar of: anonymous poster

anonymous poster

Posts: 16

June 30, 2009

NIH has been funding this work since 2002. I guess NIH Study Sections can identify innovative work.
Avatar of: anonymous poster

anonymous poster

Posts: 35

June 30, 2009

This recalls some discussions from earlier news on primate research. The obligatory stop at the monkey house seems only to delay the progress of the research. Animal researchers and animal rights protesters should agree on this one: there's no point using monkeys if you've already been able to work out the basic biology in rodents. With a bit of highly voluntary bravery by sick people with little to lose, we can cut years and millions of dollars from the cost of finding new cures, while greatly reducing the number of primates kept in laboratory settings.\n
Avatar of: anonymous poster

anonymous poster

Posts: 26

June 30, 2009

Since we know that cyclodextrin is relatively safe in humans, I agree there is no reason not to try it and see if it helps some people with AIDS. But, that does not address testing to see if it can prevent HIV transmission. For that, you have to expose a healthy individual. I don't think you'd have a lot of volunteers lining up for that... hence the SIV/primate testing. But, if you can find prison inmates with life sentences that want to volunteer for conjugal visits w/ a horny HIV-positive "donor", I'm all for it.\n\nBaxter Zappa
Avatar of: MICHAEL LINDE

MICHAEL LINDE

Posts: 1

June 30, 2009

In response to Baxter, when you test a potential microbicide in humans, you don't intentionally expose them to the infectious agent. You run the trial like a vaccine trial--with a huge cohort so you will have enough exposures to assess efficacy. I can only assume why microbicide trials have been few and far between.
Avatar of: Brian Lee

Brian Lee

Posts: 15

June 30, 2009

There are various cyclodextrins. I wonder which one(s) are relevant?
Avatar of: Alison McCook

Alison McCook

Posts: 68

July 1, 2009

Hi-\n\nIn response to the question about types of cyclodextrins, the form James Hildreth uses in his research is 2-Hydroxypropyl-beta-cyclodextrin, sometimes abbreviated at BCD or beta-cyclodextrin.\n\nAlison McCook, Deputy Editor

July 2, 2009

Cyclodextrins are large molecules (polysaccharides) and are basically not absorbed orally, thus limiting the treatment to intravenous administration with its own limitations. Although, 2-HP-b-cyclodextrins are considered relatively non toxic among different cyclodextrins, they are not "free" of side effects particularly after prolonged period of treatment. Eliminated from body exclusively through kidneys, kidney toxicity being the main concern in many species including human.
Avatar of: Dominic Joelson

Dominic Joelson

Posts: 2

July 3, 2009

Well its a good news then.\n\ngood thing they are still doing all their best.\n\n
Avatar of: John Bremner

John Bremner

Posts: 2

July 22, 2009

Researchers have known for at least the past 40 years that all viruses and bacteria attach to cells using (mainly) various sugar molecules before they invade them. Known attachment mechanisms involve mannose, glucosamine, ribose, and xylose, as well as collagen. So it's not surprising that cyclodextrin should help prevent viral attachment. Taking E.coli as an example, just interfering with the mannose attachment by putting mannose in the environment so that the bacterial and cellular mannose receptors are filled is sufficient. This is why, for example, drinking a d-mannose solution or giving a bladder instillation of mannose solves E.coli urine infections. \n\nKnowledge of surface sugars on bacteria and viruses is gradually building, and cheaper isolation of these same sugars is making them available so that in the relatively near future, if you know what virus or bacteria is invading your system you will be able to have a targeted drink or injection that will defeat that particular bug by filling all its cellular receptors.

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