Web Concepts

Posts Tagged ‘HIV’

HIV infection sends the immune system into overdrive and eventually exhausts it, which is what leads to AIDS. But removing cholesterol from HIV seems to cripple the virus' ability to over-activate part of the immune system, so it could potentially lead to a vaccine that lets the adaptive immune system attack and destroy the virus — just as it would if HIV was any other pathogen.

Dr. Adriano Boasso, an immunologist and research fellow at Imperial College London, said keeping the body’s first-responder immune cells quiet could have some benefits — the whole system may not burn out so quickly, and could potentially fight off HIV.

“Think of the immune system as a car. HIV forces the car to stay in first gear, and if you do that too long, the engine is not going to last very long,” he said in an interview. “But if we take the cholesterol away, HIV is not capable of attacking the immune system quite as well. Practically, what we’ve done is turn HIV into a normal jump-start of a car.”

Viruses replicate by invading cells and hijacking their machinery, which they use to churn out new copies of their genetic material. Among the repurposed material is cholesterol, which is important in maintaining cellular fluidity, something viruses require to interact with other cells. (This is not related to the way everyone thinks of cholesterol, which is cholesterol in the blood. That type of cholesterol, made of high-density and low-density lipoproteins, is related to heart disease, not HIV and AIDS.)

HIV quickly activates plasmacytoid dendritic cells, or pDCs, which are the first immune cells that respond to the virus. PDCs produce molecules called interferons, which both interfere with the virus’ replication and also switch on adaptive immune cells, like T cells. Boasso and other researchers believe this hyperactivation weakens the secondary immune system, undermining the body’s ability to respond.

But in a new study, Boasso and colleagues show that removing the cholesterol changes HIV, so that it cannot activate the pDCs like it normally would. By preventing these first responder cells from turning on in the first place, the secondary responders — the T cells — can organize a more effective counterassault.

“Modifying the virus affects the way the immune system sees it,” Boasso said. He said it’s like removing the weapons from HIV’s arsenal: “By removing cholesterol, we can turn those little soldiers into an armorless enemy, which can be recognized by the opponent’s army.”

Emily Deal is a postdoctoral fellow at the Gladstone Institute of Virology and Immunology, which is affiliated with the University of California-San Francisco. She studies pDC activation in viral infections, and said the cholesterol removal is allowing less of the HIV into the dendritic cells in the first place — which means there’s less of the virus for the cells to detect, which leads them to produce fewer interferons.

But keeping the pDCs from turning on could be both good and bad, she said.

“What is better for the host in the long run? Is it better to suppress replication early on, but potentially have some of your T cells die? Or what are the lon-term effects of having replication proceed in the absence of interferons, but have your T cells live?” she said. "It's a complicated system."

Ideally, further studies would look at this give-and-take relationship in monkeys, so researchers could determine if a de-cholesterolized version of HIV could be an effective form of vaccine, she said.

“I think it has a shot," she said. "However, pDCs control a lot of the immune system, and if they’re not getting turned on at all, that may have other effects. If you’re trying to use it as a vaccine, it may not induce enough of a response to be protective."

Boasso said the de-cholesterolized HIV could be studied for use in a potential vaccine, but it’s difficult to stimulate the immune system to fight off an invader when the system itself is the target.

“There’s going to be a lot of work to do,” he said.

The study, which also involved researchers at Johns Hopkins University, the University of Milan and Innsbruck University, is published in the journal Blood.

Infection-fighting proteins called restriction factors, made by both cats and humans, are powerless against their respective versions of AIDS. But monkey versions of restriction factors, like the ones produced by the gene from the rhesus macaque, are able to fight HIV and FIV, as the viruses' counter-weapons are designed to fight against human or cat proteins.

The team of American and Japanese scientists injected the antiviral gene and the GFP gene into feline eggs. Almost all of the offspring from these modified eggs had the restriction factor genes, with both fluorescent and AIDS-fighting proteins made throughout their bodies. Cells taken from the animals were found to be resistant to FIV, and the team plans to eventually expose the cats themselves to the virus to see if the restriction factors will protect them. Proof that these genes can protect cats from feline AIDS would be a huge step towards figuring out how to protect humans and prevent HIV.

[BBC]

Now if we could only pay for the medicine

A handful of big-time findings were presented, but two stand out. The first major strategy under study, known as “Treatment as Prevention,” showed that when HIV-positive people were given an early start on HIV drugs, the chances of their transmitting the virus to their non-infected partners dropped by an astounding 96 percent.

The second major finding goes by the acronym PreP, for pre-exposure prophylaxis. PreP involves giving ARVs to non-infected partners of HIV-positive subjects as opposed to the infected partner. This also works with statistically significant frequency, cutting transmission by 73 percent.

PreP, however, raises ethical issues as well. When some nine million HIV-infected people the world over are in need of daily ARVs, it’s very tough to justify giving them to those who aren’t infected just to stem the spread. Which leads us to the crux of the matter: HIV/AIDS prevention needs cash to roll these ARVs out in the field, and right now free cash around the world is on the decline.

Western nations, the major source of this kind of funding, are cutting budgets. Organization like the WHO and the UN, normally the fundraisers for this kind of relief, are tightening the purse strings right at the point when it might be possible to turn back the tide on HIV, which added 2.6 million infected people to its rolls in 2009. Says the AFP: “Just to get 15 million badly-infected people on AIDS drugs by 2015, in line with the newly stated goal by UN members, will require between $22 billion and $24 billion annually.”

So as always it comes down to money. But there is hope: Just last week California-based Giliead Sciences inked a deal with the UN’s medical patent pool to allow Indian firms that specialize in generic pharmaceuticals to make cheap copies of four leading ARVs for sale in 100 poor countries. And some low doses of ARVs can be offered now in pill form for just 25 cents a day.

[AFP, New Scientist]

HIV's strongest sections could be its greatest weaknesses

HIV has been so difficult to fight in part because it is such an adept mutant. It produces sloppy copies of itself as it replicates, leading to many variations that can withstand drugs and vaccines. And it can produce 100 billion new virus particles every day, as Ed Yong points out over at Discover, which leads to lots and lots of copies. Broad-spectrum drugs or vaccines can’t do very much against a target that morphs so quickly.

But not all the pieces of HIV mutate with such abandon, according to this new study. Some groups of amino acids known as HIV sectors are somewhat less fickle, staying the same while the rest of the virus morphs, according to researchers at the Ragon Institute, a research group bridging MIT, Harvard University and Massachusetts General Hospital. Researchers believe these sites must remain unchanged for the virus to survive and replicate properly.

Researchers led by HIV research pioneer Bruce Walker and MIT chemical engineering professor Arup Chakraborty say this stalwart section of the virus can be turned against it. If the immune system can be trained to attack all the amino acid portions in an HIV sector, the virus will either have to mutate to thwart the attack — thereby undermining its structural integrity, crippling itself — or not mutate, which would render it helpless against drugs or vaccines.

This new targeted approach came from Chakraborty, who thought Walker and colleagues were too limited in their search for solutions, Yong reports. The team turned to random matrix theory, developed in the 1950s to solve nuclear physics problems and which has been used to analyze stocks, as the Wall Street Journal notes. It can pinpoint correlations between groups of objects, so it can assess how one stock is linked to other groups of stocks, for instance.

Working with HIV proteins taken from a massive database, the team used random matrix theory to analyze HIV’s genetic code and find groups of amino acids whose mutations were coordinated. The segment that mutated the least was dubbed sector 3, on an HIV sector known as Gag, which makes up HIV’s honeycombed inner shell. If the shell mutates, the honeycomb won’t lock together, and the virus would collapse.

“Multiple mutations within this sector are very rare, indicating previously unrecognized multidimensional constraints on HIV evolution,” the authors write in a paper on their research, which is published this week in the Proceedings of the National Academy of Sciences.

Incidentally, a rare group of patients who can fight HIV without drugs — known as “elite controllers” — use their own immune systems to attack sector 3.

All this suggests a new way of thinking about HIV treatment, the WSJ and others point out. Perhaps HIV drugs should dispense with the full-on assault and opt for targeted strikes instead.

Buoyed by this research, other teams are reportedly already planning new animal studies to test just that.

[via Wall Street Journal, Not Exactly Rocket Science]

The “Berlin patient,” an American citizen living in Berlin, received a stem cell transplant back in 2007 as a treatment for his leukemia. Before the transplant he received chemotherapy treatment and total body irradiation that eradicated most of his immune cells, and received further immunosuppressive drugs to prevent his body from rejecting the stem cells.

But these were no ordinary stem cells – a mutation found in just one percent of Caucasians in northern and western Europe causes CD4 cells to lack the CCR5 receptor, a receptor necessary for early-stage HIV to infect CD4 immune system cells. People with this mutation are more or less immune to HIV infection.

Those anti-HIV stem cells took root in the Berlin patient and repopulated there. At the same time, the host CD4 cells that hadn’t been destroyed in chemotherapy and radiation completely disappeared. After 38 months, doctors still couldn’t find HIV infection in the Berlin patient – in other words, it seems by all measures that his HIV has been cured.

Now, his road to recovery from HIV was excruciating and by no means should this single case of recovery be declared a cure. But it does provide a lot of hope and perhaps new mechanisms for deterring the spread of HIV in infected patients and perhaps, someday, a means to defeat the disease in vivo through gene therapy or transplants. More than anything, it defies the idea that HIV is incurable.

That’s not the only stem cell news coming out of Berlin this week. Researchers there have also grown the world’s first hair follicle from stem cells, creating a potential cure for baldness. We don’t mean to cheapen the HIV breakthrough by lumping it in with something so cosmetic as a cure for male pattern baldness, but rather to show just how much promise this branch of scientific research likely still holds. If researchers can find potential cures for both a life-threatening disease and a widespread condition affecting millions around the world in the same vein of science in the same week, imagine what other potentially life-changing discoveries may be hiding in stem cell science.

[aidsmap]

The women involved in the study used it only 60 percent of the time, and it was still effective -- meaning an even greater prevention rate is possible if it's used more frequently.

The study (PDF here) was published online Monday in Science.

The results still need to be confirmed, and scientists disagree about whether the protection it offers is sufficient to justify using the gel right away. But it's a major step in the fight to provide women another method besides condoms to protect themselves from infection. It's especially important in sub-Saharan Africa, where more than two-thirds of the world's HIV infections occur, according to AP.

Dr. Anthony Fauci, director of the National Institute of Allergy and Infectious Diseases, tells AP the gel marks the first time researchers have seen any microbicide make a statistically significant impact.

The gel was announced at the International AIDS Conference in Vienna, where thousands of scientists, policymakers and activists are gathered. The next few days will include announcements about new drug therapies and genetic research, as well as discussions about funding for research and prevention.

The study involved 900 South African women who were administered a special gel spiked with the AIDS drug tenofovir. The gel cut the risk of HIV infection by 50 percent after one year of use and 39 percent after 2 1/2 years, compared to a gel that contained no medicine, according to the study. The women used the gel only 60 percent of the time, and those who used it more often had higher rates of protection. Scientists say more frequent use is key -- the gel does not need to be changed.

Of the 444 women who received a placebo gel, 60 became infected with HIV, versus 38 infections in the 445 women who received the microbicide, Science Express reports. That's a statistically significant difference, the researchers say.

The gel is in limited supply, but 99 percent of the women in the study said they'd definitely use it if they knew it prevented the spread of HIV.

[Science, RD Magazine]

One of the antibodies suppresses 91 percent of HIV strains, more than any AIDS antibody ever discovered, according to a report on the findings published in the Wall Street Journal. The antibodies were discovered in the cells of a 60-year-old African-American gay man whose body produced them naturally. One antibody in particular is substantially different from its precursors, the Science study says.

The antibodies could be tried as a treatment for people already infected with HIV, the WSJ reports. At the very least, they might boost the efficacy of current antiretroviral drugs.

A vaccine for HIV, the virus that causes AIDS, would likely work by activating the body's own ability to produce antibodies that would ward off the disease. The latest discovery is more promising than a trial in Thailand last year in which scientists said an HIV vaccine reduced the chances of infection by just 30 percent. That study had also been plagued with controversy because in one analysis, the results were not statistically significant.

The WSJ says the new discovery -- involving scientists from the National Institutes of Health, Harvard Medical School, Howard Hughes Medical Institute and Columbia University -- is part of a renaissance in HIV vaccine research, which will be in focus later this month in Vienna, home to this year's International AIDS Conference.

It is welcome news for the the 33 million people the United Nations estimated were living with AIDS at the end of 2008.

The WSJ outlines the painstaking method the team used to find the antibody amid the cells of the African-American man, known as Donor 45. First they designed a probe that looks just like a spot on a particular molecule on the cells that HIV infects. Then they used the probe to attract only the antibodies that efficiently attack that spot. They screened 25 million of Donor 45's cells to find just 12 cells that produced the antibodies.

Scientists have already discovered plenty of antibodies that either don't work at all or only work on a couple HIV strains. Last year marked the first time that researchers found "broadly neutralizing antibodies," which knock out many HIV strains. But none of those antibodies neutralized more than about 40 percent of them, the WSJ says. The newest antibody, at 91 percent neutralization, is a marked improvement.

Still, more work needs to be done to ensure the antibodies would activate the immune system to produce natural defenses against AIDS, the study authors say. They suggest three test methods that blend the three new antibodies together -- in raw form to prevent transmission of the virus, such as from mother to child; in a microbicide gel that women or gay men could use before sex to prevent infection; or as a treatment for HIV/AIDS, combined with antiretroviral drugs.

If the scientists can find the right way to stimulate production of the antibodies, they think most people could produce them, the WSJ says.

[Wall Street Journal, Science]