http://www.sciencecodex.com/like_a_transforme...ds_for_new_function-95267

New research has shown that a protein does something that scientists once thought impossible: It unfolds itself and refolds into a completely new shape. This protein, called RfaH, activates genes that allow bacterial cells to launch a successful attack on their host, causing disease. The researchers determined that RfaH starts out in its alpha form, composed of two spiral shapes. Later, in its beta form, it resembles spokes on a wheel and is called a barrel. When RfaH refolds, it acquires a new function – yet another finding that researchers would not have predicted. "We showed that RfaH refolds, which is a big enough deal already. You would think this is impossible. That's what you're told in school," said Irina Artsimovitch, professor of microbiology at Ohio State University and a lead author of the study. "But in this case, it's even better than that because we show that when RfaH refolds, it acquires a new function. It can do something that it couldn't do before." [...] The findings have significant implications for studies of gene expression control and protein structure. This remarkable ability to refold suggests that RfaH and similar proteins might be able to bind in ways and to other molecules that had never been considered. Scientists who engineer proteins might have an entirely new step to add to their models. And now that the first case of a complete alpha to beta structural change has been demonstrated, chances are good that researchers will find other proteins that can do the same thing. [...]

At the time of this study, the scientific community considered RfaH a transcription factor – a molecule that binds to specific DNA sequences to control the movement of genetic information from DNA to messenger RNA. Messenger RNA, also known as mRNA, carries those protein-building instructions as the gene expression process continues. Artsimovitch and colleagues recently determined that RfaH closes a critical gap in the enzyme RNA polymerase, allowing it to maintain its grip on DNA and start the activation of genes. RNA polymerase is responsible for setting gene expression in motion in all cells by wrapping itself around the double helix of DNA, using one strand to match nucleotides and make a copy of genetic material. But the researchers observed that when RfaH binds to DNA and RNA polymerase, its two halves separate, with one remaining bound to the enzyme and another holding on with just a string of a few amino acids. And then it refolds into a completely different shape. This new work shows that refolding allows RfaH to participate in translation, a completely different step in gene expression. During translation, a molecule called a ribosome binds to mRNA and uses its instructions to select amino acids and join them into chains, which then fold to compose proteins, the final products of gene expression. [...] Research had long ago established that RfaH was a transcription factor, and that this function is universally conserved – meaning it is present for this role in all living organisms and has been for generations. But this new research shows that RfaH is even more effective as a translation factor – about 100 times more powerful than it is as a transcription factor [...]

http://www.sciencecodex.com/mouse_with_human_...iv_vaccine_research-95186

Mouse with human immune system may revolutionize HIV vaccine research [...] "Our study showed not only that these humanized mice mount human immune responses against HIV but also that the ability of HIV to evade these responses by mutating viral proteins targeted by CD8 'killer' T cells is accurately reflected in these mice," says Todd Allen, PhD, senior author of the report. "For the first time we have an animal model that accurately reproduces critical host-pathogen interactions, a model that will help facilitate the development an effective vaccine for HIV." [...] Six weeks after the mice had been infected with HIV, the researchers found that the virus was rapidly evolving in regions known to be targeted by CD8 T cells. Their observation indicated that not only were the humanized mouse immune systems responding to HIV but also that the virus was mutating to avoid those responses in a manner similar to what is seen in humans. In mice expressing the protective HLA-B57 allele, just as in human patients who control viral levels, CD8 responses were directed against an essential region of the virus, preventing viral mutation and allowing the animals to more effectively contain HIV. "We now know that these mice appear to replicate the specificity of the human cellular response to HIV and that the virus is attempting to evade these responses just as it does in humans," says Allen, an associate professor of Medicine at Harvard Medical School. "We are currently studying whether we can induce human HIV-specific immune responses in these animals by vaccination, which would provide a rapid, cost-effective model to test the ability of different vaccine approaches to control or even block HIV infection. If we can do this, we'll have a very powerful new tool to accelerate HIV vaccine development, one that also may be useful against other pathogens."

http://www.boston.com/lifestyle/health/2012/0...eh0eM1IvL/singlepage.html

WASHINGTON (AP) — Science now has the tools to slash the spread of HIV even without a vaccine — and the U.S. is donating an extra $150 million to help poor countries put them in place, the Obama administration told the world’s largest AIDS conference Monday.

‘‘We want to get to the end of AIDS,’’ declared the top U.S. HIV researcher, Dr. Anthony Fauci of the National Institutes of Health. [...]

Some 34.2 million people worldwide are living with HIV, and 2.5 million were infected last year.

Secretary of State Hillary Rodham Clinton said the goal is an AIDS-free generation. That would mean no babies would be born infected, young people would have a much lower risk than today of becoming infected and people who already have HIV would receive life-saving drugs so they wouldn’t develop AIDS or spread the virus.

‘‘I am here today to make it absolutely clear the U.S. is committed and will remain committed to achieving an AIDS-free generation,’’ Clinton told the more than 20,000 scientists, people living with HIV and policymakers assembled for the conference.

But it will require smart targeting of prevention tools where they can have the greatest effect. ‘‘If we want to save more lives, we need to go where the virus is,’’ she said.

First, Clinton said it’s possible to virtually eliminate the transmission of HIV from infected pregnant women to their babies by 2015, by getting the mothers onto anti-AIDS drugs. HIV-infected births are rare in the United States and are dropping steadily worldwide, although some 330,000 children became infected last year. Clinton said the U.S. has invested more than $1 billion toward that goal in recent years and is providing an extra $80 million to help poor countries finish the job.

Much of the AIDS conference is focused on how to get treatment to all people with HIV, because good treatment can cut by 96 percent their chances of spreading the virus to sexual partners. Fauci pointed to South Africa, where healthy people who live in a region that has increased medication now have a 38 percent lower risk of infection compared with neighbors in an area where HIV treatment is less common.

Drugs aren’t the only effective protection. Fauci said male circumcision is ‘‘stunningly successful,’’ too, at protecting men from becoming infected by a heterosexual partner. Clinton said the U.S. will provide $40 million to help South Africa reach its goal of providing voluntary circumcision to half a million boys and men this year.

A tougher issue is how best to reach particularly high-risk populations: gay and bisexual men, sex workers and injecting drug users. In many countries, stigma and laws that make their activities illegal drive those populations away from AIDS programs that could teach them how to reduce their risk of infection, Clinton said.

‘‘If we’re going to beat AIDS, we can’t afford to avoid sensitive conversations, and we can’t afford not to reach the people who are at the highest risk,’’ she said.

So the U.S. will spend an additional $15 million on research to identify the best HIV prevention tools to reach those key populations in different countries, and then launch a $20 million challenge fund to support country-led efforts to implement that science.

Better prevention for gay and bisexual men is a huge issue in the U.S. as well — and a striking study presented Monday added evidence that those men are especially at risk if they’re young and black.

Government-funded researchers tracked black gay and bisexual men in six U.S. cities and found that 2.8 percent a year are becoming infected, a rate 50 percent higher than their white counterparts. Worse, the rate was nearly 6 percent a year in those men who are 30 or younger.

Phill Wilson of the Black AIDS Institute said these men are engaged ‘‘in a raging epidemic’’ that doesn’t get enough attention. He estimated that nearly 60 percent of black gay men are infected by age 40.

The world spent $16.8 billion fighting AIDS in poor countries, the hardest-hit, last year, and the United States is the leading donor.

But Bill Gates, the Microsoft founder and philanthropist, said the world is facing incredible uncertainty about whether wealthy nations will continue funding AIDS programs with the same vigor as in the past.

‘‘As these budget tradeoffs are made, the voices of the AIDS community and the global health community are going to have to be louder than ever,’’ said Gates, whose Bill & Melinda Gates Foundation has pledged more than $1 billion to global AIDS efforts.

Another $7 billion a year is needed to get to 15 million people in low- and middle-income countries by 2015, a United Nations goal. A record 8 million received potentially life-saving drugs last year.

‘‘This gap is killing people,’’ UNAIDS chief Michel Sidibe told the conference. ‘‘My friends, the end of AIDS is not free. It is not too expensive. It is priceless.’’

The prices of generic AIDS drugs in developing countries are dropping every year. One philanthropy, the Clinton Health Access Initiative, said 70 countries in Africa, Asia, Eastern Europe, Latin America and the Caribbean that participate in its drug-procurement program now can purchase the main combination for less than $200 a year. [...]

http://www.washingtonpost.com/national/health.../23/gJQA9TJt4W_story.html

[...] leaders in AIDS vaccine research say they may finally be on the cusp of a period of major discovery leading to a vaccine. [...] “broadly neutralizing” antibodies bind powerfully to HIV’s outer shell and prevent the virus from invading cells. Until recently, scientists had been able to identify only four such antibodies. But in the past three years, they have worked out the structures of nearly two dozen, and they have developed the technology to find more. [...] there are vulnerable regions in HIV’s shape-shifting armor that persist across all strains, scientists say. The one garnering most interest is called “Env,” short for “envelope glycoprotein.” Resembling spikes on the virus’s surface, each Env can bind to a white blood cell called the CD4 T cell and then pull the whole virus inside. [...] the four known antibodies, though potent, were not ideal for a vaccine — and for nearly two decades, from 1992 to 2009, scientists couldn’t find any more. Then, through a combined effort of researchers at Burton’s program and Nabel’s center, that began to change. Burton’s team led the way, discovering two new antibodies, dubbed PG9 and PG16 that are at least 10 times more effective at latching on to HIV and disabling it than any of the previous four antibodies. Three more antibodies emerged in 2010. The best of them, named VRC01, is effective against up to 90 percent of HIV strains circulating around the world. Last year, 17 more were found. Called the PGT family, these antibodies are 100 times more potent than the pre-2009 antibodies. “The fact that a single antibody can neutralize over 90 percent of circulating HIV-1 isolates is unreal,” said Peter Kwong, a scientist at Scripps involved in the vaccine initiative. [...] The next step, Burton said, is to figure out which combinations of broadly neutralizing antibodies can best work together against the greatest number of HIV strains. Then, scientists can begin to design a vaccine that would trigger the immune system to produce this combination on its own. [...]

Hi Michael2901,

Thank you for sharing the news about this very important discovery from Bruce Torbett's lab. The labs of Bruce Torbett, M.G. Finn, Valery Fokin, Dave Stout, and John Elder all collaborate with the FightAIDS@Home team. See:

http://fightaidsathome.scripps.edu/team.html


You are correct--you and the other World Community Grid participants might be asked to help advance this line of research in the future. Although we have only targeted HIV protease and HIV integrase on FightAIDS@Home thus far, we are definitely considering plans to expand this project to include other types of drug targets from HIV. We will let you know if/when we start performing calculations against nucleocapsid and other proteins from HIV. Stay tuned to:

http://fightaidsathome.scripps.edu/status

for these types of details.

Best wishes,
Alex L. Perryman, Ph.D.