Biologists deliver neutralizing antibodies that protect against HIV infection in mice

ScienceDaily (Nov. 30, 2011) — Over the past year, researchers at the California Institute of Technology (Caltech), and around the world, have been studying a group of potent antibodies that have the ability to neutralize HIV in the lab; their hope is that they may learn how to create a vaccine that makes antibodies with similar properties. Now, biologists at Caltech led by Nobel Laureate David Baltimore, president emeritus and Robert Andrews Millikan Professor of Biology, have taken one step closer to that goal: they have developed a way to deliver these antibodies to mice and, in so doing, have effectively protected them from HIV infection.

This new approach to HIV prevention -- called Vectored ImmunoProphylaxis, or VIP -- is outlined in the November 30 advance online publication of the journal Nature.

Traditional efforts to develop a vaccine against HIV have been centered on designing substances that provoke an effective immune response -- either in the form of antibodies to block infection or T cells that attack infected cells. With VIP, protective antibodies are being provided up front.

"VIP has a similar effect to a vaccine, but without ever calling on the immune system to do any of the work," says Alejandro Balazs, lead author of the study and a postdoctoral scholar in Baltimore's lab. "Normally, you put an antigen or killed bacteria or something into the body, and the immune system figures out how to make an antibody against it. We've taken that whole part out of the equation."

Because mice are not sensitive to HIV, the researchers used specialized mice carrying human immune cells that are able to grow HIV. They utilized an adeno-associated virus (AAV) -- a small, harmless virus that has been useful in gene-therapy trials -- as a carrier to deliver genes that are able to specify antibody production. The AAV was injected into the leg muscle of mice, and the muscle cells then put broadly neutralizing antibodies into the animals' circulatory systems. After just a single AAV injection, the mice produced high concentrations of these antibodies for the rest of their lives, as shown by intermittent sampling of their blood. Remarkably, these antibodies protected the mice from infection when the researchers exposed them to HIV intravenously.

The team points out that the leap from mice to humans is large -- the fact that the approach works in mice does not necessarily mean it will be successful in humans. Still, the researchers believe that the large amounts of antibodies that the mice were able to produce -- coupled with the finding that a relatively small amount of antibody has proved protective in the mice -- may translate into human protection against HIV infection.

"We're not promising that we've actually solved the human problem," says Baltimore. "But the evidence for prevention in these mice is very clear."

The paper also notes that in the mouse model, VIP worked even in the face of increased exposure to HIV. To test the efficacy of the antibody, the researchers started with a virus dose of one nanogram, which was enough to infect the majority of the mice who received it. When they saw that the mice given VIP could withstand that dose, they continued to bump it up until they were challenging them with 125 nanograms of virus.

"We expected that at some dose, the antibodies would fail to protect the mice, but it never did -- even when we gave mice 100 times more HIV than would be needed to infect 7 out of 8 mice," says Balazs. "All of the exposures in this work were significantly larger than a human being would be likely to encounter."

He points out that this outcome likely had more to do with the properties of the antibody that was tested than the method, but adds that VIP is what enabled the large amount of this powerful antibody to circulate through the mice and fight the virus. Furthermore, VIP is a platform technique, meaning that as more potent neutralizing antibodies are isolated or developed for HIV or other infectious organisms, they can also be delivered using this method.

"If humans are like mice, then we have devised a way to protect against the transmission of HIV from person to person," says Baltimore. "But that is a huge if, and so the next step is to try to find out whether humans behave like mice."

He says the team is currently in the process of developing a plan to test their method in human clinical trials. The initial tests will ask whether the AAV vector can program the muscle of humans to make levels of antibody that would be expected to be protective against HIV.

"In typical vaccine studies, those inoculated usually mount an immune response -- you just don't know if it's going to work to fight the virus," explains Balazs. "In this case, because we already know that the antibodies work, my opinion is that if we can induce production of sufficient antibody in people, then the odds that VIP will be successful are actually pretty high."

The study, "Antibody-based Protection Against HIV Infection by Vectored ImmunoProphylaxis," was funded by the Bill and Melinda Gates Foundation, the National Institutes of Health, and the Caltech-UCLA Joint Center for Translational Medicine. Caltech biology researchers Joyce Chen, Christin M. Hong, and Lili Yang also contributed to the paper, as well as Dinesh Rao, a hematologist from the University of California, Los Angeles.

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Journal Reference:

Alejandro B. Balazs, Joyce Chen, Christin M. Hong, Dinesh S. Rao, Lili Yang, David Baltimore. Antibody-based protection against HIV infection by vectored immunoprophylaxis. Nature, 2011; DOI: 10.1038/nature10660

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Do bacteria age? Biologists discover the answer follows simple economics

ScienceDaily (Oct. 27, 2011) — When a bacterial cell divides into two daughter cells and those two cells divide into four more daughters, then 8, then 16 and so on, the result, biologists have long assumed, is an eternally youthful population of bacteria. Bacteria, in other words, don't age -- at least not in the same way all other organisms do.

But a study conducted by evolutionary biologists at the University of California, San Diego questions that longstanding paradigm. In a paper published in the November 8 issue of the journal Current Biology, they conclude that not only do bacteria age, but that their ability to age allows bacteria to improve the evolutionary fitness of their population by diversifying their reproductive investment between older and more youthful daughters. An advance copy of the study appears this week in the journal's early online edition.

"Aging in organisms is often caused by the accumulation of non-genetic damage, such as proteins that become oxidized over time," said Lin Chao, a professor of biology at UC San Diego who headed the study. "So for a single celled organism that has acquired damage that cannot be repaired, which of the two alternatives is better -- to split the cellular damage in equal amounts between the two daughters or to give one daughter all of the damage and the other none?"

The UC San Diego biologists' answer -- that bacteria appear to give more of the cellular damage to one daughter, the one that has "aged," and less to the other, which the biologists term "rejuvenation" -- resulted from a computer analysis Chao and colleagues Camilla Rang and Annie Peng conducted on two experimental studies. Those studies, published in 2005 and 2010, attempted unsuccessfully to resolve the question of whether bacteria aged. While the 2005 study showed evidence of aging in bacteria, the 2010 study, which used a more sophisticated experimental apparatus and acquired more data than the previous one, suggested that they did not age.

"We analyzed the data from both papers with our computer models and discovered that they were really demonstrating the same thing," said Chao. "In a bacterial population, aging and rejuvenation goes on simultaneously, so depending on how you measure it, you can be misled to believe that there is no aging."

In a separate study, the UC San Diego biologists filmed populations of E. coli bacteria dividing over hundreds of generations and confirmed that the sausage-shaped bacteria divided each time into daughter cells that grew elongated at different rates -- suggesting that one daughter cell was getting all or most of the cellular damage from its mother while the other was getting little or none. Click this link to watch the time-lapse film of one bacterium dividing over 10 generations into 1,000 bacteria in a period of five hours and see if you can see any differences.

"We ran computer models and found that giving one daughter more the damage and the other less always wins from an evolutionary perspective," said Chao. "It's analogous to diversifying your portfolio. If you could invest $1 million at 8 percent, would that provide you with more money than splitting the money and investing $500,000 at 6 percent and $500,000 at 10 percent?"

"After one year it makes no difference," he added. "But after two years, splitting the money into the two accounts earns you more and more money because of the compounding effect of the 10 percent. It turns out that bacteria do the same thing. They give one daughter a fresh start, which is the higher interest-bearing account and the other daughter gets more of the damage."

Although E. coli bacteria appear to divide precisely down the middle into two daughter cells, the discovery that the two daughters eventually grow to different lengths suggests that bacteria do not divide as symmetrically as most biologists have come to believe, but that their division is really "asymmetrical" within the cell.

"There must be an active transport system within the bacterial cell that puts the non-genetic damage into one of the daughter cells," said Chao. "We think evolution drove this asymmetry. If bacteria were symmetrical, there would be no aging. But because you have this asymmetry, one daughter by having more damage has aged, while the other daughter gets a rejuvenated start with less damage."

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The above story is reprinted from materials provided by University of California - San Diego. The original article was written by Kim McDonald.

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Journal Reference:

Camilla U. Rang, Annie Y. Peng, Lin Chao. Temporal Dynamics of Bacterial Aging and Rejuvenation. Current Biology, 27 October 2011 DOI: 10.1016/j.cub.2011.09.018

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Building better HIV antibodies: Biologists create neutralizing antibody that shows increased potency

ScienceDaily (Oct. 27, 2011) — Using highly potent antibodies isolated from HIV-positive people, researchers have recently begun to identify ways to broadly neutralize the many possible subtypes of HIV. Now, a team led by biologists at the California Institute of Technology (Caltech) has built upon one of these naturally occurring antibodies to create a stronger version they believe is a better candidate for clinical applications.

Current advances in isolating antibodies from HIV-infected individuals have allowed for the discovery of a large number of new, broadly neutralizing anti-HIV antibodies directed against the host receptor (CD4) binding site -- a functional site on the surface of the virus that allows for cell entry and infection. Using a technique known as structure-based rational design, the team modified one already-known and particularly potent antibody -- NIH45-46 -- so that it can target the binding site in a different and more powerful way. A study outlining their process was published in the Oct. 27 issue of Science Express.

"NIH45-46 was already one of the most broad and potent of the known anti-HIV antibodies," says Pamela Bjorkman, Max Delbrück Professor of Biology at Caltech and senior author on the study. "Our new antibody is now arguably the best of the currently available, broadly neutralizing anti-HIV antibodies."

By conducting structural studies, the researchers were able to identify how NIH45-46 interacted with gp120 -- a protein on the surface of the virus that's required for the successful entry of HIV into cells -- to neutralize the virus. Using this information, they were able to create a new antibody (dubbed NIH45-46G54W) that is better able to grab onto and interfere with gp120. This improves the antibody's breadth -- or extent to which it effectively targets many subtypes of HIV -- and potency by an order of magnitude, according to Ron Diskin, a postdoctoral scholar in Bjorkman's lab at Caltech and the paper's lead author.

"Not only did we design an improved version of NIH45-46, our structural data are calling into question previous assumptions about how to make a vaccine in order to elicit such antibodies," says Diskin. "We hope that these observations will help to guide and improve future immunogen design."

By improving the efficacy of antibodies that can neutralize HIV, the researchers point to the possibility of clinical testing for NIH45-46G54W and other antibodies as therapeutic agents. It's also plausible that understanding effective neutralization by powerful antibodies may be useful in vaccine development.

"The results uncover the structural underpinnings of anti-HIV antibody breadth and potency, offer a new view of neutralization by CD4-binding site anti-HIV antibodies, and establish principles that may enable the creation of a new group of HIV therapeutics," says Bjorkman, who is also a Howard Hughes Medical Institute investigator.

Other Caltech authors on the study, "Increasing the Potency and Breadth of an HIV Antibody by Using Structure-Based Rational Design," include Paola M. Marcovecchio, Anthony P. West, Jr., Han Gao, and Priyanthi N.P. Gnanapragasm. Johannes Scheid, Florian Klein, Alexander Abadir, and Michel Nussenweig from Rockefeller University, and Michael Seaman from Beth Israel Deaconess Medical Center in Boston also contributed to the paper. The research was funded by the Bill & Melinda Gates Foundation, the National Institutes of Health, the Gordon and Betty Moore Foundation, and the German Research Foundation.

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The above story is reprinted from materials provided by California Institute of Technology. The original article was written by Katie Neith.

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Journal Reference:

Ron Diskin, Johannes F. Scheid, Paola M. Marcovecchio, Anthony P. West, Jr., Florian Klein, Han Gao, Priyanthi N. P. Gnanapragasam, Alexander Abadir, Michael S. Seaman, Michel C. Nussenzweig, Pamela J. Bjorkman. Increasing the Potency and Breadth of an HIV Antibody by Using Structure-Based Rational Design. Science, Published online Oct. 27, 2011 DOI: 10.1126/science.1213782

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