Building Better HIV Antibodies: Biologists Create Neutralizing Antibody That Shows Increased Potency

The increased potency of a new HIV antibody (green and blue) is explained by an insertion (pink) that contacts the inner domain of the HIV gp120 spike protein (yellow). 

Science Daily  — 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 more potent version they believe is a better candidate for clinical applications.

"NIH45-46 was already one of the broadest and most 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 currently available, broadly neutralizing anti-HIV antibodies."

Current advances in isolating antibodies from HIV-infected individuals have allowed for the discovery of many new, broadly neutralizing anti-HIV antibodies directed against the host receptor (CD4) binding site -- a functional site on the virus's surface 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 -- to target the binding site differently and more powerfully. A study outlining their process was published in the Oct. 27 issue of Science Express.

By conducting structural studies, the researchers could identify how NIH45-46 interacted with gp120 -- a protein on the surface of the virus required for the triumphant entry of HIV into cells -- to neutralize the virus. Using this information, they created a new antibody (dubbed NIH45-46^G54W) that is better able to grab onto and interfere with gp120. This improves the antibody's breadth -- or the extent to which it effectively targets many subtypes of HIV -- and potency by 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 to elicit such antibodies," says Diskin. "We hope these observations will help 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 NIH45-46^G54W and other antibodies as therapeutic agents. Understanding effective neutralization by potent antibodies may be helpful 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, Michel Nussenweig from Rockefeller University, and Michael Seaman from Beth Israel Deaconess Medical Center in Boston also contributed to the paper. The Bill & Melinda Gates Foundation, the National Institutes of Health, the Gordon and Betty Moore Foundation, and the German Research Foundation funded the research.

Do Bacteria Age? Biologists Discover the Answer Follows Simple Economics

 by Biomechanism

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. This week, an advance copy of the study appears 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 per cent, 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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Scientists identify first stem cell key to lung regeneration

 by Biomechanism 

“Working together, scientists and clinicians make research breakthrough that paves the way for novel therapies for respiratory diseases”

Scientists at A*STAR’S Genome Institute of Singapore (GIS) and Institute of Molecular Biology (IMB), have made a breakthrough discovery in the understanding of lung regeneration. Their research showed for the first time that distal airway stem cells (DASCs), a specific type of stem cells in the lungs, are involved in forming new alveoli to replace and repair damaged lung tissue, providing a firm foundation for understanding lung regeneration.

Lung damage is caused by a wide range of lung diseases including influenza infections and chronic respiratory diseases such as chronic obstructive pulmonary disease (COPD). Influenza infection induces acute respiratory distress syndrome (ARDS) which affects more than 150,000 patients a year in the US, with a death rate of up to 50 percent. COPD is the fifth biggest killer worldwide.

The team took a novel approach in tackling the question of lung regeneration. They cloned adult stem cells taken from three different parts of the lungs – nasal epithelial stem cells (NESCs), tracheal airway stem cells (TASCs) and distal airway stem cells (DASCs). Despite the three types of cells being nearly 99 percent genetically identical, the team made the surprising observation that only DASCs formed alveoli when cloned in vitro.

“We are the first researchers to demonstrate that adult stem cells are intrinsically committed and will only differentiate into the specific cell type they originated from. In this case, only DASCs formed alveoli because alveolar cells are found in the distal airways, not in the nasal epithelial or tracheal airway”, said Dr Wa Xian, Principal Investigator at IMB. “This is a big advancement in the understanding of adult stem cells that will encourage further research into their potential for regenerative medicine.”

Using a mouse model of influenza, the team showed that after infection, DASCs rapidly grow and migrate to influenza-damaged lung areas where they form “pods”. These “pods” mature to new alveoli which replace the alveoli that were destroyed by the infection, leading to lung regeneration.

“We have harvested these “pods” to provide insight into genes and secreted factors that likely represent key components in tissue regeneration.

These secreted factors might be used as biological drugs (biologics) to enhance regeneration of the lung and airways,” said Dr Frank McKeon, Senior Group Leader of the Stem Cell and Developmental Biology at GIS.

The research was jointly led by Dr Frank McKeon from GIS and Dr Wa Xian from IMB in collaboration with scientists at the National University of Singapore (NUS), and clinicians at the Harvard Medical School and the Brigham and Women’s Hospital in Boston.

Prof Birgitte Lane, Executive Director of IMB, said, “This groundbreaking work is a fine example of collaborative research, which has brought us new insight into lung epithelial stem cells. This will have breakthrough consequences in many areas.” Dr Edison Liu, Executive Director of GIS, added, “We will continue to seek impactful collaborations and build upon this research area where there is a need for novel therapies, which will offer hope for patients suffering from respiratory diseases.”

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Biomechanism.com is an online resource site regularly publishing the latest research news and events in biology, science, engineering, agriculture, health, and much more.  If you are interested in all current research studies, check out the two most popular research topics below: