Scientists Reveal Surprising Picture of How Powerful Antibody Neutralizes HIV

This is the PGT 128 antibody in action. (Credit: Image courtesy of the Wilson lab, The Scripps Research Institute)

Science Daily  — Researchers at The Scripps Research Institute have uncovered the surprising details of how a powerful anti-HIV antibody grabs hold of the virus. The findings, published inScience Express on October 13, 2011, highlight a major vulnerability of HIV and suggest a new target for vaccine development.

"We can now start to think about constructing mimics of these viral structures to use in candidate vaccines," said co-senior author Ian Wilson, who is Hansen Professor of Structural Biology and member of the Skaggs Institute for Chemical Biology at Scripps Research.

"What's unexpected and unique about this antibody is that it not only attaches to the sugar coating of the virus but also reaches through to grab part of the virus's envelope protein," said the report's co-senior author Dennis Burton, a professor at The Scripps Research Institute and scientific director of the International AIDS Vaccine Initiative's (IAVI) Neutralizing Antibody Center, based on the Scripps Research La Jolla campus.

Other institutions in the United States, United Kingdom, Japan, and the Netherlands contributed to the research as part of an ongoing global HIV vaccine development effort.

Getting a Better Grip on HIV

Researchers from the current team recently isolated the new antibody and 16 others from the blood of HIV-infected volunteers, in work they reported online in the journal Nature on August 17, 2011. Since the 1990s, Burton, Wilson, and other researchers have been searching for such "broadly neutralizing" antibodies against HIV -- antibodies that work against many of the various strains of the fast-mutating virus -- and by now have found more than a dozen. PGT 128, the antibody described in the new report, can neutralize about 70 percent of globally circulating HIV strains by blocking their ability to infect cells. It also can do so much more potently -- in other words, in smaller concentrations of antibody molecules -- than any previously reported broadly neutralizing anti-HIV antibody.

The new report illuminates why PGT 128 is so effective at neutralizing HIV. Using the Wilson lab's expertise in X-ray crystallography, Robert Pejchal, a research associate in the Wilson lab, determined the structure of PGT 128 joined to its binding site on molecular mockups of the virus, designed in part by Robyn Stanfield and Pejchal in the Wilson group and Bill Schief, now an IAVI principal scientist and associate professor at Scripps Research, and his group. With these structural data, and by experimentally mutating and altering the viral target site, they could see that PGT 128 works in part by binding to glycans on the viral surface.

Thickets of these sugars normally surround HIV's envelope protein, gp120, largely shielding it from attack by the immune system. Nevertheless, PGT 128 manages to bind to two closely spaced glycans, and at the same time reaches through the rest of the "glycan shield" to take hold of a small part of structure on gp120 known as the V3 loop. This penetration of the glycan shield by PGT 128 was also visualized by electron microscopy with a trimeric form of the gp120/gp41 envelope protein of HIV-1 by Reza Kayat and Andrew Ward of Scripps Research; this revealed that the PGT 128 epitope appears to be readily accessible on the virus.

"Both of these glycans appear in most HIV strains, which helps explain why PGT 128 is so broadly neutralizing," said Katie J. Doores, a research associate in the Burton lab who was one of the report's lead authors. PGT 128 also engages V3 by its backbone structure, which doesn't vary as much as other parts of the virus because it is required for infection.

PGT 128's extreme potency is harder to explain. The antibody binds to gp120 in a way that presumably disrupts its ability to lock onto human cells and infect them. Yet it doesn't bind to gp120 many times more tightly than other anti-HIV antibodies. The team's analysis hints that PGT 128 may be extraordinarily potent because it also binds two separate gp120 molecules, thus tying up not one but two cell-infecting structures. Other mechanisms may also be at work.

Toward an AIDS Vaccine

Researchers hope to use the knowledge of these antibodies' binding sites on HIV to develop vaccines that stimulate a long-term -- perhaps lifetime -- protective antibody response against those same vulnerable sites.

"We'll probably need multiple targets on the virus for a successful vaccine, but certainly PGT 128 shows us a very good target," said Burton.

Intriguingly, the basic motif of PGT 128's target may mark a general vulnerability for HIV. "Other research is also starting to suggest that you can grab onto two glycans and a beta strand and get very potent and broad neutralizing antibodies against HIV," Wilson said.

In addition to Pejchal, Doores, and Khayat, Laura M. Walker of Scripps Research and Po-Ssu Huang of University of Washington at Seattle were co-first authors of the study, "A potent and broad neutralizing antibody recognizes and penetrates the HIV glycan shield." Along with Wilson, Burton, and Ward, additional contributors were Sheng-Kai Wang, Chi-Huey Wong, Robyn L. Stanfield, Jean-Philippe Julien, Alejandra Ramos, Ryan McBride, and James C. Paulson of Scripps Research, and Pascal Poignard, and William R. Schief of Scripps Research, IAVI and University of Washington at Seattle; Max Crispin and Christopher N. Scanlan of the University of Oxford; Rafael Depetris and John P. Moore of Weill Medical College of Cornell University; Umesh Katpally, Andre Marozsan, Albert Cupo, and William C. Olson of Progenics Pharmaceuticals; Sebastien Maloveste of the National Institute of Allergy and Infectious Diseases at the National Institutes of Health; Yan Liu and Ten Feizi of Imperial College, London; Yukishige Ito of the RIKEN Advanced Science Institute in Japan; and Cassandra Ogohara of University of Washington at Seattle.

The research was supported by the International AIDS Vaccine Initiative, National Institutes of Health, the U.S. Department of Energy, the Canadian Institutes of Health Research, the UK Research Councils, the Ragon Institute, and other organizations.

How the Milky Way Killed Off Nearby Galaxies

Science Daily  — Two researchers from Observatoire Astronomique de Strasbourg have revealed for the first time the existence of a new signature of the birth of the first stars in our galaxy, the Milky Way. More than 12 billion years ago, the intense ultraviolet light from these stars dispersed the gas of our Galaxy's nearest companions, virtually halting their ability to form stars and consigning them to a dim future. Now Pierre Ocvirk and Dominique Aubert, members of the Light in the Dark Ages of the Universe (LIDAU) collaboration, have explained why some galaxies were killed off, while stars continued to form in more distant objects.

The first stars of the Universe appeared about 150 million years after the Big Bang. Back then, the hydrogen and helium gas filling the universe was cold enough for its atoms to be electrically neutral. As the ultraviolet (UV) light of the first stars propagated through this gas, it broke apart the proton-electron pairs that makeup hydrogen atoms, returning them to the so-called plasma state they experienced in the first moments of the Universe. This process, known as reionisation, also resulted in significant heating, which had dramatic consequences: the gas became so hot that it escaped the weak gravity of the lowest mass galaxies, thereby depriving them of the material needed to form stars.The two scientists publish their results in the October issue of the letters of the journal Monthly Notices of the Royal Astronomical Society.

It is now widely accepted that this process can explain the small number and large ages of the stars seen in the faintest dwarf galaxy satellites of the Milky Way. It also helps scientists understand why galaxies like the Milky Way have so few satellites around them -- the 'missing satellites' problem. The stripping out of gas from these galaxies makes them sensitive probes of the UV radiation in the reionisation epoch.

The satellite galaxies are also relatively close, from 30000 to 900000 light-years away, which allows us to study them in great detail, something that will be enhanced by the coming generation of larger telescopes. Comparing the population of their stars in each galaxy with its position could give us a unique insight into the structure of the UV radiation emitted from the earliest stars in the Milky Way.

Until now, models for this process assumed that the radiation leading to the removal of gas from galaxy satellites was produced collectively by all the large galaxies nearby, resulting in a uniform background of UV light. The new model put together by the two French researchers proves this assumption wrong.

Ocvirk and Aubert looked at the way the invisible 'dark matter' that makes up about 23% of the Universe structured itself with the stars in our Galaxy and its environs from shortly after the Big Bang to the present day. They used the high resolution numerical simulation Via Lactea II to model the formation of stars in gas trapped in the dark matter haloes that envelop galaxies, and then to describe how this gas reacted to UV radiation.

Pierre Ocvirk comments, "This is the first time that a model accounts for the effect of the radiation emitted by the first stars formed at the centre of the Milky Way on its satellite galaxies.

'In contrast to previous models, the radiation field produced is not uniform, but decreases in intensity as one moves away from the centre of the Milky Way.

'The satellite galaxies close to the galactic centre see their gas evaporate very quickly. They form so few stars that they can be undetectable with current telescopes. At the same time, the more remote satellite galaxies experience on average a weaker irradiation. Therefore they manage to keep their gas longer, and form more stars. As a consequence they are easier to detect and appear more numerous."

The new model appears to be a close match to observations of our Galaxy and its neighbourhood and suggests that the first stars of our galaxy played a major role in the photo-evaporation of the satellite galaxies' gas, adds Dr Ocvirk. "It is not large nearby galaxies but our own that caused the demise of its tiny neighbours, asphyxiating them through its intense radiation."

Computing Building Blocks Created from Bacteria and DNA

Scientists have successfully demonstrated that they can build some of the basic components for digital devices out of bacteria and DNA, which could pave the way for a new generation of biological computing devices. (Credit: Janice Haney Carr)

Science Daily  — Scientists have successfully demonstrated that they can build some of the basic components for digital devices out of bacteria and DNA, which could pave the way for a new generation of biological computing devices, in research published October 18 in the journal Nature Communications.

Professor Richard Kitney, co-author of the paper from the Centre for Synthetic Biology and Innovation and the Department of Bioengineering at Imperial College London, says: "Logic gates are the fundamental building blocks in silicon circuitry that our entire digital age is based on. Without them, we could not process digital information. Now that we have demonstrated that we can replicate these parts using bacteria and DNA, we hope that our work could lead to a new generation of biological processors, whose applications in information processing could be as important as their electronic equivalents."The researchers, from Imperial College London, have demonstrated that they can build logic gates, which are used for processing information in devices such as computers and microprocessors, out of harmless gut bacteria and DNA. These are the most advanced biological logic gates ever created by scientists.Although still a long way off, the team suggest that these biological logic gates could one day form the building blocks in microscopic biological computers. Devices may include sensors that swim inside arteries, detecting the build up of harmful plaque and rapidly delivering medications to the affected zone. Other applications may include sensors that detect and destroy cancer cells inside the body and pollution monitors that can be deployed in the environment, detecting and neutralising dangerous toxins such as arsenic.Previous research only proved that biological logic gates could be made. The team say that the advantage of their biological logic gates over previous attempts is that they behave more like their electronic counterparts. The new biological gates are also modular, which means that they can be fitted together to make different types of logic gates, paving the way for more complex biological processors to be built in the future.

In the new study, the researchers demonstrated how these biological logic gates worked. In one experiment, they showed how biological logic gates can replicate the way that electronic logic gates process information by either switching "on" or "off."

The scientists constructed a type of logic gate called an "AND Gate" from bacteria called Escherichia coli (E.Coli), which is normally found in the lower intestine. The team altered theE.Coli with modified DNA, which reprogrammed it to perform the same switching on and off process as its electronic equivalent when stimulated by chemicals.

The researchers were also able to demonstrate that the biological logic gates could be connected together to form more complex components in a similar way that electronic components are made. In another experiment, the researchers created a "NOT gate" and combined it with the AND gate to produce the more complex "NAND gate."

The next stage of the research will see the team trying to develop more complex circuitry that comprises multiple logic gates. One of challenges faced by the team is finding a way to link multiple biological logic gates together, similar to the way in which electronic logic gates are linked together, to enable complex processing to be carried out.