Newswise — Scientists at New York University School of Medicine will lead an interdisciplinary team of scientists in an international, multi-million dollar project to develop novel vaccines enabling the body to generate powerful antibodies to block infection with HIV, the virus causing AIDS.
The Bill & Melinda Gates Foundation selected the NYU Vaccine Discovery Consortium as one of the participants in its Collaboration for AIDS Vaccine Discovery. The goal of these grants is to accelerate the development of an AIDS vaccine.
Susan Zolla-Pazner, Ph.D., Professor of Pathology at NYU School of Medicine and Chief of Immunology at VA New York Harbor Healthcare System, a longtime AIDS researcher specializing in immunology, will lead the NYU AIDS Vaccine Discovery Consortium, which received a three-year grant for $8.4 million.
The project will involve collaborating researchers in immunology, virology, crystallography, and structural and computational biology. They will use sophisticated techniques to find out if a "loop" on a protein coating the HIV virus is a target for powerful neutralizing antibodies that defeat the most common strains of the virus.
The researchers plan to select the most powerful antibodies found in individuals infected with different strains of HIV. Then they will identify the structures or regions on the virus coat targeted by the antibodies and incorporate these structures into genetically engineered vaccines that will be tested in rabbits. The hope is that their work will provide a platform for the development of AIDS vaccines in humans.
Dr. Zolla-Pazner has assembled an international group of researchers to work on this project. They are affiliated with eight institutions, four in the United States, and two each in India and Cameroon in West Africa, where she has established long-term collaborations.
"The Gates Foundation grant will enable us to develop candidate vaccines that focus the immune response on the V3 loop of the gp120 protein," says Dr. Zolla-Pazner. "This is a proof-of-principle project. If it succeeds, it could be extended to the study of other parts of the HIV virus as well as to other disease causing organisms." Focusing on the coat of the virus
Although scientists first identified HIV as the cause of AIDS more than 20 years ago, there is still no vaccine. At one time many scientists hoped that HIV's protein coat, called gp120, would provide the basis for successful vaccines because the immune system produces antibodies against it. But a large clinical trial of a vaccine based on this protein failed, and some researchers had given up hope that the antibody approach would work.
Dr. Zolla-Pazner never gave up on the antibody approach despite the ingenious ways in which the virus evades the immune system. Since the early 1980s, her laboratory at the VA New York Healthcare System, an affiliate of NYU Medical Center, has focused on pieces of the proteins enveloping the HIV virus, and on the antibodies elicited by these foreign strands.
Over the years, she and other scientists have found some six regions of the virus coat proteins that induce antibodies that block the ability of the virus to infect cells. Almost all have proved to be problematic. Some regions induced weak antibodies while others elicited strong antibodies that also targeted some of the body's own proteins with potentially disastrous consequences. Still others were hidden from the immune system or were present only on a few HIV strains.
One region that remained promising was the so-called V3 loop of the gp120 protein, according to Dr. Zolla-Pazner. This region is used by the virus to gain a foothold on cells of the immune system targeted by HIV. During the process of infection, the V3 loop remains at least partially exposed to the immune system and produces strong antibodies that don't react with any of the body's own proteins. "At one time everybody thought that making antibodies to V3 was the way to prevent HIV infection and that this was going to be a slam dunk," says Dr. Zolla-Pazner. But, the field looked at the anti-V3 antibodies made in mice, she says, and found that they could recognize only a few types of HIV viruses. "So, many scientists decided that V3 was the wrong part of the virus to focus on."
The interesting V3 loop
Dr. Zolla-Pazner says that her VA laboratory had started to look at the V3 antibodies early on. "Our data showed that they weren't as specific as everybody else thought," she says. "We had found an antibody to V3 that was really interesting and had the ability to block the infection of lots of HIV strains."
The V in V3 stands for variable and, as the name implies, the loop is made of sequences of amino acids that vary widely according to the strain of HIV. Only a handful of the sequences are the same in infected individuals, and there are thousands of sequences.
With the help of crystallography and the sophisticated tools of structural biology, Dr. Zolla-Pazner and her colleagues have recently begun to unlock the paradox of how the many V3 loops are recognized by neutralizing antibodies, and how these antibodies prevent HIV from infecting cells.
A hairpin-like turn
One of the hallmarks of the loop is a hairpin-like turn. Even though the amino acid sequences of the loop vary, its fundamental structure remains the same. "The V3 region in different viruses is indeed always changing but its shape is always similar," explains Dr. Zolla-Pazner. She says that antibodies recognize the common features of the V3 loop just as our eyes recognize faces by the position of the eyes, nose, and mouth.
Dr. Zolla-Pazner's laboratory has already isolated powerful neutralizing antibodies from the blood of individuals infected with subtype B of HIV, which is found mainly in AIDS patients in the United States and Europe. As part of the antibody project, her colleagues will collect blood from HIV infected individuals in Cameroon and India in order to cull additional antibodies from people infected with subtypes A and C, which predominate in Cameroon and India. Subtypes A, B, and C account for about 86 percent of all HIV strains.
Using special assays developed by Dr. Zolla-Pazner and her colleagues, the antibodies will be tested for neutralizing activity and the most broadly acting will be crystallized along with the V3 loops that they recognize.
The crystals will provide the basis for sophisticated molecular modeling studies that will dissect the atomic structure of the V3 loop and its associated antibodies. These models, in turn, will help the researchers identify the features of the V3 loop that are eliciting the antibodies, and help them design vaccines that contain the best of the V3 loops. Several of these vaccines will be tested in rabbits by Dr. Shan Lu at the University of Massachusetts Medical Center, where he will use a special DNA and protein approach to stimulate the immune response.
Dr. Zolla-Pazner's colleagues include Phillip Nyambi, Tim Cardozo, Miroslaw Gorny, Catarina Hioe, Xiang-Peng Kong, and Suman Laal at NYU School of Medicine; Shan Lu at the University of Massachusetts, Worcester, MA; Abraham Pinter at the Public Health Research Institute, Newark, New Jersey; and Maxim Totrov and Ruben Abagyan at Molsoft LLC, La Jolla, Calif. In Cameroon, two hospitals are involved in the project, the Alpha Royal Medical Center in Bamenda and the Buea District Health Center. In India, the King Edward Memorial Hospital and the Lokmanya Tilak Municipal General Hospital in Mumbai are involved.
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