A natural approach for HIV vaccine

March 16, 2009

Research suggests scientists should follow the body's lead to prevent HIV from taking root

For 25 years, researchers have tried and failed to develop an HIV vaccine, primarily by focusing on a small number of engineered "super antibodies" to fend off the virus before it takes hold. So far, these magic bullet antibodies have proved impossible to produce in people. Now, in research to be published March 15 online by Nature, scientists at The Rockefeller University have laid out a new approach. They have identified a diverse team of antibodies in "slow-progressing" HIV patients whose coordinated pack hunting knocks down the virus just as well as their super-antibody cousins fighting solo.

By showcasing the dynamic, natural immune response in these exceptional patients, the research, led by Michel C. Nussenzweig, Sherman Fairchild Professor and head of the Laboratory of Molecular Immunology, suggests that an effective HIV vaccine may come from a shotgun approach using of a wide range of natural antibodies rather than an engineered magic bullet.

"We wanted to try something different, so we tried to reproduce what's in the patient. And what's in the patient is many different antibodies that individually have limited neutralizing abilities but together are quite powerful," says Nussenzweig, who also is a Howard Hughes Medical Institute investigator. "This should make people think about what an effective vaccine should look like."

HIV strains mutate rapidly, making them especially wily adversaries of the immune system. But one element is shared almost universally among the diverging strains - a protein on the envelope of the virus called gp140 that HIV needs to infect immune cells. Prior research has shown that four randomly engineered antibodies that block the activity of that protein prevent the virus from infecting immune cells in culture, but all attempts to coax the human body into producing those four have failed.

So Johannes Scheid, a visiting student in Nussenzweig's lab who is now a doctoral candidate, turned his attention to the antibodies produced by six people infected with HIV whose immune systems put up an exceptionally strong fight. The patients represent the roughly 10 to 20 percent of HIV patients who are able to control the virus and are very slow to progress to disease. Their immune systems' memory B cells produce high levels of antivirus antibodies, but until now, researchers have known little about the antibodies or how effective they are.

With help from Rockefeller's Center for Clinical and Translational Science and Rockefeller scientists David D. Ho and Jeffrey V. Ravetch, Scheid and colleagues isolated 433 antibodies from these individuals' blood serum that specifically targeted the envelope protein - the chink in HIV's protean armor. He cloned the antibodies and produced them in bulk, mapped which part of the envelope protein each targeted, and gauged how effective each was in neutralizing the virus. In the process, he identified a new structure within the envelope protein - called the gp120 core - that had never been recognized as a potential target for antibodies. "It's the first time that anyone has defined what is really happening in the B cell response in these patients," says Scheid.

Scheid's work shows that it's common for these antibodies to have neutralizing activity, says Nussenzweig. But each antibody alone has limited ability to fight the virus. "Individually, they're not as strong as the Famous Four," says Nussenzweig, referring to the high-profile super antibodies on which several vaccine attempts have been based. But in high concentrations, a combination of the sets of antibodies cloned from the individual patients seemed to act as teams to knock down the virus in cell culture as well as any single antibody studied to date. These natural antibodies were also able to recognize a range of HIV strains, indicating that their diversity may be an advantage over a single super antibody that focuses on only one part of the virus, which can mutate. The findings suggest that research into vaccines that mimic this natural antibody response could pay off.

Rockefeller University

---

---

	Immunology and the Quest for an HIV Vaccine: A New Perspective by Dr. Omar Bagasra (Author) How many human immune systems are there? How old are they? Why is there no AIDS vaccine? Is a new approach needed? Why is public opinion growing skeptical of the scientific community after three decades of public awareness about HIV/AIDS? Consider answers to these puzzling questions. Learn from the decades of experience of two senior scholars: Dr. Omar Bagasra (an eminent molecular biologist, immunologist, and retrovirologist) and Dr. Donald Gene Pace (a highly published writer who examines public health policy). Explore intriguing new possibilities about human immunity, and the development of an effective AIDS vaccine. Read Immunology and the Quest for an HIV Vaccine. Benefit from an informed synthesis backed by a wealth of peer-reviewed scientific references. Review basic concepts of...
	HIV And Molecular Immunity: Prospects for the AIDS Vaccine by Omar Bagasra (Author) How old is the AIDS virus (HIV-1) and where did it come from? Is it the result of a recombinant event in simian immunodeficiency viruses (SIVs)? Why do SIVs naturally occur in a variety of nonhuman African primates without inducing AIDS in their natural hosts? HIV-1 has devastated human society, although chimpanzees carry an SIV that is genetically almost identical to HIV-1 but causes no known illness in these great apes. How are Chimpanzees immune to HIV-1? Can humans acquire this immunity? Why do most newborns infected with HIV-1 in utero or during birth become long-term non-progressors while 20% rapidly develop AIDS and die in less than a year? Why are some adults asymptomatic for over 10 years after infection? Dr. Omar Bagasra, an eminent molecular biologist, immunologist, and...
	Expanding Access to Investigational Therapies for HIV Infection and AIDS by Roundtable for the Development of Drugs and Vaccines Against AIDS (Author), Institute of Medicine (Author) The call for a "parallel track" for AIDS drug development-a proposal that would allow the early distribution of AIDS drugs to large numbers of patients in parallel with the conventional clinical trials that assess the drugs' safety and efficacy-has sparked controversy within the scientific community. Questions have arisen about the risks to patients of such a plan, about its potential effect on the successful completion of standard controlled trials, and about whether the parallel track will generate useful data. Larger questions have also been raised about whether the parallel track heralds fundamental changes in the philosophy underlying drug regulation in the United States, about the costs and financing of investigational therapies and associated medical costs, and about the role of...
	AIDS Vaccine Research by WonG-Staal/Gall (Author) This reference describes the latest advances in the development and design of an HIV preventive vaccine-detailing the pathogenesis and genetic variability of HIV infection for the construction of molecular and therapeutic strategies to reduce the progression and transmission of AIDS. With contributions by universally recognized authorities in the field, AIDS Vaccine Research discusses § major obstacles in the identification of a preventive vaccine § the role of innate immunity in management of HIV infection § the impact of highly active antiretroviral therapy (HAART) on AIDS research § the creation of an effective mucosal DNA vaccine § the effect of the AIDS epidemic on developing countries Offering nearly 2000 contemporary references to facilitate further study, AIDS Vaccine...
	The Search for an AIDS Vaccine: Ethical Issues in the Development and Testing of a Preventive HIV Vaccine (Medical Ethics) by Christine Grady (Author) "The book is a balanced and comprehensive treatment of an important social issue. It is accessible to the general reader and belongs in public as well as academic libraries." —Religious Studies Review"Painstaking analysis of the knotty ethical problems involved in human-subjects research, and a well-thought-out proposal for a community approach to conducting field trials for an HIV vaccine.... Highly recommended for medical ethicists and anyone concerned about the AIDS epidemic and how HIV research is conducted." —Kirkus Reviews"... a carefully reasoned account of how research for and trial of a preventive vaccine differ from the methods used to discover a therapy." —Booklist"I highly recommend reading this book which I would attest to be a thrilling, ethically challenging,...
	Ethical Issues in HIV Vaccine Trials. by Thomas A. KERNS (Author)
	AIDS: Anti HIV Agents, Therapies And Vaccines (Annals of the New York Academy of Sciences) by Vassil St. Georgiev (Author), John J. McGowan (Editor)
	AIDS Vaccines, HIV Receptors, and AIDS Research by Lawrence B. Kendow (Author) Acquired immune deficiency syndrome or acquired immunodeficiency syndrome (AIDS or Aids) is a set of symptoms and infections resulting from the damage to the human immune system caused by the human immunodeficiency virus (HIV). This condition progressively reduces the effectiveness of the immune system and leaves individuals susceptible to opportunistic infections and tumours. HIV is transmitted through direct contact of a mucous membrane or the bloodstream with a bodily fluid containing HIV, such as blood, semen, vaginal fluid, pre-seminal fluid, and breast milk. This transmission can involve anal, vaginal or oral sex, blood transfusion, contaminated hypodermic needles, exchange between mother and baby during pregnancy, childbirth, or breastfeeding, or other exposure to one of the above...
	The First Decade of Safe and Effective HIV Vaccines by Jeremiah O. A. Abalaka (Author) Since 1984, the world has been spending, on the average, over $700 million annually in a futile effort at developing safe and effective HIV vaccines. During this period, over 25 million people have perished from the HIV/AIDS scourge, 90 per cent of them in the poor developing countries of sub-Saharan Africa. The socio-economic wreck caused by the HIV/AIDS pandemic is mind-boggling. The years of wayward search for safe and effective HIV vaccines since 1984 should have shown the world that the recipe for HIV vaccines that they have been following religiously without success should be appraised. That has not been done up till today. Instead, the entire world has persisted with the unscientific, unreasonable, bizarre, and ridiculous dogmas and established knowledge. Globally, the world has...
	HIV/Vaccine Needs - Procs of the Intl Seminar on Planetary Emergencies, 24th Session by Richard C. Ragaini (Author), Ragaini Richard (Author) This exploration of HIV/AIDS vaccine needs is taken from the 24th Session of the International Seminar on Nuclear War and Planetary Emergencies. Topics covered include: biotechnology; neuropathologies; development; sustainability; energy; water; and more.