Barriers to HIV Vaccine Response Explored

Researchers at The Scripps Research Institute (TSRI) discovered that an antibody that binds and neutralizes HIV likely also targets the body's own "self" proteins. This finding could complicate the development of HIV vaccines designed to elicit this protective antibody, called 4E10, and others like it, as doing so might be dangerous or inefficient.

"We developed two new mouse models that allow us to visualize the fate of the rare B cells that can see HIV and we thought could be stimulated by vaccines to produce neutralizing antibodies -- the type of antibodies we seek to produce in response to a vaccine," said David Nemazee, PhD, professor in the Department of Immunology and Microbial Science at TSRI and senior author of the study. "We were able to study vaccine responses of b12, an antibody that sees the CD4 binding site of HIV, but, surprisingly to us, not 4E10, an antibody that sees the stem of the HIV envelope protein."

Nemazee and his team went on to discover that cells with the potential to produce 4E10 antibodies trigger several natural safeguards that shut down the production of any antibody that might recognize and destroy the body's own tissues. They concluded that 4E10 cross-reacts with host tissues in this way, prompting its removal before it can do any harm - or good.

HIV Vaccine Development

4E10 antibodies were originally isolated from a human HIV patient. The antibodies specifically recognize and bind an HIV surface protein called gp41. The virus uses gp41 like a long spike to poke holes in its host's immune cells. But when 4E10 antibodies clog up gp41, the virus is neutralized and host cells are protected.
4E10 especially interests HIV researchers because the antibody recognizes and binds to gp41 on the surface of many different strains of the virus, not just the one strain with which the patient was most recently infected. If a vaccine could be made to specifically and safely stimulate 4E10-like production, recipients would likely be protected against multiple HIV strains.

In humans, HIV slowly destroys the immune system, leading to Acquired Immune Deficiency Syndrome (AIDS). According to the Centers for Disease Control and Prevention, more than 1.1 million people in the U.S. are living with HIV infection. While treatments developed in the past decade can keep the virus in check for many years, there is no vaccine and there is no cure.

Proceeding with Caution

In several ongoing studies, the TSRI team and others are working out how to make a vaccine that stimulates the production of 4E10, b12 and other broadly neutralizing anti-HIV antibodies. However, this latest study indicates that this approach might be complicated by unwanted self-reactivity. Antibodies that cross-react with host tissue -- like 4E10 has now been shown to do -- are associated with autoimmune diseases such as multiple sclerosis and lupus.
The TSRI study also raises the question of how 4E10 was generated in the first place. According to Nemazee, 4E10 may be a fluke, cropping up in an HIV patient who was also prone to autoimmune diseases. Alternatively, the autoreactive antibody could have arisen in the patient as a consequence of the disease -- perhaps the body's normal mechanism for weeding out such antibodies failed, allowing the serendipitous production of an anti-HIV antibody.

Despite this new concern, there is still hope for 4E10's role in HIV vaccine development. A companion paper published in the same issue of The Journal of Immunology (http://www.jimmunol.org/content/191/6/3179.long) found that another potent, broadly neutralizing anti-HIV antibody, b12, was not self-reactive and could respond to a candidate vaccine preparation provided by Richard Wyatt, TSRI Professor of Immunology and Director of Viral Immunology at the International AIDS Vaccine Initiative Neutralizing Antibody Center.

"It's still possible that we could safely elicit the 4E10-like antibody in order to protect against HIV," Nemazee said. "We just have to think about how to generate the best antibodies without causing other problems. We have a lot of questions. And now we have a good model to help us answer them."

Man cured of AIDS after receiving stem cell transplant

In what many in the mainstream media and medical community have now dubbed their first known case of cured AIDS, Timothy Ray Brown's miraculous healing from the deadly syndrome is sending shock waves throughout the world. After receiving a bone marrow stem cell transplant back in 2007, Brown inherited a genetic immunity from those stem cells that cured him of not only AIDS, but also leukemia.

Dubbed "The Berlin Patient," Brown first tested positive for HIV back in 1995. And for years, he unsuccessfuly battled the disease using conventional methods. But when doctors decided to give him a stem cell transplant, everything changed.

"I quit taking my HIV medication the day that I got the transplant and haven't had to take any since," said Brown to reporters from CBS 5 in San Francisco. "I'm cured of HIV. I had HIV, but I don't anymore."

According to reports, roughly one percent of Caucasians have a natural immunity to HIV and AIDS, and the stem cells Brown received came from someone within this rare one percent. As a result, the white blood cells created in his body via the injected stem cells ended up giving him that same immunity.

Brown's doctors, as well as various other experts and scientific journals, have all confirmed that Brown has been cured of both his AIDS and his leukemia. And Dr. Judy Auerbach from the San Francisco AIDS Foundation told CBS reporters that "things have shifted" in terms of using the word "cure" in reference to AIDS, which is breathing new hope into those hopeful for a cure themselves.

However, despite the numerous references in the media to Brown being the first person ever to have been cured of AIDS, there have actually been many others who have successfully defeated the syndrome through immune support -- but these cases, of course, have been ignored by the mainstream medical and scientific community. In fact, a healthy immune system is the true key to both resisting HIV infection, and successfully reversing it. 

HIV: Predicting Treatment Response More Accurately

The HI virus is feared, not least, because of its great adaptability. If the virus mutates at precisely the point targeted by a drug, it is able to neutralise the attack and the treatment fails. To minimise these viral defence mechanisms, doctors treat patients with modern combination therapies involving the simultaneous administration of several drugs. This approach forces the virus to run through a series of mutations before it becomes immune to the drugs.

"It is not easy to decide which of the over 30 combination therapies is best suited to a patient," says Huldrych Günthard from Zurich University Hospital, president of the Swiss HIV Cohort Study. The decision is based on the prospects of success and therefore on the genetic make-up of a particular virus. The established prediction models already consider the genetics of the virus but they neglect that the virus continuously evolves through sequential mutations.

Choosing the right therapy for each patient

In cooperation with the Swiss HIV Cohort Study, Niko Beerenwinkel and his team from ETH Zurich have now developed a more accurate prediction model based on a probabilistic method. This model calculates the possible evolutionary paths of the virus and yields a new predictive measure for the development of resistances: the so-called individualised genetic barrier. When applied retrospectively to 2185 patients of the HIV Cohort, the new approach made it possible to predict treatment success more accurately compared to the existing models. "We are now introducing the individualised genetic barrier in a pilot project and hope that it will help us in the future to identify the best therapy for each patient," says Günthard.