Understanding the Expanding Role for Broadly Neutralizing Antibodies
Could the same antibodies that have become the crux of vaccine research have a role in treating or even curing HIV?
The ongoing discovery of infection-fighting proteins called antibodies that can inactivate or neutralize a wide swath of different HIV strains has revolutionized the quest for a globally effective preventive HIV vaccine (see VAX Feb. 2007Primer on Understanding Neutralizing Antibodies). Since 2009 when the first wave of so-called broadly neutralizing antibodies (bNAbs) were identified, HIV prevention researchers have made multiple advances in understanding how these antibodies are able to neutralize HIV so effectively and are beginning to harness this knowledge to develop new vaccine candidates. Now teams of researchers from the HIV prevention field are demonstrating that these same broadly neutralizing antibodies may also have a therapeutic role that could possibly even advance the search for an HIV cure.
Antibodies’ immune arsenal
Antibodies are involved in a broad repertoire of immune functions that allow the body to fight off infection. They are made by B cells, a type of immune cell that is activated when exposed to a pathogen like HIV. Once activated, the B cell becomes a plasma cell that makes antibodies against a specific pathogen. Some HIV-specific antibodies are capable of neutralizing the virus by latching onto it directly. But not all antibodies are neutralizing, and in fact, both neutralizing and non-neutralizing antibodies also act in other ways. Some help other types of immune cells do their jobs. For example, antibodies can bind to cells that already are infected with virus and facilitate their destruction by other immune cells via a mechanism called antibody-dependent cellular cytotoxicity, or ADCC (see VAX Jan. 2010Primer on Understanding Antibody Functions: Beyond Neutralization). Findings from the RV144 AIDS vaccine efficacy trial that showed modest protection against HIV for the first time, indicate that the non-neutralizing antibodies induced by the vaccine candidate likely facilitated ADCC, suggesting this antibody function may play an important role.
Antibodies at work
Based on the results of RV144 and the recent discoveries around bNAbs, researchers are now widely in agreement that a preventive HIV vaccine would need to induce some type of antibody response. A handful of recent studies have also shown that antibodies may have an important role to play in treating HIV infection, even in advancing the quest for an HIV cure.
Typically, a cure involves complete banishment of a virus from a person’s body. But in the case of HIV, it is also possible that a person may have residual virus but remain unharmed, even without taking antiretroviral drugs (ARVs). In this case, the immune system is able to keep the remaining virus in check. This is often referred to as a “functional” cure.
ARV therapy prevents the spread of HIV by inhibiting various stages of HIV’s life cycle, but the drugs do not directly kill the virus or remove all virus from an infected person. As a consequence, if therapy is discontinued the virus eventually rebounds in most individuals, making treatment for HIV-infected individuals a life-long prospect. Hence researchers have been increasingly focusing on different avenues of research to cure HIV-infected individuals. One approach that has shown promise in babies is to use early and aggressive ARV treatment (see Spotlight, this issue). Other approaches involve complicated methods of teasing HIV out of its hiding places in the body and eliminating it while a person remains on ARVs. Another approach that has shown some success in animal models involves administering some of the same bNAbs that are the centerpiece of HIV vaccine research.
In 2012, researchers showed that a cocktail of bNAbs could effectively control HIV virus replication in humanized mice (genetically altered so that they have the components of a human immune system). After stopping treatment, the antibody-treated mice were able to control HIV for an even longer time than those that just received ARVs.
Last year, reports by two teams of investigators showed similar findings in monkeys using a single bNAb or multiple bNAbs in combination. In both studies, the infusion of bNAbs significantly reduced the quantity of virus in the blood. This suppression of virus lasted for weeks, as long as antibody levels were maintained. In one case, a single antibody was able to achieve the same level of virus suppression as multiple bNAbs. Researchers even observed that the antibody-treated monkeys cleared the virus faster than HIV-infected humans taking ARVs, suggesting that these potent antibodies may have a role in HIV treatment or even efforts toward a cure.
Researchers at the National Institute of Allergy and Infectious Diseases are now recruiting HIV-infected individuals for the first clinical trial to evaluate the therapeutic potential of a bNAb discovered by scientists at the Institute. This is not the first time antibodies have been tested as a treatment, but researchers are hoping for even better results using the new more potent antibodies available today.
A global blueprint for cure research laid out by leading scientists in 2012 puts antibodies front and center among strategies to control viral replication and kill already HIV-infected cells. Although cure research is in its infancy, it is a burgeoning field. And while vaccine researchers face the challenge of figuring out how to induce these powerful bNAbs via vaccination, the challenge in using these antibodies for treatment will be to engineer antibodies that are potent enough, easy enough to manufacture, and practical enough to administer to millions of HIV-infected people worldwide.
Written by Donna Rubens, PhD, Senior Writer.