Understanding Advances in the Search for Antibodies Against HIV
What are some of the recent developments that are helping researchers identify new targets for HIV vaccine design?
Vaccines protect against disease by priming the immune system to generate the specific types of immune responses necessary to stop an invading pathogen before it causes harm.
Most vaccines induce different types of immune responses, including B cells. B cells produce antibodies—Y-shaped proteins that can latch on to viruses and inactivate or neutralize them—which are considered critical to the protection afforded by many, if not all, vaccines (see VAX February 2007 Primer on Understanding Neutralizing Antibodies). Antibodies can also help inhibit infection through other mechanisms of action that don’t involve direct neutralization (see VAX January 2010 Primer on Understanding Antibody Functions: Beyond Neutralization).
Many scientists believe that an AIDS vaccine will need to induce antibodies, in addition to other immune responses, to be highly effective at protecting against HIV. And because the circulating strains of HIV are so diverse, antibodies that can neutralize a broad array of HIV variants, so-called broadly neutralizing antibodies (bNAbs), have been a major target for HIV vaccine researchers.
To design vaccine candidates capable of inducing these bNAbs, researchers are using a reverse engineering approach. They start by identifying the antibody or antibodies the vaccine should induce and then try to identify precisely where these antibodies attach to HIV. This site is then used by scientists to design vaccine immunogens—the non-infectious fragments of HIV that are included in vaccine candidates. These immunogens are then tested to see if they can elicit these antibodies in people.
Until recently, only a handful of bNAbs were identified, limiting the number of targets that could be exploited for vaccine design. However, in the past year, researchers have unearthed a fresh crop of new, and in many cases more potent, antibodies. Five of the eight newly discovered antibodies were isolated from individuals infected with the clades of HIV most prevalent in Africa, where the HIV/AIDS burden is greatest and a vaccine is needed most.
Identifying new targets
The search for new bNAbs typically involves screening blood from HIV-infected individuals to see if it can neutralize a panel of laboratory viruses. These viruses are ranked by how easy or difficult they are to neutralize.
If serum, a component of blood, from an HIV-infected individual can neutralize several different viruses in a laboratory test, then researchers isolate the antibodies present in the serum. While HIV-specific antibodies are common in HIV-infected individuals, bNAbs are much rarer.
Two of the recently discovered antibodies—PG9 and PG16—were discovered by IAVI scientists in collaboration with researchers from The Scripps Research Institute in California. After screening blood from 1,800 HIV-infected individuals in Africa, North America, Europe, Asia, and Australia, researchers identified these two potent bNAbs from a single HIV-infected individual in Africa (see VAX October 2009 Spotlight article, Vaccine Research Gains Momentum).
Three other antibodies—HJ16, HGN194, and HK20—were discovered after screening 400 HIV-infected individuals through the Collaboration for HIV Vaccine Discovery (CAVD), in an effort led by a researcher from the Institute for Research in Biomedicine in Switzerland.
The remaining three antibodies, one known as VRC01, were identified by scientists at the Vaccine Research Center (VRC) at the US National Institute of Allergy and Infectious Diseases.
Different laboratory techniques were used to identify these antibodies. For instance, PG9 and PG16 were identified by screening first for neutralization and then for the ability of the antibodies to bind to HIV. This was important because these antibodies bind only weakly to HIV in the form in which it is studied in the laboratory, and had the binding test been conducted first, researchers might not have discovered these antibodies. The VRC01 antibody was found by combining B cells from HIV-infected individuals with virus particles that had been manipulated so that researchers could detect only those antibodies that bind to a specific site on the virus.
Researchers are now focusing on using these antibodies to reverse engineer vaccine candidates, starting with characterizing where on HIV these antibodies bind. Most of them bind to the spike-like protrusions on the surface of HIV, which is called the Envelope protein because it envelopes the virus’ genetic material.
Some of the recently discovered antibodies target different parts of HIV’s Envelope protein, suggesting to researchers that there are a number of ways to neutralize HIV and thereby prevent infection. (see VAX October 2009 Spotlightarticle, Vaccine Research Gains Momentum). PG9 and PG16 target a section of the virus that is more accessible to bNAbs, making it a promising target for vaccine developers. VRC01 and HJ16, as well as one of the older bNAbs known as b12, all bind to HIV at the site where the virus binds to human CD4+ T cells, the preferred target of the virus.
Work is now underway to characterize these sites on the virus and to design immunogens based on them. Although there are still many challenges involved, researchers hope that improved candidates based on these bNAbs will eventually be ready for testing in clinical trials.