By the Blouin News Science & Health staff

Antibody evolution reveals an HIV Achilles heel

by in Medicine, Research.

An HIV-infected patient displays medicine at a hospital in Payao province, Thailand, on  November 28, 2007

An HIV-infected patient displays medicine at a hospital in Payao province, Thailand, on November 28, 2007 (REUTERS/Sukree Sukplang)

Researchers from Duke University School of Medicine identified an antibody in a Human Immunodeficiency Virus (HIV) patient which evolves together with the constantly changing virus and can attack a variety of HIV strains. The results of the study, led by Barton Ford Haynes, M.D. and published in the journal Nature (April 3rd 2013), documented the path of antibody evolution and are a very important step for the design of novel HIV vaccines.

The viral genome is protected by an envelope made of proteins. Some proteins on the viral envelope, called antigens, sensitize the immune system and create memory B-cells (B-cell germline), which promote the maturation of specific antibodies. The first anti-HIV antibodies able to neutralize the virus in the body of an infected individual are produced during several weeks after infection.

Initially, our body seems to win the fight. But HIV constantly changes its genome. Viral particles in a human body will sustain several mutations which heavily differentiate them from the initial virus at the time of infection. Due to subsequent mutations on viral proteins, the altered virus escapes from the immune system. About 80% of those infected with HIV end up with antibodies of poor specificity unable to kill most of the HIV. This is the main reason why our body cannot produce specific antibodies to fight HIV infection and why vaccines fail to promote immunity.

However, about 20% of patients produce neutralizing antibodies with broader range (BnAbs), which cross-react with and kill many HIV strains other than the original strain which induced their production. These antibodies arise from a B-cell germline of unknown origin. Their success lies in the fact that they target regions of the virus which do not mutate and that they have additional characteristics which prompted scientists to suggest that they evolve in parallel with the viral envelope protein, and therefore manage to fight chronic infections. For these reasons, they are considered a very promising tool for vaccine development. But what drives the maturation of broadly neutralizing antibodies? And why can’t all patients can produce them? Scientists could not answer these questions because they did not know which viral envelope proteins promote BnAb maturation.

To answer these questions, researchers Barton Ford Haynes led a research team which followed an HIV-1 infected patient four weeks after infection over the course of three years. They analyzed the viral envelope proteins and the antibodies periodically and compared their amino acid sequences over time. They first found a broad neutralizing antibody at week 136 after infection and later followed back the mutations on this antibody, as well as the viral antigens at each time. They identified all steps required for BnAb maturation as well as the viral envelope protein which induced its maturation. This information is vital for researchers to develop viral particles and to design vaccines that lead to the production of broadly neutralizing antibodies.

William R. Schief, who did not participate in the Haynes study, but led another study in which his team designed synthetic HIV immunogens (a substance which can induce the production of antibodies and immunity) that could induce broadly neutralizing antibodies, said: “The big question now is, once one has activated that germline B cell, how does one get that B cell to undergo maturation to produce a broadly neutralizing antibody?”

But “immunizing with a one-structure envelope is probably not going to fit the bill,” Haynes says. Indeed, combinatorial vaccinations seem to be the most suitable approach for the future. Klein and colleagues, from Laboratory of Molecular Immunology at The Rockefeller University, New York, U.S.A., have shown that a combination of broadly neutralizing antibodies can be an effective HIV treatment strategy which can suppress the viral load to very low levels.

Interestingly, this new knowledge can also hold true for other viral infections as broadly neutralizing antibodies are thought to be a promising strategy for the eradication of human hepatitis C virus (HCV).

Despite that the Haynes study is based on a single patient and the new antibody could kill 55% of all viral particles, a little more than half, it has created a “roadmap” of a broadly neutralizing HIV antibody from the production of the antibody to maturation. Researchers can now develop immunogens which can induce the production of broadly neutralizing antibodies in all HIV patients and increase their chances to fight HIV more effectively.