ANTIBODY EVOLUTION AND HIV VACCINE DEVELOPMENT

Co-evolution of virus and antibody – The evolution of the viral protein (green) from 14 weeks through 100 weeks post-transmission is compared to the maturation of the human antibody. Image courtesy Los Alamos National Laboratory.

 
FROM: LOS ALAMOS NATIONAL LABORATORY
Antibody Evolution Could Guide HIV Vaccine Development

LOS ALAMOS, N.M., April 4, 2013—Observing the evolution of a particular type of antibody in an infected HIV-1 patient, a study spearheaded by Duke University, including analysis from Los Alamos National Laboratory, has provided insights that will enable vaccination strategies that mimic the actual antibody development within the body.

The kind of antibody studied is called a broadly cross-reactive neutralizing antibody, and details of its generation could provide a blueprint for effective vaccination, according to the study’s authors. In a paper published online in Nature this week, the team reported on the isolation, evolution and structure of a broadly neutralizing antibody from an African donor followed from the time of infection.

The observations trace the co-evolution of the virus and antibodies, ultimately leading to the development of a strain of the potent antibodies in this subject, and they could provide insights into strategies to elicit similar antibodies by vaccination.

Patients early in HIV-1 infection have primarily a single "founder" form of the virus that has been strong enough to infect the patient, even though the population in the originating patient is usually far more diverse and contains a wide variety of HIV mutations. Once the founder virus is involved in the new patient’s system, the surrounding environment stimulates the HIV to mutate and form a unique, tailored population of virus that is specific to the individual.

The team, including Bette Korber, Peter Hraber, and S. Gnanakaran, of Los Alamos National Laboratory, led by Barton Haynes of Duke University School of Medicine in Durham, North Carolina, with colleagues at Boston University, the National Institutes of Health, and other institutions as part of a large collaboration, showed that broadly neutralizing antibodies developed only after the population of viruses in the individual had matured and become more diverse.

"Our hope is that a vaccine based on the series of HIV variants that evolved within this subject, that were together capable of stimulating this potent broad antibody response in his natural infection, may enable triggering similar protective antibody responses in vaccines," said Bette Korber, leader of the Los Alamos team.

This study was supported by the National Institutes of Allergy and Infectious Diseases (NIAID) and by intramural National Institutes of Health (NIH) support for the NIAID Vaccine Research Center, by grants from the NIH, NIAID, AI067854 (the Center for HIV/AIDS Vaccine Immunology) and AI100645 (the Center for Vaccine Immunology-Immunogen Discovery). Use of sector 22 (Southeast Region Collaborative Access team) at the Advanced Photon Source at Argonne National Laboratory was supported by the US Department of Energy, Basic Energy Sciences, Office of Science, under contract number W-31-109-Eng-38.

LOS ALAMOS NATIONAL LABORATORY LOOKS AT HOW HIV ATTACKS

FROM: LOS ALAMOS NATIONAL LABORATORY
Research Deciphers HIV Attack Plan
Scientists get inside look at how AIDS virus grooms its assault team

LOS ALAMOS, N.M., March 29, 2013—A new study by Los Alamos National Laboratory and University of Pennsylvania scientists defines previously unknown properties of transmitted HIV-1, the virus that causes AIDS. The viruses that successfully pass from a chronically infected person to a new individual are both remarkably resistant to a powerful initial human immune-response mechanism, and they are blanketed in a greater amount of envelope protein that helps them access and enter host cells.

These findings will help inform vaccine design and interpretation of vaccine trials, and provide new insights into the basic biology of viral/host dynamics of infection.

During the course of each AIDS infection, the HIV-1 virus evolves within the infected person to escape the host’s natural immune response and adapt to the local environment within the infected individual. Because HIV evolves so rapidly and so extensively, each person acquires and harbors a complex, very diverse set of viruses that develops over the years of their infection. Yet when HIV is transmitted to a new person from their partner, typically only a single virus from the diverse set in the partner is transmitted to establish the new infection.

The key discoveries here are the specific features that distinguish those specific viruses which successfully move to the new host, compared with the myriad forms in the viral population present in a chronically infected individual.

"The viruses that make it through transmission barriers to infect a new person are particularly infectious and resilient," said Los Alamos National Laboratory scientist Bette Korber. "Through this study we now better understand the biology that defines that resilience."

The team set out to determine whether the viruses that were successfully transmitted to a new patient might share distinct biological properties relative to those typically isolated from people with long-term, chronic infection. To do this, the group at U Penn cloned a set of intact viruses from acute infection, and a set of viruses from chronically infected people, and characterized them by measuring quantities that might be related to the virus's ability to successfully establish a new infection. They discovered several clear correlations. For example, transmitted viruses were both more infectious and contained more protective "envelope" per virus; envelope is the protein the virus uses to enter host cells.

The team identified an additional interesting property that could be a general characteristic of new viral infections: the transmitted HIV was capable of replicating and growing well in the presence of alpha interferon. Alpha interferon production is part of our innate human immune response to a new infection. As soon as a new viral infection is initiated in our bodies, local immune cells at the site of infection start secreting molecules called cytokines that have general antiviral activity and can inhibit the production of the newly infected virus. Alpha interferon is one of these potent cytokines.

In the early days of an HIV infection, this innate immune response increases to an intense level, called a "cytokine storm," which gradually recedes during infection. For a newly transmitted HIV to successfully establish infection, it must grow and expand in the new host while facing this cytokine storm. Although typical chronic viruses are sensitive to and inhibited by alpha interferon, transmitted HIV-1 viruses grew well in the presence of interferon.