Part of AIDS Virus Can Hide Itself
Mark Evans, Associated Press Writer; December 16, 2002
This report is in 3 parts: first is AP report, second is the published report in the journal Nature, and third is CDC commentary.|
A part of the AIDS virus that was considered vulnerable to attack can camouflage itself by changing shapes, says a study that helps show why HIV is so hard to target and kill.
HIV cripples the immune system by infecting and killing T-cells. It uses a protein structure on its surface called gp120 to gain entry to the cells.
In 1998, scientists announced that they had figured out much about the structure of gp120 and hoped that finding a vulnerability in it could lead to vaccines against HIV.
But finding gp120's weakness has remained elusive, in part because the protein varies from strain to strain. Some scientists believed that the best hope was in targeting an area of gp120 common to all strains - a vulnerable region where it must expose its core in order to bind to a T-cell.
But the new work shows that this region is more elusive than previously thought, because it is composed of very flexible parts that let it take on different shapes.
That camouflages gp120 against the blood proteins called antibodies launched by the immune system as a defense, researchers report in the Dec. 12 issue of the journal Nature.
Antibodies that do manage to latch on to the protein are less potent at killing the virus, possibly because of the trouble it takes to fix gp120 rigidly, said Joseph Sodroski of the Dana-Farber Cancer Institute in Boston, one of the researchers.
"There's a lot of mobility within the protein. It's a blurry, moving structure that is very difficult for the immune system to deal with," he said.
The scientists made the discovery by studying 20 different antibodies, measuring their interactions with gp120.
Another study author, Peter Kwong of the National Institutes of Health, said the finding doesn't rule out the possibility of finding an AIDS vaccine. He said there may be ways to overcome the mobile nature of gp120. Exactly how remains uncertain.
Theodore Jardetzky, a Northwestern University molecular biologist
not connected with the study, called the findings surprising.
"How big a deal this is, we're going to have to wait and see. They've pointed us in a new direction," he said.
HIV-1 evades antibody-mediated neutralization through conformational masking of receptor-binding sites
Study summary: The ability of human immunodeficiency virus (HIV-1) to persist and cause AIDS is dependent on its avoidance of antibody-mediated neutralization. The virus elicits abundant, envelope-directed antibodies that have little neutralization capacity. This lack of neutralization is paradoxical, given the functional conservation and exposure of receptor-binding sites on the gp120 envelope glycoprotein, which are larger than the typical antibody footprint and should therefore be accessible for antibody binding. Because gp120-receptor interactions involve conformational reorganization, we measured the entropies of binding for 20 gp120-reactive antibodies. Here we show that recognition by receptor-binding-site antibodies induces conformational change. Correlation with neutralization potency and analysis of receptor-antibody thermodynamic cycles suggested a receptor-binding-site 'conformational masking' mechanism of neutralization escape. To understand how such an escape mechanism would be compatible with virus-receptor interactions, we tested a soluble dodecameric receptor molecule and found that it neutralized primary HIV-1 isolates with great potency, showing that simultaneous binding of viral envelope glycoproteins by multiple receptors creates sufficient avidity to compensate for such masking. Because this solution is available for cell-surface receptors but not for most antibodies, conformational masking enables HIV-1 to maintain receptor binding and simultaneously to resist neutralization. Nature 2002 Dec 12;420(6916):678-82
The properties of the HIV-1 envelope glycoproteins that simultaneously allow the retention of function and the evasion of the humoral immune response are gradually becoming apparent. Antigenic and structural analyses of the most exposed component of the trimeric envelope glycoprotein complex, gp120, reveal four surfaces: a non-neutralizing face, a variable surface, a neutralizing face and an immunologically 'silent' face24. The non-neutralizing face, the variable surface and the 'silent' face are protected from the immune system by occlusion on the oligomer, by mutational variation and by carbohydrate masking, respectively. Our results suggest that the potentially vulnerable receptor-binding sites on gp120 are protected by a novel type of camouflage: conformational or entropic masking. The consequence of this conformational
mask is that antibodies against the receptor-binding regions incur an energetic handicap to binding not faced by other anti-gp120 antibodies. This energetic barrier might influence the efficiency with which receptor-binding-site antibodies are generated as well as the neutralization efficacy of these antibodies. Additional tertiary/quaternary structural features of the
envelope glycoprotein spikes on primary HIV-1 isolates are thought to provide further constraints on antibody interaction with receptor-binding sites, while allowing sufficient affinity/avidity for receptors to support infection. An understanding of the properties of the HIV-1 envelope that permit neutralization resistance will guide attempts to create vaccines as well
as therapeutics that target receptor binding‹as we have done with the extraordinarily potent D1D2-Igtp.
Commentary from CDC HIV/STD/TB Prevention News Update 12/13/02:
Scientists have discovered a new way HIV evades the body's immune response, helping to explain why it has been so hard to develop a broadly effective AIDS vaccine. The finding adds the "final piece to the puzzle" of how HIV eludes the immune system's infection-fighting antibodies, which are produced in large numbers when the virus invades, said Dr. Peter Kwong, a vaccine researcher at the US National Institute of Allergy and Infectious Diseases and the study's lead author. The full report, "HIV-1 Evades Antibody-Mediated Neutralization Through Conformational Masking of Receptor-Binding Sites," is published in this week's issue of Nature (2002;420:623-624,678-681).
"All these antibodies are generated, but virtually none neutralizes the virus," said Kwong. And while scientists have learned a great deal in recent
years about HIV's ability to evade the body's defenses, a big question has been precisely how a key protein on HIV's surface, gp120, escapes being
neutralized by antibodies. Gp120 plays a vital role in getting HIV into the cells it targets for infection. But the protein also offers large exposed
binding sites for neutralizing antibodies to latch onto, Kwong explained. So the question has been why these antibodies - whether unleashed from
the natural immune response or elicited by a vaccine - largely fail to neutralize HIV.
Kwong and colleagues looked at the interaction between the gp120 molecule and a number of antibodies. They found that, in the face of nearly all of
the antibodies, an "energetic barrier" was set up around the gp120 receptor sites. "The barrier's set up in a very specific way to prevent neutralization," Kwong said.
Kwong explained the antibodies only bind one at a time to the gp120 receptor sites on HIV. In contrast, the immune system cells that HIV infects
have multiple sites that simultaneously bind to the gp120 receptors. So it appears that HIV is set up to have a barrier against interaction with
antibodies, but not with its target cells.
Because of gp120's role in HIV infection, many experimental HIV vaccines have been based on the premise of generating neutralizing antibodies
against the protein. The current study should spark efforts already under way to refine gp120-based HIV vaccines, according to Theodore Jardetsky of
Northwestern University, whose commentary accompanies the findings. Kwong noted that researchers are also developing HIV vaccines that focus on immune system components other than the antibody arm.