May 13, 2003
Howard Hughes Medical Institute researchers and colleagues have determined that the common HIV-1 strain uses a strategy previously unseen in other viruses to escape attack by antibodies, one of the immune system's main weapons against invading viruses and bacteria.
Typically, viruses vary the protein sequence, or epitope, of the viral envelope that acts as a docking station for antibodies. This variation alters the docking region on the virus and prevents antibodies from attaching and targeting the virus for destruction. In contrast, HIV-1 continuously changes the arrangement of large sugar molecules studded across its gp120/41 protein coat, thereby obstructing those docking regions for antibodies.
The research team, led by Howard Hughes Institute investigator George M. Shaw at the University of Alabama-Birmingham, termed the mechanism an evolving "glycan shield," and acknowledged the discovery was a surprise. Shaw and colleagues were equally surprised at the rapidity and extent to which the replicating virus population in infected patients escaped antibody recognition. "Before these findings, the role of antibodies in combating the virus that causes AIDS was not altogether clear. The new data suggest a more active role for HIV-1 neutralizing antibodies in virus containment and an unexpected mechanism of virus escape," said Shaw.
During the course of their work, Shaw and colleagues developed a new strategy for detecting HIV-1 antibodies that prevent entry of the virus into human cells. They reasoned that since variants of HIV-1 that are resistant to antiretroviral drugs can be detected in the bloodstream of AIDS patients, if neutralizing antibodies were present and did affect virus replication in vivo, then by testing patients for strains of the virus that had become resistant to antibodies, they could infer their presence and their biological activity.
Shaw emphasized that the newly discovered evolving glycan shield mechanism of antibody escape is but one of several ways in which HIV-1 is virally persistent in the face of an evolving antibody repertoire. "The trick," suggested Shaw, "will be to understand these multiple mechanisms more fully and to find the Achilles' heel."
The study, "Antibody Neutralization and Escape by HIV-1," was published in Nature (2003;422:307-312).