Master of microevolution  pg. 3

Mutating to survive

HIV is not without its vulnerabilities. There are now more than 20 different drugs or drug combinations that can block the actions of key enzymes necessary for viral replication. More drugs are in development. Resistance is a major problem, however.

Each time HIV copies its genome, on average one error, or mutation, is introduced. Some errors are crippling: the resulting viral particle is no longer infectious. But other mutations enable the virus to hide from the immune defenses that are trying to neutralize it, or become “resistant” to the drugs that try to block it. These are the viruses that survive and thrive—because they are the fittest. “There is almost no end to the ability of the virus to change its genetic structure,” says Paul Spearman, M.D., director of Pediatric Infectious Diseases at Emory University, who is trying to understand the assembly process of the virus in order to develop an effective vaccine against it. “It’s definitely the most variable virus that we’ve ever encountered as a major pathogen.”

Not every part of HIV mutates rapidly. Some regions of a viral envelope protein called gp120 are relatively stable or “conserved,” though usually hidden from view. Gp120 exists as a trimer, three proteins bound tightly together in a sugar coat. When it binds to the CD4 receptor on the helper T cell, the trimer opens up, allowing further binding to a second “co-receptor” on the cell surface, and exposing the conserved region of the protein. Virus and cell membranes then fuse, allowing the viral contents to be “dumped” into the cell.

It’s this more vulnerable part of gp120 that Spearman and his colleagues are targeting. They’ve begun animal tests of a “pseudo-virion,” a fake (and non-infectious) viral particle, consisting of the gp120 trimer attached to the CD4 receptor in such a way that the normally hidden, genetically conserved and less mutable region of the viral receptor is exposed. The hope is that this potential vaccine will generate antibodies that recognize and attach to this viral “Achilles tendon,” thereby neutralizing the virus and preventing it from entering its target cell.

Other researchers are exploring ways to boost the effectiveness of cytotoxic T cells. Although HIV does not attack cytotoxic T cells (they bear another type of receptor, called CD8), their ability to rid the body of infected cells declines as the directions from helper T cells weaken.

Some people infected with HIV seem to be able to control the virus for long periods of time—even without drug therapy. “These are people who for whatever reason managed to get the upper hand very early,” says Spyros Kalams, M.D., director of the HIV Vaccine Clinical Research Site at Vanderbilt, whose worked helped define the critical interaction between helper and cytotoxic T cells in defending against HIV.

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