A team led by Douglas D. Richman, MD, a virologist and physician with the Veterans Affairs (VA) San Diego Healthcare System and the University of California, San Diego (UCSD) School of Medicine, found that patients infected with HIV rapidly develop a strong antibody response against the virus. But the same antibodies tasked with recognizing and disabling the germ appear to force its ongoing evolution into new strains that dance around the antibody response and continue to replicate.
"The neutralizing antibodies are exerting a very strong selective pressure on the virus, and the virus is continually mutating to avoid it," said Richman, a noted AIDS researcher who recently won VA's Middleton Award, the agency's highest honor for biomedical researchers.
The researchers used sophisticated new technology, made by California-based ViroLogic, Inc., to clone actual virus from the blood plasma of HIV patients and genetically combine it with a gene that makes luciferase, the same light-emitting enzyme in fireflies. The glowing enzyme helped the scientists track the virus' replication.
Richman and colleagues took viral samples periodically from HIV patients and incubated the virus with antibody-containing plasma samples from the same patients. Blood plasma contains antibodies but no white blood cells. This way, the researchers could tease out the effects of antibodies alone on the virus, independent of the rest of the immune system.
The results, based on tests of 19 patients over 39 months, showed that most patients developed a high concentration, or titer, of antibodies to HIV within a few months, and the antibodies continually changed their "spectrum of activity" to keep pace with the ever-changing virus. That is, the antibodies evolved in their ability to recognize different protein shapes on the outer coating of the virus.
However the virus consistently evolved faster than the antibody response, developing new protein structures on its surface, so that antibodies from previous months' samples were ineffective in neutralizing new virus from the same patient.
"The bad news is that the virus is always staying a step ahead, and the neutralizing antibody response can't control it," said Richman.
At the same time, Richman said neutralizing antibodies could hold promise as a therapy, or vaccine, if scientists can engineer them to recognize many different strains of virus.
"An optimistic view is that this antibody response is a very potent selective force," said Richman. "If it were present at the time of exposure [to the virus], it could provide some protection."
The AIDS virus has been described as a "genetic moving target" because of its frustrating ability to rapidly mutate and escape the body's efforts to neutralize or destroy it. In fact, up to dozens of strains can develop within the same person. Also, HIV infects and disables the very immune cells, helper T cells, which are supposed to mobilize the immune system against the virus. Richman's study is the first to track in detail how the virus outpaces the antibody response over time.
Since 1987, researchers have studied about 60 potential HIV vaccines to help stem the AIDS epidemic. So far, no vaccine has won Food and Drug Administration approval as safe and effective. Most scientists agree that for a vaccine to work, it will need to activate both arms of the immune system: antibodies, which are key in thwarting the initial infection; and killer white blood cells, which provide longer-term protection. In recent years, AIDS scientists have made progress on the cellular front; several vaccines using this approach are in the pipeline for clinical trials. But understanding how to get neutralizing antibodies to work against HIV has proved a tougher challenge.
According to the Centers for Disease Control and Prevention, 800,000 to 900,000 Americans are living with HIV infection. VA, the nation's largest health-care system, is also the nation's largest single provider of health care to those with HIV. In fiscal year 2001, more than 18,500 veterans received care for HIV at VA medical centers and clinics.
Richman directs VA's Research Center for AIDS and HIV Infection and the Center for AIDS Research at UCSD. Collaborating with him on the study were Susan J. Little, MD, a principal investigator in UCSD's Antiviral Research Center and a VA infectious disease specialist; and Terri L. Wrin and Christos J. Petropoulos of ViroLogic, Inc. The firm, which specializes in HIV drug resistance testing, developed the DNA viral test used in the study. Richman serves on the company's scientific advisory board.
Funding for the study was provided by the National Institutes of Health, VA, and UCSD.
Cynthia Butler (VA)
Sue Pondrom (UCSD)