"The virus is gradually evolving and learning how to evade the immune system," says the senior author of the study Bruce Walker, MD, of the Partners AIDS Research Center at MGH. "This study shows for the first time that minor mutations in the virus can have a major impact on the ability of the immune defenses to recognize it."
When HIV infects a cell, the cell alerts the immune system that it contains a foreign invader by displaying viral protein fragments on the cell surface. This is a suicide signal that alerts the immune system to kill the infected cell. The immune response that is generated is dependent on the ability to recognize the displayed HIV fragment. Walker and his colleagues have found that the virus can mutate these targeted regions and in doing so evade this attack.
"Our study indicates that the virus can learn how to evade the immune response in one person, and that it retains this ability even after it is transmitted to the next person," says Philip Goulder, MD, the lead author on the study. When this happens, the immune system is forced to use a second-line attack strategy that was less effective in containing the virus in the patients studied. These studies, which were performed in HIV-infected mothers who transmitted virus to their infants, showed that the infected infants are less able to control the virus because of mutations that occurred in the mothers. The effects of these mutations were particularly apparent in the children since they inherit key elements of their immune systems from their parents, and thus there is a strong chance that they will be programmed to target the same regions that the mother targeted. In mothers in whom mutations had already arisen, the children could not target the virus effectively.
The authors also examined adults who recently had been infected with HIV by sexual transmission, and found that the viruses presently being transmitted have already evolved to be able to avoid a number of important immune responses. Once these mutations arise, they do not appear to revert to the original strain, suggesting that escape mutations are likely to accumulate as the epidemic progresses.
The findings have significant implications for vaccines that are presently in development. "Vaccines being tested today are based on strains that were isolated a number of years ago, " says Walker. "These vaccines are attempting to induce immune responses to regions of the virus that may have already mutated, and thus the immune responses may be less effective." In the same way that influenza virus evolves to escape detection by immune responses and requires new vaccines to be made on a regular basis, HIV also is evolving. The extent to which this will affect present vaccine candidates is not known, but the present study indicates that this is something that will need to be monitored very closely.
The current work was supported by the Medical Research Council (UK), the NIH, the Doris Duke Charitable Foundation, the Lloyd Foundation and the Elizabeth Glaser Pediatric AIDS Foundation and a number of private donors.
The Massachusetts General Hospital, established in 1811, is the original and largest teaching hospital of Harvard Medical School. The MGH conducts the largest hospital-based research program in the United States, with an annual research budget of more than $300 million and major research centers in AIDS, the neurosciences, cardiovascular research, cancer, cutaneous biology, transplantation biology and photo-medicine. In 1994, the MGH joined with Brigham and Women's Hospital to form Partners HealthCare System, an integrated health care delivery system comprising the two academic medical centers, specialty and community hospitals, a network of physician groups and nonacute and home health services.