"We were quite surprised and disappointed when we saw this person's viral levels rise," says Bruce Walker, MD, director of the Partners AIDS Research Center based at MGH, senior author of the Nature report. "He had previously achieved a strong, broad immune response against HIV, so we had been feeling very optimistic. Clearly this indicates that vaccine development is going to be a greater challenge than we have anticipated." Walker, who is director of the Division of AIDS at Harvard Medical School, gave a preliminary report on this development in June at the International AIDS Conference in Barcelona.
In earlier studies published in Science and Nature, Walker's team reported that starting patients on HAART (highly active antiretroviral therapy) within the first weeks to months after infection could allow the immune system to fight back against HIV. The 1997 Science paper showed how early HAART caused virus levels in the blood to drop and induced production of T helper cells targeted against HIV. These cells -- the 'generals' of the immune system -- are usually killed off by HIV, cutting off their normal function of directing the T killer cells -- the immune system's 'infantry' -- to attack and destroy virus-infected cells.
A 2000 report in Nature described an MGH study in which patients who maintained strong T helper cell response after several months of HAART volunteered to discontinue therapy. While some of the participants needed to reinstate HAART temporarily, all of them eventually achieved some level of longer-term viral control. It appeared that, when treatment discontinuation allowed viral levels to rise, the participants' immune systems responded by producing HIV-specific T killer cells to keep the virus in check.
The patient in the current study was one of those in the 2000 report. He had achieved stable viral control after his second treatment interruption, but seven months later his viral level began to rise again. When subsequent treatment reinstatement and reinterruption did not again establish viral control, Walker's team became concerned.
"The virus was coming back quicker than it ever had, and for the first time the T killer cell response declined instead of increasing in response to higher viral levels," Walker says. "For some reason the immune system 'infantry' was not being mobilized against the enemy."
To solve the mystery, Walker's team ran a series of detailed tests of the patient's anti-HIV immune response. Virus samples taken early and later in the course of treatment proved to have significant genetic differences, and further examination established that, while only one viral strain, termed virus A, was present in early samples, a second strain, virus B, had suddenly appeared and become dominant in all later samples.
Although they represent distinct viral strains, both viruses are from the same group of closely related viruses, called a clade. This is the first reported instance of a patient's being infected by two viral strains from the same clade. While the overall differences in the amino acid sequences of virus A and virus B were only 12 percent -- normal for strains found in North America -- those protein segments targeted by the immune system differed by 50 percent, meaning that the immune cells were encountering a practically new virus.
However, the researchers did make one positive observation. The patient's immune system did generate some new responses against the unique parts of the virus B. "Even in a chronic infection situation, it looks like there is a chance to generate broader immune responses against the unique parts of a new strain of virus," Walker says. "If we had been able to generate these new immune responses by a therapeutic vaccine prior to this patient's exposure to the new virus, we might have made him better able to prevent new infection."
Walker also stresses how important it is for HIV-infected individuals to continue practicing safer sex, even when their partners also are HIV positive. The patient in this study did admit having an unprotected sexual encounter a couple of months before the first detection of virus B. In the weeks following that exposure, he developed the flu-like symptoms characteristic of acute HIV infection.
"It's clear that a preventive vaccine is going to have to target the many strains of HIV that are out there to be successful," Walker says. "That's going to be a much bigger challenge than that of coming up with a new flu vaccine every year." He and his colleagues are currently examining the differences in specific parts of the viruses targeted by the immune system and how the immune response may impact the evolution of the virus.
Other authors of the Nature report are co-first authors Marcus Altfeld, MD, and Todd Allen, PhD, Xu G. Yu, MD, Mary Johnston, Deepak Agrawal, MD, Ben Davis, MD, Paul Lee, Erica Maier, Jason Harlow, Philip Goulder, MD, PhD, Christian Brander, PhD, and Eric Rosenberg, MD, all of the Partners/MGH AIDS Research Center and the HMS Divison of AIDS; Bette Korber, PhD, of Los Alamos National Laboratory in New Mexico; David Montefiori, PhD, of Duke University Medical Center; and David O'Connor, PhD, of University of Wisconsin. The study was supported by grants from the Doris Duke Charitable Foundation, the National Institute for Allergy and Infectious Diseases, the Foundation for AIDS & Immune Research, and the Partners/Fenway/Shattuck Center for AIDS Research.
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 almost $300 million and major research centers in AIDS, the neurosciences, cardiovascular research, cancer, cutaneous biology, transplantation biology and photomedicine. 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.
Journal
Nature