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Immune system control of HIV may not
protect against second infection
Report may complicate vaccine development,
supports importance of safer sex practices
BOSTON - November 27, 2002 - Although research has shown
that antiviral therapy during the earliest stages of infection can
enable HIV-infected individuals to eventually control the virus
with their immune systems alone, that immune control may not protect
patients from infection with a different but related strain of HIV.
In the Nov. 28 issue of Nature, a research team based at
Massachusetts General Hospital (MGH) reports on a study participant
who, having maintained successful immune control of HIV for almost
a year, became infected with another strain of the virus after an
unprotected sexual encounter. Moreover, the patient's immune system
has not effectively controlled the second viral strain.
"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.
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Media Contact: Susan
McGreevey, MGH Public Affairs
Physician Referral Service: 1-800-388-4644
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