November 28, 2002
Infection with Second Strain of HIV Compromises Treatment
Howard Hughes Medical Institute researchers are reporting that a
patient undergoing experimental therapy for HIV infection became
“superinfected” with a second strain of the virus, which
compromised his treatment.
“This finding has strong public health implications because it
means that if you are already infected with HIV you can become infected
with a second strain of the virus,” said the study’s senior
author Bruce D. Walker, a Howard Hughes Medical Institute investigator
at Harvard Medical School and Massachusetts General Hospital. “We
now know that superinfection is possible, but we still need to
determine how frequently people become infected by a second virus upon
exposure.”
“Our study doesn’t say that a vaccine is not possible. It says that the cross-protective immunity generated by natural infection is not that great.”
Bruce D. Walker
Walker cautioned that the findings in no way undercut the importance
of developing an effective HIV vaccine. But they do emphasize that
vaccine developers are likely to be locked in a long-term duel with a
continually mutating virus, he said.
Walker and colleagues from Los Alamos National Laboratory, Duke
University Medical Center, University of Wisconsin and Oxford
University published their article in the November 28, 2002, issue of
the journal Nature.
The patient described in the article was enrolled in a clinical
trial of an experimental antiviral drug therapy known as supervised
treatment interruption, or STI. The regimen aims to boost anti-HIV
immune response in patients with acute infection. During treatment,
physicians periodically interrupt antiviral therapy to allow the
patient’s immune system to mobilize to help control the infection.
Doctors carefully monitor the level of virus present in the
patient’s blood. Drug therapy is reinstated if levels of the virus
rise significantly.
Walker and his colleagues found that even though the patient’s
immune system showed enhanced responses and prolonged immune control
following treatment interruption, he abruptly developed an increase in
the level of virus in his bloodstream.
“After a prolonged period of relative control, we saw a sudden
increase in viremia that necessitated reinstitution of therapy,”
said Walker. “When we interrupted therapy again, the virus came
back even quicker than in previous interruptions and rose to an even
higher level.” After a final interruption in antiviral treatment,
in which the virus level rose and persisted, the patient chose to end
the therapy.
“When this patient experienced sudden increase in the level of
virus in his blood, we originally thought it was probably due to the
virus slowly evolving a new variant that could escape the existing
immune response,” said Walker. He and his colleagues pursued the
cause of the sudden rebounds in viral load, recognizing that the answer
might yield insight into how HIV infection persists.
Initial analysis of the patient’s HIV-fighting immune cells,
called CD8+ T-cells, indicated that they were not responding to
infection as they should. This raised the possibility that a distinct,
unrelated variant of the HIV virus had infected the patient.
The case for superinfection being the culprit was strengthened when
the patient reported that he had unprotected sex with a partner before
the appearance of new symptoms and coincident with the predominant rise
of the new virus. Indeed, genetic analyses of blood samples from the
patient confirmed the presence of a second type of HIV in the patient.
Walker and his colleagues then showed that even though the
patient’s immune cells had some cross-reactivity with the new
virus, this was not sufficient to control the secondary infection.
While the scientists’ findings may influence the direction of
future vaccine development strategies, Walker cautions that patients
with superinfection present unique challenges. “For one thing, we
studied the immune system in a person who is already infected, and that
amount of immunity in somebody who actually harbors HIV may be very
different functionally than the immunity if you could induce it with a
vaccine before the patient encountered HIV.
“Importantly, our study doesn’t say that a vaccine is not
possible,” said Walker. “It says that the cross-protective
immunity generated by natural infection is not that great.”
Particularly striking, said Walker, was that even though the two
strains of virus were only about 12 percent different genetically, the
difference in the surface proteins targeted by the immune cells was 50
percent. This broader immunity-related difference was what rendered the
new virus unrecognizable by the existing immune response, he said.
“This has important basic research implications, because
investigators have long believed in a phenomenon of ‘innocent
bystander activation,’ in which if you boost immunity to one viral
strain, it will boost immunity to others,” he said.
While there had been previous reports of superinfection of people by
different strains of HIV from disparate regions of the world, the
report of superinfection from two relatively close North American
strains of HIV is especially cautionary, said Walker. “This study
emphasizes the importance of achieving broad cross-reactive immunity
and incorporating immune responses to as much of the virus as possible
to counteract these problems,” he said.
Although the emergence of documented cases of superinfection
suggests that no single HIV vaccine is likely to be completely
effective for all strains of the virus, “if patients develop even
partially effective cellular immunity, they may end up with lower viral
load than they would otherwise have and will do better,” said
Walker.
Walker said that strategies to develop HIV vaccines may need to take
a cue from influenza, where efforts to develop new vaccines are ongoing
because new strains of the virus are emerging continually. “On
the other hand,” said Walker, “we’re learning an
incredible amount about the immune system and how it deals with chronic
viruses. I think that these kinds of insights are going to lead to
effective new strategies just by having a better understanding of how
the virus does its damage.”
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