For
First Time, Scientists Show an HIV Vaccine Impacts the Genetic
Makeup of the Virus
Results
suggest new vaccine strategies to debilitate viruses by tapping
into this response
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Dr.
James I. Mullins, professor of microbiology
at the University of Washington in Seattle,
led a study of the selective pressure of an
HIV-1 vaccine on the virus (Photo
courtesy of University of Washington).
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March
1, 2011 -- An AIDS vaccine tested in people, but found to be
ineffective, influenced the genetic makeup of the virus that
slipped past. The findings suggest new ideas for developing
HIV vaccines.
The results were published Feb. 27 in Nature Medicine.
This is the first evidence that vaccine-induced cellular immune
responses against HIV-1 infection exert selective pressure on
the virus. "Selective pressure" refers to environmental
demands that favor certain genetic traits over others.
The senior author of the multi-institutional study is Dr. James
I. Mullins, University of Washington (UW) professor of microbiology.
The research team analyzed the genome sequences in HIV-1 isolated
from 68 newly infected volunteers in the STEP HIV-1 vaccine
trial. Mullins and the other principal researchers who carried
out this study were not involved in the STEP trial.
The STEP trial was a double-blind, Phase 2B test-of-concept
of a Merck HIV-1 subtype B vaccine. The vaccine, MRKAd5, was
designed to make the body produce infection-fighting white blood
cells, commonly called killer T-cells, that could recognize
and target specific parts of HIV-1 known as Gag, Pol and Nef.
The STEP trial was conducted at 34 North American, Caribbean,
South American and Australian locations where the HIV-1 subtype
B was the predominant virus in the local HIV-infected populations.
The trial enrolled 3,000 participants.
Preliminary tests indicated the vaccine was encouraging the
appearance of the desired virus-attacking cells. More than 75
percent of vaccinated participants produced HIV-1 specific T
cells.
Nevertheless, this response to the vaccine did not predict protection.
The trial failed. Immunizations were halted, Mullins recalled,
after the first interim analysis indicated that the vaccine
neither prevented HIV-1 infection nor reduced the load of virus
in the body.
"Even though the T-cell responses were not sufficient to
prevent infection," Mullins said, "we were interested
in whether the vaccine-elicited T-cells had any impact on those
strains of HIV-1 that established infections in the study subjects."
The research team tested for a "sieve effect," which,
Mullins explained, occurs when a vaccine successfully blocks
some strains of virus and not others. The researchers wanted
to know, What are the genetic characteristics of those breakthrough
viruses that slipped past the immunization barrier erected by
the MRKAd5 vaccine?
The research team isolated strains of HIV-1 from both vaccine
and placebo recipients in the study, and compared the genetic
sequences of the strains. This would help researchers to determine
if any changes in the "founder virus" -- the virus
first detected in the infection -- might have helped it evade
the vaccine-induced immune response and take hold in the vaccinated
individuals.
The researchers identified potential T-cell targets in the protein-producing
regions of the founder virus genetic sequences and compared
these to the virus protein-targets of the vaccine -- Gag, Pol
and Nef. The researchers found that the distances for these
viral genetic sequences were greater for the viruses taken from
the vaccinated individuals, compared to those from the placebo
recipients.
The most significant virus genetic site distinguishing vaccine
from placebo recipients was in the region known as Gag-84, which
was encompassed by several of the viral segments targeted by
the vaccine.
Moreover, the researchers said that the extended divergence
between the viruses from the vaccinated and the placebo groups
was confined only to the sequences for the proteins targeted
by the vaccine components (Gag, Pol and Nef) and was not found
in other HIV-1 protein sequences. The influence of the vaccine
on the virus genotype, Mullins said, was subtle.
Mullins and his team, as well as their collaborators from the
STEP trials studies, are doing similar studies of the genetic
impact of the Thailand vaccine RV144 on the AIDS virus. The
RV144 vaccine was the first to show some probable effectiveness,
but its efficacy was not great enough to put it to more general
use.
The researchers added that their findings on breakthrough viruses
suggest that new vaccines should be designed to put selective
pressure on the virus in a controlled manner.
Such a vaccine, Mullins said, should select for genetic mutations
in regions of the virus known to be associated with viral control
and should avoid selecting for strains that can either escape
the immune defense or act as decoys to fool the immune system.
The researchers propose a goal for new designs of vaccines aimed
at inducing killer T-cell responses: corner the virus into assuming
forms that debilitate it. This would make the infecting virus
fitness-impaired -- unable to adapt, reproduce in great numbers
and cause disease progression.
"Despite the sad results of the STEP trial," Mullins
said, "it has provided clues to ways for science to go
forward in the search for an HIV vaccine.
Investigator affiliations:
Department of Microbiology, University of Washington, Seattle,
WA; U.S. Military HIV Research Program, Rockville, MD; Vaccine
and Infectious Disease Institute, Fred Hutchinson Cancer Research
Center, Seattle, WA; Merck Research Laboratories, West Point,
PA; San Francisco Department of Health, San Francisco, CA; Bill
and Melinda Gates Foundation, Seattle, WA.
This research was supported by a grant from the U.S. Public
Health Service.
