International team finds gene variants that affect response to HIV infection
Program builds scientific capacity in South Africa
A team of researchers based partly in South Africa has identified a key set of
immune system molecules that helps determine how effectively a person resists
infection with human immunodeficiency virus (HIV). Their work shows that mothers
with a specific type of genetic makeup may be less likely to pass HIV to their
offspring.
The finding has important implications for the development of vaccines to
combat the AIDS epidemic, according to Bruce Walker, a Howard Hughes Medical
Institute researcher. Walker is one of the leaders of the project, and a
professor of medicine at Harvard Medical School and director of the Partners
AIDS Research Center at Massachusetts General Hospital.
The research also offers an intriguing glimpse into the simultaneous
evolution of a pathogen and its human host. "This is the closest we have
come to being able to watch as the evolution of the human population is affected
by a pathogen," Walker said.
The other leaders of the project were Philip Goulder, assistant professor of
medicine at Partners AIDS Research Center, and Hoosen (Jerry) Coovadia,
professor of HIV/AIDS research at the Nelson R. Mandela School of Medicine at
the University of KwaZulu-Natal. A paper describing their work was published in
the December 9, 2004, issue of Nature.
AIDS researchers long have wondered why people have varying responses to HIV
infection. "Some people rapidly progress to illness within a year or two,
while others after 20 years of follow-up are still doing fine," said
Walker. "The range of outcomes is widespread."
To examine the question, Walker and his colleagues focused on the class I
human leukocyte antigen (HLA) molecules that occur in most of the cells in the
body. When a cell is infected with a virus, the HLA molecules grab pieces of the
proteins made by the virus and display the protein fragments on their surface.
Other immune system cells recognize the foreign proteins presented by the HLA
molecules and kill the infected cell, thereby stemming the infection.
The research team found that an individual's response to HIV infection
depends heavily on the varieties -- or alleles -- of the genes encoding HLA
molecules that the person has. But not all categories of HLA genes are equally
important. The class I HLA alleles are divided into three categories -- HLA-A,
HLA-B, and HLA-C. Specific HLA-B alleles generate much stronger immune responses
than do other HLA alleles. For example, in a study of 706 infected individuals
in South Africa who had not yet begun treatment, the type of HLA-B alleles a
person had affected the amount of virus in the blood; the number of CD4 cells a
person had (a common measure of immune system health); and immune reaction to
proteins made by HIV. By contrast, different alleles of HLA-A and HLA-C genes
had no effect on the immune response.
"The B alleles are doing most of the work," said Walker. Vaccine
developers therefore should give close attention to responses generated by the
HLA-B alleles, "since those seem to be the critical ones that influence
viral load."
The involvement of the HLA-B alleles was particularly interesting to the
researchers, since HLA-B alleles are much more diverse than either HLA-A or HLA-C
alleles in human populations. Immunologists often have speculated that the
greater diversity of HLA-B alleles indicates that they have been important
during human history in fending off attacks from other pathogens. For instance,
evolutionary forces may have promoted the diversification of HLA-B alleles so
that human populations would present a multifaceted defense against infection.
In their Nature paper, Walker and his colleagues point out that the
evolutionary influence of the HIV epidemic on HLA-B alleles already can be seen
in the offspring of mothers infected with HIV. Mothers with protective alleles
pass on HIV infection to their children less often than do mothers with alleles
that do less to stop the progression of the disease. As a result, the frequency
of the protective alleles would be expected to grow in the population.
The researchers conducted much of their work at the new Doris Duke Medical
Research Institute in Durban, which is the largest city of KwaZulu-Natal
Province in South Africa. The province is at the epicenter of the HIV epidemic
in sub-Saharan Africa. In KwaZulu-Natal province, a third of pregnant women are
infected with HIV, and in Durban, prevalence among pregnant women exceeds 50
percent.
Doing AIDS research in South Africa "is one of the things we're most
excited about," said Walker. Based on previous research experiences in the
country, Walker and several colleagues associated with Harvard Medical School
and Massachusetts General Hospital knew that South Africa had very talented
scientists. But they were also aware that those researchers did not usually have
the financial support to develop professionally.
"We decided to set our sights high," Walker said. "We decided
to build the world's best biomedical research institute and put it right in the
middle of the world's worst HIV epidemic, because we knew that that would
facilitate the science needed to understand why the epidemic is so bad there, as
well as vaccine development."
Funding from the Doris Duke Charitable Foundation through Massachusetts
General Hospital enabled construction of the institute at the University of
KwaZulu-Natal's Nelson R. Mandela School of Medicine. "The institute opened
its doors in July 2003, and in December 2004 we have a Nature paper by a
first-author, who is South African and who was not doing research when we
arrived because of a lack of opportunities," said Walker.
Photini Kiepiela, the first author of the article and a researcher at the
institute, agreed that the establishment of the institute was critical in
generating the new results. "The purpose of doing this work here is to
nurture local South African scientists. [And] if not for this institute, it
would not have been possible to do this work here." - EurekAlert
More information:
Nelson R. Mandela School of
Medicine
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