December 09, 2004
Gene Variants May Help Fend Off HIV Infection
HHMI investigator Bruce D. Walker reviews patient data with nurses at a clinic 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 D. 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 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.”
Bruce D. Walker
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 has affected the amount of virus in the blood; the number of CD4
cells a person has (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 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.”
Photo: Courtesy of Bruce D. Walker
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