Genetic Mutation That Protects Against HIV Confers No Resistance
to Plague, Scripps Research Scientists Find
By Jason Socrates Bardi
A group of scientists at The Scripps Research Institute
have provided strong evidence that a popular hypothesis concerning
the origins of a genetic mutation common among Caucasians
of Northern European descent that protects against human immunodeficiency
virus (HIV) is wrong.
The hypothesis suggests that the mutation conferred resistance
against bubonic plague in the Middle Ages, much as it does
against HIV today. This idea was based on the fact that the
mutation first appeared around the same time that the "Black
Death" plague epidemic killed a third of Europe's population
in the years 1346–1352. Since HIV was not present in
Europe at this time, individuals with the mutation must have
been protected against some other disease.
In a brief communication to be published this week in the
journal Nature, Scripps Research Immunology Professor
Donald Mosier and his colleagues show this hypothesis to be
incorrect.
Mosier performed studies that demonstrate that the mutation
does not protect against plague infection in mouse models
and that it is unlikely to have offered any protection against
the plague in humans during the Middle Ages.
An Important Receptor
The mutation in question is in the C–C chemokine receptor
5 gene, which makes the human receptor protein called CCR5.
CCR5 is a seven trans-membrane spanning protein of 332 amino
acids that inserts into the cell membranes of human CD4+ T
helper cells. HIV particles use CCR5 to gain entry into CD4+
T cells.
The CCR5 Δ32 mutation—a deletion of 32 bases of
DNA from the CCR5 gene—was first identified in 1996 in
individuals who seemed to be protected from infection with
HIV despite having had multiple high-risk exposures to the
virus.
The resistant individuals all had the 32-base pair mutation
in their CCR5 genes, and that left them with CD4+ T cells
with no CCR5 receptors, conferring resistance to HIV infection.
Later data showed that individuals who were heterozygous for
the mutation had lower CCR5 expression levels, less cell-to-cell
infection, and brighter clinical prognoses.
In order to test the HIV–plague hypothesis, an attenuated,
non-transmissible form of Yersinia pestis, the bacterial
cause of plague, was tested on mice both with and without
the CCR5 Δ32 mutation. There was no difference in susceptibility
between the two groups, says Mosier.
The possibility still exists, says Mosier, that the CCR5
Δ32 mutation arose due to the influence of some other
disease that was prevalent in the Middle Ages, such as smallpox.
Mosier plans to address this possibility next.
The brief communication, "CCR5 mutation and protection against
plague" was authored by Joan Mecsas, Greg Franklin,William
A. Kuziel, Robert R. Brubaker, Stanley Falkow, and Donald
E. Mosier and appears in the February 12, 2004 issue of the
journal Nature.
This work was supported by the National Institutes of Health.
Send comments to: jasonb@scripps.edu
|
