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ANN ARBOR,
MI - Absence of a genetic mutation that protects people from
HIV infection could be a major factor responsible for the current
AIDS epidemic in sub-Saharan Africa, according to a new model developed
by University of Michigan scientists.
"The critical
mutation is in the gene for a receptor molecule called CCR5, which
the HIV virus uses to infect immune cells in its human host,"
says Denise Kirschner, Ph.D., an associate professor of microbiology
and immunology in the U-M
Medical School.
"People
with two copies or alleles of this mutation are almost completely
protected against HIV," explains Kirschner. "Those with
one mutated and one normal copy can be infected, but they carry
lower levels of the virus and take two years longer, on average,
to develop AIDS. People with two normal copies of the CCR5 gene
are most susceptible to HIV infection."
Previous studies
by other scientists found that the CCR5 mutation is much more common
in people of European descent than in African or Asian populations.
So Kirschner and her colleagues developed a mathematical model to
test their hypothesis that the prevalence of CCR5 mutations can
limit the spread of AIDS in an entire population. Results of the
model were published in the August 21 on-line edition of the Proceedings
of the National Academy of Sciences.
"We designed
our model to compare the rate of HIV transmission in two populations,"
explains Kirschner. "All the individuals in one group had two
copies of the normal CCR5 gene. The second group was a combination
of individuals -- some with two mutated CCR5 alleles, some with
one mutated and one normal allele, and others with two copies of
the normal gene."
Estimates of
infectivity, transmission and disease progression were based on
recent HIV research, according to Kirschner. The model used demographic
data and initial values for infection from UNAIDS surveys conducted
in Malawi, Zimbabwe and Botswana.
In the model
population without the protective mutation, U-M researchers found
that HIV/AIDS prevalence increased logarithmically for the first
35 years of the epidemic, reaching 18 percent before leveling off.
In the model population with the mutated CCR5 gene, the epidemic
spread more slowly for the first fifty years and HIV/AIDS prevalence
reached approximately 12 percent. Prevalence began to decline after
70 years.
"Our results
suggest that the CCR5 mutation limits the epidemic by decreasing
the probability of infection due to lower viral loads in people
with one copy of the mutated gene," Kirschner says.
Since HIV eventually
kills its human host, the number of individuals with the protective
mutation tends to increase over time in any population exposed to
the virus. Kirschner suggests that the mutation may be more common
in European populations, because of widespread epidemics of smallpox
and bubonic plague during the Middle Ages. Several studies have
suggested that plague and smallpox use the same CCR5 receptor to
infect cells.
"Our model
suggests that the CCR5 mutation could have reached its present frequency
in Northern European populations within this time frame, if selected
for by a disease with virulence patterns similar to HIV," Kirschner
says. "It also supports the idea that HIV has only recently
been introduced as a pathogen into African populations."
In future mathematical
models, Kirschner hopes to include interactions with other diseases
and genetic factors affecting HIV transmission.
Development
of the U-M model was funded by the National
Heart, Lung and Blood Institute of the National Institutes of
Health. Amy D. Sullivan, Ph.D., a former U-M post-doctoral fellow
now with the Centers for Disease Control and Prevention Epidemiology
Program Office, and Janis Wigginton, former research associate in
the U-M Medical School, were co-authors on the PNAS study.
Written by
Sally Pobojeewski
For more
information, contact Kara Gavin or Mary Beth Reilly, UMHS Public
Relations, 734-764-2220, or by e-mail.
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