- 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 http://www.med.umich.edu/medschool/ 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 <http://www.pnas.org/ 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 <http://www.nhlbi.nih.gov/index.htmNational
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.
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- For more information, contact Kara Gavin or Mary Beth
Reilly, UMHS Public Relations, 734-764-2220, or by <mailto:UMHSmedia@umich.edue-mail.
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- http://www.med.umich.edu/opm/newspage/kirschneraids.htm
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