"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.
Mary Beth Reilly, reillymb@umich.edu
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Journal
Proceedings of the National Academy of Sciences