Selective Pressures for the HIV-1 Resistance Allele

David Borota and Peder Digre Honors 396 Autumn 2010

"

Mechanism behind HIV-1 Infection and Resistance

The most common viral entryway for HIV-1 is through the CD4 and

CCR5 chemokine coreceptors found on the surface membranes of macrophages.

Once inside the target cell, the retrovirus RNA genome is converted

to DNA and then integrated within the host cells DNA through its own retroviral integrase enzyme, allowing the virus genome to be replicated by the host cell, furthering proliferation of the virus. nonfunctioning CCR5 receptor that stays in the cytoplasm of the macrophage.

The CCR5-32 confers resistance to HIV infection by producing a

HIV-1 Infection in Heterozygous Individuals

Characteristics of the Allele

The CCR5-32 allele is found almost exclusively in

European populations with a frequency of about 10%.

Allele frequency shows a distinct north-south gradient. HIV has only been recorded infecting humans since the

early 1980s, far too recent for it to have produced this frequency gradient.

What selective pressures caused the frequency in European

populations? Was the Black Plague, Viking expansion, or Roman conquest responsible?

CCR5-32 Allele Frequency

Data Adapted From Papers by E. Faure and G. Lucotte

Selective Pressures by the Black Death

Argument: The allele conferred a degree of resistance to

Yersinia pestis infection and thus the allele offers a selective advantage in humans.
Plague bacillus Yersinia pestis infects macrophages Black Death killed millions, with infection rates as high as 78%

in some populations

Assumption: The Black Death affected Europe most

extensively, providing the necessary selection for the resistance allele that yielded the high frequency observed today.

Selective Pressures by the Black Death

Evidence against the hypothesis:
The Black Death did not affect Europe exclusively. Rates of death were as

high or higher in Eastern regions of the world. North-south gradient does not reflect the rates of infection and mortality caused by the Black Death. The allele does not protect against Yersinia pestis infection.
CCR5-deficient mice not resistant to infection. No statistical difference in allele frequency between plague mass graves and famine gravesites.

The allele does not deviate from Hardy-Weinberg proportions at the time

of the Black Death. The alleles origin and high frequency predates the Black Death by several hundred years.

Selective Pressures by Viking Expeditions

Vikings spread the mutation from 800 1000 CE Present-day frequencies correspond to Viking Expeditions Descendants of Vikings have the highest frequencies

(Iceland)
Vikings were a numerically small group small selective

pressure

Selective Pressures by Roman Expansion

Spread of pathogens that negatively selected for the CCR5-32

allele

Extended time period for selective pressure The longer the Romans occupied an area, the lower the frequency

is today

Why would the frequency not have changed in Liechtenstein/

Germany?

Roman Expansion did not reach the area and affect the

frequencies

Colonization Dates and Allele Frequencies

Figure by E. Faure

Figure by E. Faure

Summary

Black Death not associated with establishing frequencies of

CCR5-32

Source of gradient cannot be positively identified selective

pressures are not mutually exclusive

Information helpful to understand and develop new venues

of utilizing this particular allele to offer new methods of treatment and facilitate the development of a potential cure or preventative care.

Sources

Cohn, S. K., and L. T. Weaver. "The Black Death and AIDS: CCR5-32 in Genetics and History." QJM 99.8 (2006): 497-503. Web. Faure, Eric, and Manuela Royer-Carenzi. "Is the European Spatial Distribution of the HIV-1-Resistant CCR5-32 Allele Formed by a Breakdown of the Pathocenosis due to the Historical Roman Expansion?" Infection, Genetics and Evolution 8.6 (2008): 864-74. Web. Galvani, A.P., and Montgomery, S. "Evaluating Plague and Smallpox as Historical Selective Pressures for the CCR5-32 HIV-Resistance Allele." Proceedings of the National Academy of Sciences of the United States of America 100.25 (2003): pp. 15276-15279. Web. Hedrick, Philip W., and Brian C. Verrelli. "Ground Truth for Selection on CCR5-32." Trends in Genetics 22.6 (2006): 293-6. Web.

Hummel, S, et al. "Detection of the CCR5- 32 HIV resistance gene in Bronze Age skeletons." Genes & Immunity 6.4 (2005): 371-374. Academic Search Complete. EBSCO. Web. 29 Nov. 2010. Lucotte, Grard, and Florent Dieterlen. "More about the Viking Hypothesis of Origin of the 32 Mutation in the CCR5 Gene Conferring Resistance to HIV-1 Infection." Infection, Genetics and Evolution 3.4 (2003): 293-5. Web. Sabeti P.C., Walsh E., Schaffner S.F., Varilly P., Fry B., et al. 2005 The Case for Selection at CCR5-32. PLoS Biol 3(11): e378.doi:10.1371/journal.pbio.0030378 Zawicki, Przemysaw, and Henryk W. Witas. "HIV-1 Protecting CCR5-32 Allele in Medieval Poland." Infection, Genetics and Evolution 8.2 (2008): 146-51. Web.