TY - JOUR
T1 - Dynamics of haplotype frequency change in a CD8+TL epitope of simian immunodeficiency virus
AU - Hughes, Austin L.
AU - O'Connor, Shelby
AU - Dudley, Dawn M.
AU - Burwitz, Benjamin J.
AU - Bimber, Benjamin N.
AU - O'Connor, David
N1 - Funding Information:
This work was supported by NIH grant numbers 1 R01 AI077376-01 and 1 R21 AI082880-01 to D.H.O. and by 1 R01 GM GM43940-21 to A.L.H. This publication was made possible in part by Grant Number P51 RR000167 from the National Center for Research Resources (NCRR) , a component of the National Institutes of Health (NIH), to the Wisconsin National Primate Research Center, University of Wisconsin-Madison. This research was conducted in part at a facility constructed with support from Research Facilities Improvement Program grant numbers RR15459-01 and RR020141-01 . This publication's contents are solely the responsibility of the authors and do not necessarily represent the official views of NCRR or NIH.
PY - 2010/5
Y1 - 2010/5
N2 - Deep pyrosequencing of a CD8+TL epitope from the Tat protein of simian immunodeficiency virus (SIV) from four infected rhesus macaques carrying the restricting MHC allele (Mamu-A*01) for that epitope, revealed that natural selection favoring escape mutations led to an increase in the frequency of haplotypes in the epitope region that differed from the inoculum. After 20 weeks of infection, a new sequence haplotype in the epitope region had increased to a frequency greater than 50% in each of the four monkeys (range 57.9-98.9%); but the predominant haplotype was not the same in all four monkeys. Thus, even under strong selection favoring escape from CD8+TL recognition, the random nature of mutation itself is the primary factor affecting which escape mutation is likely to become predominant within an individual host. The relationship between the frequency of the inoculum haplotype in the epitope region and time post-infection approximated a simple hyperbola. On this assumption, the expected ratio of the frequencies at the inoculum at two times t1 and t2, fi(t2)/fi(t1), will be given by t1/t2. Because standard phylogenetic methods for reconstructing ancestral sequences failed to predict the inoculum sequence correctly, we used this relationship to predict the inoculum sequence with 100% accuracy, given data on haplotype frequencies at different time periods.
AB - Deep pyrosequencing of a CD8+TL epitope from the Tat protein of simian immunodeficiency virus (SIV) from four infected rhesus macaques carrying the restricting MHC allele (Mamu-A*01) for that epitope, revealed that natural selection favoring escape mutations led to an increase in the frequency of haplotypes in the epitope region that differed from the inoculum. After 20 weeks of infection, a new sequence haplotype in the epitope region had increased to a frequency greater than 50% in each of the four monkeys (range 57.9-98.9%); but the predominant haplotype was not the same in all four monkeys. Thus, even under strong selection favoring escape from CD8+TL recognition, the random nature of mutation itself is the primary factor affecting which escape mutation is likely to become predominant within an individual host. The relationship between the frequency of the inoculum haplotype in the epitope region and time post-infection approximated a simple hyperbola. On this assumption, the expected ratio of the frequencies at the inoculum at two times t1 and t2, fi(t2)/fi(t1), will be given by t1/t2. Because standard phylogenetic methods for reconstructing ancestral sequences failed to predict the inoculum sequence correctly, we used this relationship to predict the inoculum sequence with 100% accuracy, given data on haplotype frequencies at different time periods.
KW - Cytotoxic T lymphocyte
KW - Escape mutation
KW - Positive selection
KW - Pyrosequencing
KW - Simian immunodeficiency virus
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U2 - 10.1016/j.meegid.2010.02.001
DO - 10.1016/j.meegid.2010.02.001
M3 - Article
C2 - 20149896
AN - SCOPUS:77951978212
SN - 1567-1348
VL - 10
SP - 555
EP - 560
JO - Infection, Genetics and Evolution
JF - Infection, Genetics and Evolution
IS - 4
ER -