Mathematical modeling of ultradeep sequencing data reveals that acute CD8+ T-lymphocyte responses exert strong selective pressure in simian immunodeficiency virus-infected macaques but still fail to clear founder epitope sequences

J Virol. 2010 Jun;84(11):5802-14. doi: 10.1128/JVI.00117-10. Epub 2010 Mar 24.


The prominent role of antiviral cytotoxic CD8(+) T-lymphocytes (CD8-TL) in containing the acute viremia of human and simian immunodeficiency viruses (HIV-1 and SIV) has rationalized the development of T-cell-based vaccines. However, the presence of escape mutations in the acute stage of infection has raised a concern that accelerated escape from vaccine-induced CD8-TL responses might undermine vaccine efficacy. We reanalyzed previously published data of 101,822 viral genomes of three CD8-TL epitopes, Nef(103-111)RM9 (RM9), Tat(28-35)SL8 (SL8), and Gag(181-189)CM9 (CM9), sampled by ultradeep pyrosequencing from eight macaques. Multiple epitope variants appeared during the resolution of acute viremia, followed by the predominance of a single mutant epitope. By fitting a mathematical model, we estimated the first acute escape rate as 0.36 day(-1) within escape-prone epitopes, RM9 and SL8, and the chronic escape rate as 0.014 day(-1) within the CM9 epitope. Our estimate of SIV acute escape rates was found to be comparable to very early HIV-1 escape rates. The timing of the first escape was more highly correlated with the timing of the peak CD8-TL response than with the magnitude of the CD8-TL response. The transmitted epitope decayed more than 400 times faster during the acute viral decline stage than predicted by a neutral evolution model. However, the founder epitope persisted as a minor population even at the viral set point; in contrast, the majority of acute escape epitopes were completely cleared. Our results suggest that a reservoir of SIV infection is preferentially formed by virus with the transmitted epitope.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Amino Acid Sequence
  • Animals
  • Antibodies, Viral
  • Antigens, Viral
  • CD8-Positive T-Lymphocytes / immunology*
  • Epitopes*
  • Founder Effect
  • Immune Evasion / immunology*
  • Immunity, Cellular
  • Macaca
  • Models, Immunological*
  • Models, Theoretical
  • Simian Acquired Immunodeficiency Syndrome / immunology
  • Simian Immunodeficiency Virus / immunology*


  • Antibodies, Viral
  • Antigens, Viral
  • Epitopes