title: Epitope-specific CD8+ T lymphocytes cross-recognize mutant simian immunodeficiency virus (SIV) sequences but fail to contain very early evolution and eventual fixation of epitope escape mutations during SIV infection.
abstract: Human immunodeficiency virus (HIV) and simian immunodeficiency virus (SIV) evade containment by CD8(+) T lymphocytes through focused epitope mutations. However, because of limitations in the numbers of viral sequences that can be sampled, traditional sequencing technologies have not provided a true representation of the plasticity of these viruses or the intensity of CD8(+) T lymphocyte-mediated selection pressure. Moreover, the strategy by which CD8(+) T lymphocytes contain evolving viral quasispecies has not been characterized fully. In the present study we have employed ultradeep 454 pyrosequencing of virus and simultaneous staining of CD8(+) T lymphocytes with multiple tetramers in the SIV/rhesus monkey model to explore the coevolution of virus and the cellular immune response during primary infection. We demonstrated that cytotoxic T lymphocyte (CTL)-mediated selection pressure on the infecting virus was manifested by epitope mutations as early as 21 days following infection. We also showed that CD8(+) T lymphocytes cross-recognized wild-type and mutant epitopes and that these cross-reactive cell populations were present at a time when mutant forms of virus were present at frequencies of as low as 1 in 22,000 sequenced clones. Surprisingly, these cross-reactive cells became enriched in the epitope-specific CD8(+) T lymphocyte population as viruses with mutant epitope sequences largely replaced those with epitope sequences of the transmitted virus. These studies demonstrate that mutant epitope-specific CD8(+) T lymphocytes that are present at a time when viral mutant epitope sequences are detected at extremely low frequencies fail to contain the later accumulation and fixation of the mutant epitope sequences in the viral quasispecies.
authors.affiliation: Division of Viral Pathogenesis, Beth Israel Deaconess Medical Center, 330 Brookline Avenue, E/CLS 1043, Boston, MA 02215, USA.
authors.forename: Evan M
authors.initials: EM
authors.lastname: Cale
authors.forename: Peter
authors.initials: P
authors.lastname: Hraber
authors.forename: Elena E
authors.initials: EE
authors.lastname: Giorgi
authors.forename: Will
authors.initials: W
authors.lastname: Fischer
authors.forename: Tanmoy
authors.initials: T
authors.lastname: Bhattacharya
authors.forename: Thomas
authors.initials: T
authors.lastname: Leitner
authors.forename: Wendy W
authors.initials: WW
authors.lastname: Yeh
authors.forename: Cheryl
authors.initials: C
authors.lastname: Gleasner
authors.forename: Lance D
authors.initials: LD
authors.lastname: Green
authors.forename: Cliff S
authors.initials: CS
authors.lastname: Han
authors.forename: Bette
authors.initials: B
authors.lastname: Korber
authors.forename: Norman L
authors.initials: NL
authors.lastname: Letvin
mesh_terms: D000818:Animals; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology*; D003429:Cross Reactions; D018984:Epitopes, T-Lymphocyte / Q000235:genetics / Q000276:immunology; D019143:Evolution, Molecular; D059014:High-Throughput Nucleotide Sequencing; D008253:Macaca mulatta; D020125:Mutation, Missense; D016097:Simian Acquired Immunodeficiency Syndrome / Q000276:immunology* / Q000821:virology*; D015302:Simian Immunodeficiency Virus / Q000235:genetics* / Q000276:immunology*; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology
chemical_list: D018984:Epitopes, T-Lymphocyte