title: Epitope-specific CD8+ T cell kinetics rather than viral variability determine the timing of immune escape in simian immunodeficiency virus infection.
abstract: CD8(+) T cells are important for the control of chronic HIV infection. However, the virus rapidly acquires "escape mutations" that reduce CD8(+) T cell recognition and viral control. The timing of when immune escape occurs at a given epitope varies widely among patients and also among different epitopes within a patient. The strength of the CD8(+) T cell response, as well as mutation rates, patterns of particular amino acids undergoing escape, and growth rates of escape mutants, may affect when escape occurs. In this study, we analyze the epitope-specific CD8(+) T cells in 25 SIV-infected pigtail macaques responding to three SIV epitopes. Two epitopes showed a variable escape pattern and one had a highly monomorphic escape pattern. Despite very different patterns, immune escape occurs with a similar delay of on average 18 d after the epitope-specific CD8(+) T cells reach 0.5% of total CD8(+) T cells. We find that the most delayed escape occurs in one of the highly variable epitopes, and that this is associated with a delay in the epitope-specific CD8(+) T cells responding to this epitope. When we analyzed the kinetics of immune escape, we found that multiple escape mutants emerge simultaneously during the escape, implying that a diverse population of potential escape mutants is present during immune selection. Our results suggest that the conservation or variability of an epitope does not appear to affect the timing of immune escape in SIV. Instead, timing of escape is largely determined by the kinetics of epitope-specific CD8(+) T cells.
authors.affiliation: Centre for Vascular Research, University of New South Wales, Sydney, New South Wales 2052, Australia; and.
authors.forename: Alexey P
authors.initials: AP
authors.lastname: Martyushev
authors.affiliation: Centre for Vascular Research, University of New South Wales, Sydney, New South Wales 2052, Australia; and.
authors.forename: Janka
authors.initials: J
authors.lastname: Petravic
authors.affiliation: Centre for Vascular Research, University of New South Wales, Sydney, New South Wales 2052, Australia; and.
authors.forename: Andrew J
authors.initials: AJ
authors.lastname: Grimm
authors.affiliation: Centre for Vascular Research, University of New South Wales, Sydney, New South Wales 2052, Australia; and.
authors.forename: Hamid
authors.initials: H
authors.lastname: Alinejad-Rokny
authors.affiliation: Department of Microbiology and Immunology, Peter Doherty Institute for Infection and Immunity, University of Melbourne, Parkville, Victoria 3010, Australia.
authors.forename: Shayarana L
authors.initials: SL
authors.lastname: Gooneratne
authors.affiliation: Department of Microbiology and Immunology, Peter Doherty Institute for Infection and Immunity, University of Melbourne, Parkville, Victoria 3010, Australia.
authors.forename: Jeanette C
authors.initials: JC
authors.lastname: Reece
authors.affiliation: Centre for Vascular Research, University of New South Wales, Sydney, New South Wales 2052, Australia; and.
authors.forename: Deborah
authors.initials: D
authors.lastname: Cromer
authors.affiliation: Department of Microbiology and Immunology, Peter Doherty Institute for Infection and Immunity, University of Melbourne, Parkville, Victoria 3010, Australia.
authors.forename: Stephen J
authors.initials: SJ
authors.lastname: Kent
authors.affiliation: Centre for Vascular Research, University of New South Wales, Sydney, New South Wales 2052, Australia; and m.davenport@unsw.edu.au.
authors.forename: Miles P
authors.initials: MP
authors.lastname: Davenport
mesh_terms: D000818:Animals; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology*; D018984:Epitopes, T-Lymphocyte / Q000276:immunology*; D057131:Immune Evasion / Q000276:immunology*; D007700:Kinetics; D008251:Macaca; D016097:Simian Acquired Immunodeficiency Syndrome / Q000276:immunology* / Q000821:virology*; D015302:Simian Immunodeficiency Virus / Q000235:genetics / Q000276:immunology*; D013997:Time Factors
chemical_list: D018984:Epitopes, T-Lymphocyte