Involvement of multiple epitope-specific cytotoxic T-lymphocyte responses in vaccine-based control of simian immunodeficiency virus replication in rhesus macaques.
Cytotoxic T-lymphocyte (CTL) responses are crucial for the control of immunodeficiency virus replication. Possible involvement of a dominant single epitope-specific CTL in control of viral replication has recently been indicated in preclinical AIDS vaccine trials, but it has remained unclear if multiple epitope-specific CTLs can be involved in the vaccine-based control. Here, by following up five rhesus macaques that showed vaccine-based control of primary replication of a simian immunodeficiency virus, SIVmac239, we present evidence indicating involvement of multiple epitope-specific CTL responses in this control. Three macaques maintained control for more than 2 years without additional mutations in the provirus. However, in the other two that shared a major histocompatibility complex haplotype, viral mutations were accumulated in a similar order, leading to viral evasion from three epitope-specific CTL responses with viral fitness costs. Accumulation of these multiple escape mutations resulted in the reappearance of plasma viremia around week 60 after challenge. Our results implicate multiple epitope-specific CTL responses in control of immunodeficiency virus replication and furthermore suggest that sequential accumulation of multiple CTL escape mutations, if allowed, can result in viral evasion from this control.
Kawada
Miki
M
Department of Microbiology, Graduate School of Medicine, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-0033, Japan.
Igarashi
Hiroko
H
Takeda
Akiko
A
Tsukamoto
Tetsuo
T
Yamamoto
Hiroyuki
H
Dohki
Sachi
S
Takiguchi
Masafumi
M
Matano
Tetsuro
T
D019943:Amino Acid Substitution; D000818:Animals; D018791:CD4 Lymphocyte Count; D018984:Epitopes, T-Lymphocyte / Q000276:immunology*; D006239:Haplotypes; D007111:Immunity, Cellular; D008253:Macaca mulatta; D008285:Major Histocompatibility Complex / Q000235:genetics; D008297:Male; D020125:Mutation, Missense; D011533:Proviruses / Q000235:genetics; D018449:SAIDS Vaccines / Q000276:immunology*; D016097:Simian Acquired Immunodeficiency Syndrome / Q000276:immunology* / Q000821:virology; D015302:Simian Immunodeficiency Virus / Q000276:immunology* / Q000502:physiology*; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology*; D014766:Viremia; D014779:Virus Replication
D018984:Epitopes, T-Lymphocyte; D018449:SAIDS Vaccines