Cytotoxic T lymphocyte-based control of simian immunodeficiency virus replication in a preclinical AIDS vaccine trial.
Recently, encouraging AIDS vaccine trials in macaques have implicated cytotoxic T lymphocytes (CTLs) in the control of the simian human immunodeficiency virus SHIV89.6P that induces acute CD4(+) T cell depletion. However, none of these vaccine regimens have been successful in the containment of replication of the pathogenic simian immunodeficiency viruses (SIVs) that induce chronic disease progression. Indeed, it has remained unclear if vaccine-induced CTL can control SIV replication. Here, we show evidence suggesting that vaccine-induced CTLs control SIVmac239 replication in rhesus macaques. Eight macaques vaccinated with DNA-prime/Gag-expressing Sendai virus vector boost were challenged intravenously with SIVmac239. Five of the vaccinees controlled viral replication and had undetectable plasma viremia after 5 wk of infection. CTLs from all of these five macaques rapidly selected for escape mutations in Gag, indicating that vaccine-induced CTLs successfully contained replication of the challenge virus. Interestingly, analysis of the escape variant selected in three vaccinees that share a major histocompatibility complex class I haplotype revealed that the escape variant virus was at a replicative disadvantage compared with SIVmac239. These findings suggested that the vaccine-induced CTLs had "crippled" the challenge virus. Our results indicate that vaccine induction of highly effective CTLs can result in the containment of replication of a highly pathogenic immunodeficiency virus.
Matano
Tetsuro
T
Department of Microbiology, Graduate School of Medicine, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-0033, Japan. matano@m.u-tokyo.ac.jp
Kobayashi
Masahiro
M
Igarashi
Hiroko
H
Takeda
Akiko
A
Nakamura
Hiromi
H
Kano
Munehide
M
Sugimoto
Chie
C
Mori
Kazuyasu
K
Iida
Akihiro
A
Hirata
Takahiro
T
Hasegawa
Mamoru
M
Yuasa
Takae
T
Miyazawa
Masaaki
M
Takahashi
Yumiko
Y
Yasunami
Michio
M
Kimura
Akinori
A
O'Connor
David H
DH
Watkins
David I
DI
Nagai
Yoshiyuki
Y
D016915:AIDS Vaccines / Q000276:immunology*; D000818:Animals; D004195:Disease Models, Animal; D015752:Genes, env; D015754:Genes, nef; D006801:Humans; D008253:Macaca mulatta; D008297:Male; D016097:Simian Acquired Immunodeficiency Syndrome / Q000276:immunology; D015302:Simian Immunodeficiency Virus / Q000235:genetics* / Q000276:immunology / Q000502:physiology*; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology*; D014779:Virus Replication / Q000276:immunology*
D016915:AIDS Vaccines