Cytotoxic T lymphocyte-based control of simian immunodeficiency virus replication in a preclinical AIDS vaccine trial - PubMed (original) (raw)
. 2004 Jun 21;199(12):1709-18.
doi: 10.1084/jem.20040432.
Masahiro Kobayashi, Hiroko Igarashi, Akiko Takeda, Hiromi Nakamura, Munehide Kano, Chie Sugimoto, Kazuyasu Mori, Akihiro Iida, Takahiro Hirata, Mamoru Hasegawa, Takae Yuasa, Masaaki Miyazawa, Yumiko Takahashi, Michio Yasunami, Akinori Kimura, David H O'Connor, David I Watkins, Yoshiyuki Nagai
Affiliations
- PMID: 15210746
- PMCID: PMC2212812
- DOI: 10.1084/jem.20040432
Cytotoxic T lymphocyte-based control of simian immunodeficiency virus replication in a preclinical AIDS vaccine trial
Tetsuro Matano et al. J Exp Med. 2004.
Abstract
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.
Figures
Figure 1.
Gag-specific T cell frequencies in vaccinated macaques. Macaques V1, V2, V3, and V4 were boosted with a replication-competent SeV-Gag, whereas macaques V5, V6, V7, and V8 were boosted with a replication-defective F(−)SeV-Gag. *, macaques that controlled SIV replication after challenge. (A) Gag-specific CD8+ T cell frequencies per million PBMCs. The frequencies at week 7 after vaccination (1 wk after boost), at week 8 after vaccination (2 wk after boost), at week 19 after vaccination (just before challenge), and at week 2 after challenge (2 wk after challenge) are shown. (B) Gag-specific CD4+ T cell frequencies per million PBMCs at week 7 after vaccination (1 wk after boost). The frequencies were calculated by subtracting the IFN-γ+ T cell frequencies after nonspecific Vv control stimulation from those after Gag-specific Vv Gag stimulation. The background IFN-γ+ T cell frequencies after nonspecific stimulation were <2.0 × 102.
Figure 2.
Changes in peripheral CD4+ T cell levels and plasma viral loads after SIVmac239 challenge. (A) Percents of CD4+ T cells in peripheral blood. (B) CD4+ T cell counts in peripheral blood. (C) Plasma viral loads (SIV RNA copy number/ml). The left panels show the naive controls (N1, N2, N3, and N4), the middle panels show the vaccinees that failed to control SIV replication (V1, V2, and V7), and the right panels show the vaccinees that controlled SIV replication (V3, V4, V5, V6, and V8). The portion until week 10 after challenge is enlarged.
Figure 3.
Mutations in SIV gag. (A) Schematic representation of the positions of aa changes in SIV Gag in each macaque after challenge. 6–10 clones of plasmids carrying the whole gag region amplified from plasma RNA at week 5 after challenge were obtained from each macaque and sequenced. Each lane represents the whole gag sequence derived from each clone and the positions of aa changes detected are indicated. Total number of aa changes and number of clones sequenced are shown in the parentheses. All the changes at aa 58 were glutamine to lysine, and all at aa 377 were isoleucine to threonine. All the changes at aa 216 other than the one indicated as 216P were L to S. The 216P represents L to P change at aa 216. (B) Frequencies of the CTL escape mutants at weeks 2, 3, and 5 in the vaccinees that controlled SIV replication. The ratio of the number of the clones with the escape mutation to the number of the sequenced clones is shown.
Figure 4.
Peptide-specific T cell frequencies in the vaccinees that controlled SIV replications. (A) Comparison between the epitope peptide–specific and the variant peptide–specific CD8+ T cell responses. PBMCs at week 10 after vaccination in macaque V3, at week 10 after vaccination in V4, at week 15 after vaccination in V5, at week 3 after challenge in V6, and at week 3 after challenge in V8 were used. The open bars indicate the levels of CD8+ T cells specific for Gag206–216 peptide in V3, V4, and V5, Gag367–381 peptide in V6, and Gag50–65 peptide in V8, respectively. The solid bars indicate the levels of CD8+ T cells specific for Gag206–216L216S peptide in V3, V4, and V5, Gag367–381I377T peptide in V6, and Gag50–65Q58K peptide in V8, respectively. (B) Gag206–216-specific CD8+ T cell levels in macaques V3, V4, and V5 after challenge. The background IFN-γ+ CD8+ T cell frequencies after nonspecific stimulation were <1.0 × 102.
Figure 5.
Comparison of replication efficiencies between the wild-type SIVmac239 and the escape variant SIVmac239G216S. (A) Replication kinetics of SIVmac239 (▿) and SIVmac239G216S (•) in macaque PBMCs. MT4 cells were transfected with pBRmac239 and pBRmac239G216S to obtain SIVmac239 and SIVmac239G216S, respectively. PBMCs were infected with the viruses at a multiplicity of infection of 0.0002 and concentrations of SIV Gag p27 in their culture supernatants were measured by ELISA (Beckman Coulter). A representative result from three independent experiments is shown. (B) Plasma viral loads (SIV RNA copy number/ml) in macaques M1 (○) and M2 (♦) after inoculation with both of the wild-type SIVmac239 molecular clone DNA and the mutant SIVmac239G216S molecular clone DNA. (C) Frequencies of the mutant viral genome in plasma in the macaques inoculated with both of the wild-type SIVmac239 molecular clone DNA and the mutant SIVmac239G216S molecular clone DNA. In case of direct sequencing of the PCR products (indicated by direct), ++ indicates detection of both the wild-type and the mutant at comparable levels, + indicates detection of the wild-type predominantly and the mutant slightly, and − indicates detection of the wild-type only. In case of sequencing clones (indicated by clones), the ratio of the number of the mutant clones to the number of the sequenced clones is shown.
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