Role of Escape Mutant-Specific T Cells in Suppression of HIV-1 Replication and Coevolution with HIV-1
Role of Escape Mutant-Specific T Cells in Suppression of HIV-1 Replication and Coevolution with HIV-1
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逃逸突变特异性 T 细胞在抑制 HIV-1 复制和与 HIV-1 共同进化中的作用
DOI：
10.1128/jvi.01151-20
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发表时间：
2020
影响因子：
5.4
通讯作者：
Takiguchi Masafumi
中科院分区：
文献类型：
--
作者：
Zhang Yu;Kuse Nozomi;Akahoshi Tomohiro;Chikata Takayuki;Gatanaga Hiroyuki;Oka Shinichi;Murakoshi Hayato;Takiguchi Masafumi
HIV-1逃逸突变的积累影响HIV-1特异性T细胞对HIV-1的控制。这些突变中的一些可以引起逃逸的mu特异性T细胞，但仍然不清楚它们是否可以抑制HIV-1突变体的复制。已知HLA-B*52：01限制性RI 8（Gag 275至282; RMYSPTSI）是HIV-1亚型B感染的日本个体中的保护性T细胞表位，尽管在其中26%的人中发现3个Gag 280 A/S/V突变。Gag 280 S和Gag 280 A是HLA-B*52：01相关突变，而Gag 280 V不是，这意味着Gag 280突变积累的不同机制。在本研究中，我们研究了HIV-1与RI 8特异性T细胞的协同进化及其逃逸的RI 8特异性T细胞对HIV-1复制的抑制作用。感染Gag 280 A/S突变病毒的HLA-B*52：01+个体未能引发这些突变表位特异性T细胞，而感染Gag 280 V突变病毒的那些个体有效地引发RI 8 -6V突变特异性T细胞。这些RI 8 - 6V特异性T细胞抑制Gag 280 V病毒和选择的野生型病毒的复制，表明在HLA-B*52：01+个体中不提供Gag 280 V突变积累的机制。对野生型（RI 8 - 6 T）和RI 8 -6V突变体肽的应答者具有比无应答者显著更高的CD 4计数，表明不仅RI 8 - 6 T特异性T细胞的存在而且RI 8 - 6V特异性T细胞的存在与良好的临床结果相关。本研究阐明了逃逸突变体特异性T细胞在HIV-1进化和控制HIV-1过程中的作用。重要提示逃逸突变体感染者体内可诱导产生逃逸突变体特异性CD 8 +T细胞，但这些CD 8 +T细胞是否具有抑制HIV-1复制的功能尚不清楚。我们阐明了Gag 280 V突变是由GagRI 8保护性表位特异性的HLA-B*52：01限制性CD 8 +T细胞选择的，而Gag 280 V病毒通常可以引发GagRI 8 -6V突变特异性CD 8 +T细胞。GagRI 8 -6V突变体特异性T细胞在体外和体内均具有较强的抑制Gag 280 V突变体病毒复制的能力。此外，这些T细胞有助于在HLA-B*52：01+日本个体中选择野生型病毒。我们首次证明了逃逸mu特异性CD 8 +T细胞可以抑制HIV-1的复制，并在与HIV-1的协同进化中发挥重要作用。因此，本研究强调了逃逸mu特异性T细胞在控制HIV-1和与HIV-1共同进化中的重要作用。
The accumulation of HIV-1 escape mutations affects HIV-1 control by HIV-1-specific T cells. Some of these mutations can elicit escape mutant-specific T cells, but it still remains unclear whether they can suppress the replication of HIV-1 mutants. It is known that HLA-B*52:01-restricted RI8 (Gag 275 to 282; RMYSPTSI) is a protective T cell epitope in HIV-1 subtype B-infected Japanese individuals, though 3 Gag280A/S/V mutations are found in 26% of them. Gag280S and Gag280A were HLA-B*52:01-associated mutations, whereas Gag280V was not, implying a different mechanism for the accumulation of Gag280 mutations. In this study, we investigated the coevolution of HIV-1 with RI8-specific T cells and suppression of HIV-1 replication by its escape mutant-specific T cells bothin vitroandin vivo. HLA-B*52:01+individuals infected with Gag280A/S mutant viruses failed to elicit these mutant epitope-specific T cells, whereas those with the Gag280V mutant one effectively elicited RI8-6V mutant-specific T cells. These RI8-6V-specific T cells suppressed the replication of Gag280V virus and selected wild-type virus, suggesting a mechanism affording no accumulation of the Gag280V mutation in the HLA-B*52:01+individuals. The responders to wild-type (RI8-6T) and RI8-6V mutant peptides had significantly higher CD4 counts than nonresponders, indicating that the existence of not only RI8-6T-specific T cells but also RI8-6V-specific ones was associated with a good clinical outcome. The present study clarified the role of escape mutant-specific T cells in HIV-1 evolution and in the control of HIV-1.IMPORTANCEEscape mutant-specific CD8+T cells were elicited in some individuals infected with escape mutants, but it is still unknown whether these CD8+T cells can suppress HIV-1 replication. We clarified that Gag280V mutation were selected by HLA-B*52:01-restricted CD8+T cells specific for the GagRI8 protective epitope, whereas the Gag280V virus could frequently elicit GagRI8-6V mutant-specific CD8+T cells. GagRI8-6V mutant-specific T cells had a strong ability to suppress the replication of the Gag280V mutant virus bothin vitroandin vivo. In addition, these T cells contributed to the selection of wild-type virus in HLA-B*52:01+Japanese individuals. We for the first time demonstrated that escape mutant-specific CD8+T cells can suppress HIV-1 replication and play an important role in the coevolution with HIV-1. Thus, the present study highlighted an important role of escape mutant-specific T cells in the control of HIV-1 and coevolution with HIV-1.
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影响因子：
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作者：
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