CD8+ and CD4+ cytotoxic T cell escape mutations precede breakthrough SIVmac239 viremia in an elite controller.
CD8+ and CD4+ cytotoxic T cell escape mutations precede breakthrough SIVmac239 viremia in an elite controller.
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DOI：
10.1186/1742-4690-9-91
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发表时间：
2012-11-06
期刊：
影响因子：
3.3
通讯作者：
Sacha JB
中科院分区：
文献类型：
--
作者：
Burwitz BJ;Giraldo-Vela JP;Reed J;Newman LP;Bean AT;Nimityongskul FA;Castrovinci PA;Maness NJ;Leon EJ;Rudersdorf R;Sacha JB
病毒特异性 T 细胞是遏制免疫缺陷病毒感染的关键成分。虽然 CD8+ T 细胞的保护作用已通过 CD8+ T 细胞介导的病毒逃逸研究得到充分证实，但 CD4+ T 细胞是否也能对复制病毒施加足够的选择压力以驱动高频逃逸变体的出现仍不清楚。鉴定高频 CD4+ T 细胞驱动的逃逸突变将为这些细胞介导的直接免疫压力提供令人信服的证据。在这里，我们研究了一只感染 SIVmac239 的精英控制恒河猴，在疾病进展和死于艾滋病相关并发症之前，其血浆病毒载量自发增加了 1,000 倍。我们对突破前和突破后的病毒基因组进行了测序，并证明 CD8+ T 细胞驱动了 Env 之外的大部分氨基酸取代。然而，在仅由 CD4+ T 细胞靶向的 Gag p27CA 区域内，我们发现了一种独特的突破后突变，Gag D205E，它消除了 CD4+ T 细胞的识别。此外，我们证明 Gag p27CA 特异性 CD4+ T 细胞表现出细胞溶解活性，并且携带 Gag D205E 突变的 SIV 在体外逃避了这种 CD4+ T 细胞效应功能。总的来说，这些结果证实了病毒特异性 CD8+ T 细胞的重要性，并证明 CD4+ T 细胞在低水平病毒复制过程中也可以对体内免疫缺陷病毒施加显着的选择性压力。这些结果还表明，对 CD4+ T 细胞逃逸的进一步研究应重点关注具有自发病毒突破的精英控制病例。
Virus-specific T cells are critical components in the containment of immunodeficiency virus infections. While the protective role of CD8+ T cells is well established by studies of CD8+ T cell-mediated viral escape, it remains unknown if CD4+ T cells can also impose sufficient selective pressure on replicating virus to drive the emergence of high-frequency escape variants. Identifying a high frequency CD4+ T cell driven escape mutation would provide compelling evidence of direct immunological pressure mediated by these cells. Here, we studied a SIVmac239-infected elite controller rhesus macaque with a 1,000-fold spontaneous increase in plasma viral load that preceded disease progression and death from AIDS-related complications. We sequenced the viral genome pre- and post-breakthrough and demonstrate that CD8+ T cells drove the majority of the amino acid substitutions outside of Env. However, within a region of Gag p27CA targeted only by CD4+ T cells, we identified a unique post-breakthrough mutation, Gag D205E, which abrogated CD4+ T cell recognition. Further, we demonstrate that the Gag p27CA-specific CD4+ T cells exhibited cytolytic activity and that SIV bearing the Gag D205E mutation escapes this CD4+ T cell effector function ex vivo. Cumulatively, these results confirm the importance of virus specific CD8+ T cells and demonstrate that CD4+ T cells can also exert significant selective pressure on immunodeficiency viruses in vivo during low-level viral replication. These results also suggest that further studies of CD4+ T cell escape should focus on cases of elite control with spontaneous viral breakthrough.
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影响因子：
3.7
作者：
Almeida RR;Rosa DS;Ribeiro SP;Santana VC;Kallás EG;Sidney J;Sette A;Kalil J;Cunha-Neto E
通讯作者：
Cunha-Neto E
影响因子：
82.9
作者：
Ciurea, A;Hunziker, L;Zinkernagel, RM
通讯作者：
Zinkernagel, RM
影响因子：
5.4
作者：
O'Connor, DH;McDermott, AB;Watkins, DI
通讯作者：
Watkins, DI
影响因子：
15.3
作者：
Casazza, Joseph P.;Betts, Michael R.;Price, David A.;Precopio, Melissa L.;Ruff, Laura E.;Brenchley, Jason M.;Hill, Brenna J.;Roederer, Mario;Douek, Daniel C.;Koup, Richard A.
通讯作者：
Koup, Richard A.
影响因子：
5.4
作者：
Brennan, Catherine A.;Ibarrondo, F. Javier;Jamieson, Beth D.
通讯作者：
Jamieson, Beth D.