Broad CTL response is required to clear latent HIV-1 due to dominance of escape mutations.
Broad CTL response is required to clear latent HIV-1 due to dominance of escape mutations.
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DOI：
10.1038/nature14053
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发表时间：
2015-01-15
期刊：
影响因子：
64.8
通讯作者：
Siliciano, Robert F.
中科院分区：
文献类型：
--
作者：
Deng, Kai;Pertea, Mihaela;Rongvaux, Anthony;Wang, Leyao;Durand, Christine M.;Ghiaur, Gabriel;Lai, Jun;McHugh, Holly L.;Hao, Haiping;Zhang, Hao;Margolick, Joseph B.;Gurer, Cagan;Murphy, Andrew J.;Valenzuela, David M.;Yancopoulos, George D.;Deeks, Steven G.;Strowig, Till;Kumar, Priti;Siliciano, Janet D.;Salzberg, Steven L.;Flavell, Richard A.;Shan, Liang;Siliciano, Robert F.
尽管进行了抗逆转录病毒治疗(ART)，但HIV-1仍持续存在稳定的潜伏期，主要存在于静止的记忆CD4+T细胞中。这个蓄水池是治愈HIV-1感染的主要障碍。为了清除这个储存库，已经提出了潜伏的HIV-1的药理再激活，并在体外和体内进行了测试。剩下的一个关键问题是，在潜伏期逆转后，包括细胞溶解T淋巴细胞(CTL)在内的病毒特异性免疫机制是否能够清除ART治疗患者中的感染细胞。在这里，我们显示了HIV-1 Gag表位的CTL逃逸突变存在一个惊人的全有或无模式。除非及早开始抗逆转录病毒治疗，否则绝大多数(98%)潜伏病毒携带CTL逃逸突变，使感染细胞对针对共同表位的CTL不敏感。为了解决这个问题，我们确定了可以识别潜伏的HIV-1表位的CTL，这些表位在每个接受测试的慢性感染患者中都是未突变的。在刺激下，这些CTL在体外和患者来源的人源化小鼠中清除感染了来自潜伏库的自体病毒的靶细胞。CTL耐药病毒在潜伏库中的优势对病毒的根除构成了重大挑战。我们的结果表明，慢性感染患者保留了广谱的病毒特异性CTL反应，可能需要适当增强这种反应以消除潜伏的宿主。
Despite antiretroviral therapy (ART), HIV-1 persists in a stable latent reservoir, primarily in resting memory CD4+ T cells. This reservoir presents a major barrier to the cure of HIV-1 infection. To purge the reservoir, pharmacological reactivation of latent HIV-1 has been proposed and tested both in vitro and in vivo. A key remaining question is whether virus-specific immune mechanisms including cytolytic T lymphocytes (CTL) can clear infected cells in ART-treated patients after latency is reversed. Here we show that there is a striking all or none pattern for CTL escape mutations in HIV-1 Gag epitopes. Unless ART is started early, the vast majority (>98%) of latent viruses carry CTL escape mutations that render infected cells insensitive to CTLs directed at common epitopes. To solve this problem, we identified CTLs that could recognize epitopes from latent HIV-1 that were unmutated in every chronically infected patient tested. Upon stimulation, these CTLs eliminated target cells infected with autologous virus derived from the latent reservoir, both in vitro and in patient-derived humanized mice. The predominance of CTL-resistant viruses in the latent reservoir poses a major challenge to viral eradication. Our results demonstrate that chronically infected patients retain a broad spectrum viral-specific CTL response and that appropriate boosting of this response may be required for the elimination of the latent reservoir.
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影响因子：
48
作者：
Langmead, Ben;Salzberg, Steven L.
通讯作者：
Salzberg, Steven L.
HIV-1组M保守元素疫苗。
影响因子：
6.7
作者：
Rolland M;Nickle DC;Mullins JI
通讯作者：
Mullins JI
影响因子：
15.9
作者：
Liu, Michael K. P.;Hawkins, Natalie;Goonetilleke, Nilu
通讯作者：
Goonetilleke, Nilu
影响因子：
64.8
作者：
Goulder, PJR;Brander, C;Walker, BD
通讯作者：
Walker, BD
DOI：
10.1073/pnas.0736332100
发表时间：
2003-04-15
影响因子：
11.1
作者：
Strain, MC;G端nthard, HF;Wong, JK
通讯作者：
Wong, JK