C-C chemokine receptor type 5 (CCR5) utilization of transmitted and early founder human immunodeficiency virus type 1 envelopes and sensitivity to small-molecule CCR5 inhibitors.
C-C chemokine receptor type 5 (CCR5) utilization of transmitted and early founder human immunodeficiency virus type 1 envelopes and sensitivity to small-molecule CCR5 inhibitors.
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DOI：
10.1099/vir.0.025270-0
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发表时间：
2010-12
期刊：
影响因子：
--
通讯作者：
Shattock RJ
中科院分区：
文献类型：
--
作者：
Hu Q;Huang X;Shattock RJ
人类免疫缺陷病毒的包膜糖蛋白（Env）是病毒进入易感靶细胞的关键，因此是设计疫苗和抗病毒药物的主要靶标。C-C趋化因子受体5型（CCR 5）-使用（R5）Env是与早期传播和急性感染相关的主要表型。本研究探讨了CCR 5使用的机制和一组传递或早期创始人（T/F）Env对CCR 5抑制剂的敏感性。数据显示，大多数T/F Env使用CCR 5，许多也使用CCR 3，尽管效率较低。尽管使用野生型CCR 5的能力相似，但个体Env对CCR 5抑制剂maraviroc、CMPD-167和SCH-412147的敏感性显著不同。抑制剂图谱实验表明，maraviroc、CMPD-167和SCH-412147干扰了CCR 5 mAb与CCR 5第二胞外环2的C端半部分的结合。有趣的是，对马拉韦罗、CMPD 167和SCH-412147耐药的Env对TAK-779仍然敏感。进一步的研究表明，Envs对CCR 5抑制剂的敏感性与CCR 5使用的分子解剖学相关，揭示了对CCR 5 N末端敏感的Envs几乎不使用CCR 5 N末端，而抗性Envs显示出其使用的显著增加。 总之，这些发现表明，T/F R5 Env在CCR 5利用机制方面是异质的。这些数据可能对基于CCR 5的抗逆转录病毒药物的治疗性和预防性使用有影响。
The envelope glycoprotein (Env) of human immunodeficiency virus is key to viral entry of susceptible target cells and is therefore a major target for the design of vaccines and antiviral drugs. C-C chemokine receptor type 5 (CCR5)-using (R5) Env is the predominant phenotype associated with early transmission and acute infection. This study investigated the mechanism of CCR5 use and the sensitivity to CCR5 inhibitors of a panel of transmitted or early founder (T/F) Envs. The data showed that the majority of T/F Envs used CCR5 and that many also used CCR3, although less efficiently. Despite a similar ability to use wild-type CCR5, individual Envs differed significantly in their sensitivity to the CCR5 inhibitors maraviroc, CMPD-167 and SCH-412147. Inhibitor mapping experiments demonstrated that maraviroc, CMPD-167 and SCH-412147 interfered with the binding of CCR5 mAb to the C-terminal half of the second extracellular loop 2 of CCR5. Interestingly, Envs resistant to maraviroc, CMPD167 and SCH-412147 remained sensitive to TAK-779. Further studies indicated that the sensitivity of Envs to CCR5 inhibitors correlated with the molecular anatomy of CCR5 use, revealing that the inhibitor-sensitive Envs barely used the CCR5 N terminus, whereas resistant Envs showed a marked increase in its use. Taken together, these findings demonstrate that T/F R5 Envs are heterogeneous with respect to the mechanisms of CCR5 utilization. These data may have implications for therapeutic and prophylactic use of CCR5-based antiretrovirals.
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影响因子：
5.4
作者：
Aasa-Chapman, Marlen M. I.;Seymour, Craig R.;McKnight, Aine
通讯作者：
McKnight, Aine
DOI：
10.1073/pnas.0811713106
发表时间：
2009-03-31
影响因子：
11.1
作者：
Anastassopoulou, Cleo G.;Ketas, Thomas J.;Moore, John P.
通讯作者：
Moore, John P.
影响因子：
3.7
作者：
Ogert, Robert A.;Wojcik, Lisa;Howe, John A.
通讯作者：
Howe, John A.
影响因子：
5.4
作者：
Hu, QX;Barry, AP;Greenberg, ML
通讯作者：
Greenberg, ML
DOI：
10.1056/nejmoa0803152
发表时间：
2008-10-02
期刊：
The New England journal of medicine
影响因子：
--
作者：
Gulick RM;Lalezari J;Goodrich J;Clumeck N;DeJesus E;Horban A;Nadler J;Clotet B;Karlsson A;Wohlfeiler M;Montana JB;McHale M;Sullivan J;Ridgway C;Felstead S;Dunne MW;van der Ryst E;Mayer H;MOTIVATE Study Teams
通讯作者：
MOTIVATE Study Teams