Potent targeted activator of cell kill molecules eliminate cells expressing HIV-1
Potent targeted activator of cell kill molecules eliminate cells expressing HIV-1
复制标题
DOI：
10.1126/scitranslmed.abn2038
复制
发表时间：
2023-02-22
影响因子：
17.1
通讯作者：
Converso, Antonella
中科院分区：
文献类型：
--
作者：
Balibar, Carl J.;Klein, Daniel J.;Converso, Antonella
抗逆转录病毒疗法抑制HIV-1复制，但由于病毒整合到宿主基因组后建立了持久的储库，因此不能治愈。因此，减少储库是一个重要的HIV-1治疗策略。一些HIV-1非核苷逆转录酶抑制剂在体外诱导HIV-1选择性细胞毒性，但需要的浓度远远超过批准的剂量。专注于这种次要活性，我们发现了在临床可达到的浓度下具有HIV-1感染细胞杀伤效力的双功能化合物。这些靶向的细胞杀伤激活因子（TACK）分子结合单体Gag-Pol的逆转录酶-p66结构域，并作为变构调节剂加速二聚化，通过过早的细胞内病毒蛋白酶激活导致HIV-1（+）细胞死亡。TACK分子保留了有效的抗病毒活性，并选择性地清除从HIV-1感染者中分离出的受感染的CD 4（+）T细胞，支持免疫独立的清除策略。
Antiretroviral therapy inhibits HIV-1 replication but is not curative due to establishment of a persistent reservoir after virus integration into the host genome. Reservoir reduction is therefore an important HIV-1 cure strategy. Some HIV-1 nonnucleoside reverse transcriptase inhibitors induce HIV-1 selective cytotoxicity in vitro but require concentrations far exceeding approved dosages. Focusing on this secondary activity, we found bifunctional compounds with HIV-1-infected cell kill potency at clinically achievable concentrations. These targeted activator of cell kill (TACK) molecules bind the reverse transcriptase-p66 domain of monomeric Gag-Pol and act as allosteric modulators to accelerate dimerization, resulting in HIV-1(+) cell death through premature intracellular viral protease activation. TACK molecules retain potent antiviral activity and selectively eliminate infected CD4(+) T cells isolated from people living with HIV-1, supporting an immune-independent clearance strategy.