UCLA1 aptamer inhibition of human immunodeficiency virus type 1 subtype C primary isolates in macrophages and selection of resistance.
UCLA1 aptamer inhibition of human immunodeficiency virus type 1 subtype C primary isolates in macrophages and selection of resistance.
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DOI：
10.1016/j.bbrep.2016.07.005
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发表时间：
2016-09
影响因子：
2.7
通讯作者：
Khati M
中科院分区：
文献类型：
--
作者：
Mufhandu HT;Alexandre KB;Gray ES;Morris L;Khati M
我们以前已经表明，适体，UCLA 1，能够抑制HIV-1复制在外周血单核细胞（PBMC）的结合残基在gp 120。在这项研究中，我们检查了UCLA 1是否对单核细胞衍生的巨噬细胞（MDM）中的HIV-1亚型C分离株有效。在测试的4种嗜巨噬细胞分离株中，3种在低纳摩尔范围内（IC 80 <29 nM）被UCLA 1抑制。一个对UCLA 1敏感性降低（<50 nM）的分离株在CD 4和辅助受体（CoR）结合复合物旁边的α5螺旋中含有突变。为了进一步评估适体抗性，在PBMC中使两种原代病毒经受浓度增加的UCLA 1 84天的时间。一个分离株显示出与遗传变化相关的IC 80（351 nM）增加了7倍，其中一些先前与耐药性有关。这包括C2区的F223 Y和CD 4和CoR结合复合物内的P369 L。第二个分离株显示IC 80（118 nM）增加了3倍，但未显示任何遗传变化。总的来说，这些数据表明，UCLA 1可以有效地阻断MDM和PBMC中的HIV-1感染，在长时间暴露于适体后，一些分离株中出现逃逸突变。这支持了UCLA 1适体作为HIV-1进入抑制剂的进一步开发。UCLA 1适体抑制单核细胞源性巨噬细胞的HIV-1亚型C感染。进行了UCLA 1耐药性评价，一种病毒产生了耐药性。gp 120的遗传变化发生在可变环、CD 4和辅助受体结合位点。
We have previously shown that the aptamer, UCLA1, is able to inhibit HIV-1 replication in peripheral blood mononuclear cells (PBMCs) by binding to residues in gp120. In this study we examined whether UCLA1 was effective against HIV-1 subtype C isolates in monocyte-derived macrophages (MDMs). Of 4 macrophage-tropic isolates tested, 3 were inhibited by UCLA1 in the low nanomolar range (IC80<29 nM). One isolate that showed reduced susceptibility (<50 nM) to UCLA1 contained mutations in the α5 helix next to the CD4 and co-receptor (CoR) binding complex. To further evaluate aptamer resistance, two primary viruses were subjected to increasing concentrations of UCLA1 over a period of 84 days in PBMCs. One isolate showed a 7-fold increase in IC80 (351 nM) associated with genetic changes, some of which were previously implicated in resistance. This included F223Y in the C2 region and P369L within the CD4 and CoR binding complex. A second isolate showed a 3-fold increase in IC80 (118 nM) but failed to show any genetic changes. Collectively, these data show that UCLA1 can efficiently block HIV-1 infection in MDMs and PBMCs with escape mutations arising in some isolates after prolonged exposure to the aptamer. This supports the further development of the UCLA1 aptamer as a HIV-1 entry inhibitor. UCLA1 aptamer inhibited HIV-1 subtype C infection of monocyte-derived macrophages. Evaluation of UCLA1 resistance was performed and one virus developed resistance. Genetic changes to gp120 were in variable loops, CD4 and co-receptor binding sites.