Perez Lautaro G, Chen Haiyan, Liao Hua-Xin, Montefiori David C
Department of Surgery, Duke University Medical Center, Durham, North Carolina, USA.
Duke Human Vaccine Institute, Duke University Medical Center, Durham, North Carolina, USA.
J Virol. 2014 Sep;88(18):10767-77. doi: 10.1128/JVI.03296-13. Epub 2014 Jul 9.
The HIV-1 surface glycoprotein gp120 has been reported to bind and signal through α4β7 by means of a tripeptide motif in the V2 loop that mimics structures present in the natural ligands for α4β7, suggesting that α4β7 may facilitate HIV-1 infection of CD4(+) T cells in the gut. Furthermore, immune correlates in the RV144 vaccine efficacy trial generated the hypothesis that V1V2 antibodies to an epitope near the putative α4β7 binding motif may play a role in protection against HIV-1 infection. In the interest of developing an assay to detect antibodies that block gp120 binding to α4β7, we used retinoic acid (RA)-activated human peripheral blood mononuclear cells (PBMCs) and transfected HEK293T (293T) cells expressing the integrin complex to study the α4β7 binding properties of 16 HIV-1 envelope glycoproteins. The natural ligand for α4β7, mucosal addressin cell adhesion molecule-1 (MAdCAM-1), bound efficiently to RA-activated PBMCs and transfected 293T cells, and this binding was blocked by antibodies to α4. gp120 from multiple HIV-1 subtypes bound to RA-activated PBMCs from three donors in a CD4-dependent manner, but little or no α4β7 binding was detected. Similarly, little or no binding to α4β7 on transfected 293T cells was detected with multiple gp120s and gp140s, including gp120s from transmitted/founder strains, or when gp120 was produced in CHO, 293T, and 293S/GnT1(-/-) cells. Finally, we found no evidence that infectious HIV-1 virions produced in either PBMCs or 293T cells could bind α4β7 on transfected 293T cells. Infectious HIV-1 virions and most gp120s/gp140s appear to be poor ligands for the α4β7 integrin complex under the conditions tested here.
Certain HIV-1 gp120 envelope glycoproteins have been shown to bind the gut-homing receptor α4β7, and it has been suggested that this binding facilitates mucosal transmission and virus replication in the gut mucosa. Additional evidence has generated the hypothesis that antibodies that bind near the putative α4β7 binding motif in the V2 loop of gp120, possibly disrupting gp120-α4β7 binding, may be important for HIV-1 vaccines. Our evidence indicates that infectious HIV-1 virions and many gp120s lack detectable α4β7 binding activity, suggesting that this homing receptor may play a limited role in direct HIV-1 infection of cells.
据报道，HIV-1表面糖蛋白gp120通过V2环中的三肽基序与α4β7结合并发出信号，该基序模拟了α4β7天然配体中的结构，这表明α4β7可能促进HIV-1感染肠道中的CD4(+)T细胞。此外，RV144疫苗疗效试验中的免疫相关因素提出了一个假设，即针对假定的α4β7结合基序附近表位的V1V2抗体可能在预防HIV-1感染中发挥作用。为了开发一种检测阻断gp120与α4β7结合的抗体的检测方法，我们使用视黄酸（RA）激活的人外周血单核细胞（PBMC）和转染了表达整合素复合物的HEK293T（293T）细胞来研究16种HIV-1包膜糖蛋白的α4β7结合特性。α4β7的天然配体黏膜地址素细胞黏附分子-1（MAdCAM-1）有效地结合到RA激活的PBMC和转染的293T细胞上，并且这种结合被抗α4抗体阻断。来自多种HIV-1亚型的gp120以CD4依赖的方式结合来自三个供体的RA激活的PBMC，但未检测到α4β7结合或仅有少量结合。同样，用多种gp120和gp140，包括来自传播/奠基者毒株的gp-120，或者当gp120在CHO、293T和293S/GnT1(-/-)细胞中产生时，在转染的293T细胞上未检测到与α4β7的结合或仅有少量结合。最后，我们没有发现证据表明在PBMC或293T细胞中产生感染性HIV-1病毒粒子能够结合转染的293T细胞上的α4β7。在此测试的条件下，感染性HIV-1病毒粒子和大多数gp120/gp140似乎是α4β7整合素复合物的不良配体。
某些HIV-1 gp120包膜糖蛋白已被证明可结合肠道归巢受体α4β7，并且有人提出这种结合促进了肠道黏膜中的黏膜传播和病毒复制。其他证据提出了一个假设，即结合在gp120的V2环中假定的α4β7结合基序附近、可能破坏gp120-α4β7结合的抗体可能对HIV-1疫苗很重要。我们的证据表明，感染性HIV-1病毒粒子和许多gp120缺乏可检测到的α4β7结合活性，这表明这种归巢受体在HIV-1直接感染细胞中可能起有限的作用。
