Role of HIV Envelope Proteins In Viral Replication and HIV Pathogenesis

我们确定HIV gp 120与4 '946的活化形式结合。 因为4 ′ 946是淋巴细胞归巢至肠相关淋巴组织（GALT）固有层的主要整联蛋白，并且HIV感染的CD 4 T细胞优先定位于淋巴组织，特别是GALT，所以我们的发现表明HIV gp 120和4 ′ 946之间的直接相互作用可能是优先建立和/或维持HIV在GALT中复制所必需的。 gp 120与4 ′的结合是由V2环中的LDV肽序列介导的，该肽序列重复了MadCAM-1、VCAM-1和纤连蛋白（4 ′的天然配体）上存在的结构同源结合基序。 去除HIV包膜中的该序列消除了与4 ′ 946整联蛋白的结合。 基于LDV序列的原型4 ′肽拮抗剂消除与gp 120的结合。因此，HIV通过分子模拟获得了一种与整合素受体结合的机制，该机制主要参与将淋巴细胞引导至肠道固有层，即HIV复制的主要部位。 在CD 4 + T细胞上，4 ′的gp 120接合导致LFA-1的快速活化，LFA-1是参与病毒学突触建立的中心整联蛋白。已知LFA-1的激活会增加HIV复制。 粘膜组织中的活化和静息CD 4 + T细胞在HIV-1性传播后感染的最早阶段发挥重要作用，这是一个效率低下的过程。我们发现，4 7高CD 4 + T细胞比4 7低-阴性CD 4 + T细胞更容易受到生产性感染，部分原因是因为这个细胞亚群富含代谢活性的CD 4 + T细胞。α4 7高CD 4 + T细胞为CCR 5高、CXCR 4低。 我们发现，在这些细胞4 - 7出现在一个复杂的CD 4。这是第一次证明这两种受体一起出现在CD 4 + T细胞表面的复合物中。整合素4 - 7在HIV发病机制中的作用的描述为理解HIV传播和HIV介导的免疫功能障碍的基本机制提供了重要的新信息。

We determined that HIV gp120 binds to an activated form of α4&#946. Because α4&#946 is the principal integrin involved in lymphocyte homing to the lamina propria of gut associated lymphoid tissue (GALT), and HIV-infected CD4 T-cells preferentially localize to lymphoid tissues, particularly GALT, our finding suggests that a direct interaction between HIV gp120 and α4&#946 may be necessary for preferential establishment and/or maintenance of HIV replication in GALT. The binding of gp120 to α4&#946 is mediated by an LDV peptide sequence in the V2 loop that reiterates a structurally homologous binding motif present on MadCAM-1, VCAM-1 and fibronectin, the natural ligands for α4&#946. Removal of this sequence in the HIV envelope abrogates binding to α4&#946 integrin. A prototypical α4&#946 peptide antagonist based on the LDV sequence abrogates binding to gp120. Thus, HIV has acquired, through molecular mimicry, a mechanism to bind to the integrin receptor principally involved in directing lymphocytes to the lamina propria of the gut, the primary site of HIV replication. On CD4+ T cells, gp120 engagement of α4&#946 results in a rapid activation of LFA-1, the central integrin involved in the establishment of virological synapses. Activation of LFA-1 is known to increase HIV replication. Both activated and resting CD4+ T cells in mucosal tissues play important roles in the earliest phases of infection after sexual transmission of HIV-1, a process that is inefficient. We find that α4β7high CD4+ T cells are more susceptible to productive infection than α4β7low-neg CD4+ T cells, in part, because this cellular subset is enriched with metabolically active CD4+ T cells. α4β7high CD4+ T cells are CCR5high and CXCR4low. We find that on these cells α4β7 appears in a complex with CD4. This is the first demonstration that these two receptors appear together in a complex on the surface of a CD4+ T cell. The delineation of the role of integrin α4β7 in HIV pathogenesis provides critical new information to understand the basic underlying mechanisms of HIV transmission and HIV-mediated immune dysfunction.