Role of HIV Envelope Proteins In Viral Replication and HIV Pathogenesis

我们确定HIV gp120结合于激活形式的&4和#946。由于主要整合素参与淋巴细胞归巢到肠道相关淋巴组织(GALT)固有层，而HIV感染的CD4T细胞优先定位于淋巴组织，特别是GALT，我们的发现表明HIV gp120和&4和#946之间的直接相互作用可能是在GALT中优先建立和/或维持HIV复制所必需的。 Gp120与&#945；4和#946的结合是由V2环中的LDV肽序列介导的，该序列重申了在MadCAM-1、VCAM-1和纤维连接蛋白上存在的结构上同源的结合基序，这是&#945；4和#946的天然配体。去除HIV包膜中的该序列将取消与整合素的结合。基于LDV序列的典型的&4&946肽拮抗剂取消与gp120的结合。因此，通过分子模拟，HIV已经获得了一种与整合素受体结合的机制，主要涉及将淋巴细胞引导到肠道固有层，这是HIV复制的主要部位。 在CD4+T细胞上，gp120参与&#945；4和#946导致LFA-1的快速激活，LFA-1是参与建立病毒学突触的中央整合素。已知激活LFA-1会增加HIV的复制。 粘膜组织中激活的和静止的CD4+T细胞在HIV-1性传播后感染的早期阶段发挥着重要作用，这是一个效率低下的过程。我们发现，高CD4+T细胞比低阴性CD4+T细胞更容易受到生产性感染，部分原因是这一细胞亚群富含代谢活性的CD4+T细胞。高CD4+T细胞CCR5高，CXCR4低。我们发现，在这些细胞上，&4和7出现在与CD4的复合体中。这是第一次证明这两种受体同时出现在CD4+T细胞表面的复合体中。整合素在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潜在机制提供了关键的新信息。

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.