Laboratory of Immunoregulation, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland, United States of America.
PLoS Pathog. 2011 Feb;7(2):e1001301. doi: 10.1371/journal.ppat.1001301. Epub 2011 Feb 24.
Mucosal transmission of HIV is inefficient. The virus must breach physical barriers before it infects mucosal CD4+ T cells. Low-level viral replication occurs initially in mucosal CD4+ T cells, but within days high-level replication occurs in Peyer's patches, the gut lamina propria and mesenteric lymph nodes. Understanding the early events in HIV transmission may provide valuable information relevant to the development of an HIV vaccine. The viral quasispecies in a donor contracts through a genetic bottleneck in the recipient, such that, in low-risk settings, infection is frequently established by a single founder virus. Early-transmitting viruses in subtypes A and C mucosal transmission tend to encode gp120s with reduced numbers of N-linked glycosylation sites at specific positions throughout the V1-V4 domains, relative to typical chronically replicating isolates in the donor quasispecies. The transmission advantage gained by the absence of these N-linked glycosylation sites is unknown. Using primary α₄β₇/CD4+ T cells and a flow-cytometry based steady-state binding assay we show that the removal of transmission-associated N-linked glycosylation sites results in large increases in the specific reactivity of gp120 for integrin-α₄β₇. High-affinity for integrin α₄β₇, although not found in many gp120s, was observed in early-transmitting gp120s that we analyzed. Increased α₄β₇ affinity is mediated by sequences encoded in gp120 V1/V2. α₄β₇-reactivity was also influenced by N-linked glycosylation sites located in C3/V4. These results suggest that the genetic bottleneck that occurs after transmission may frequently involve a relative requirement for the productive infection of α₄β₇+/CD4+ T cells. Early-transmitting gp120s were further distinguished by their dependence on avidity-effects to interact with CD4, suggesting that these gp120s bear unusual structural features not present in many well-characterized gp120s derived from chronically replicating viruses. Understanding the structural features that characterize early-transmitting gp120s may aid in the design of an effective gp120-based subunit vaccine.
HIV 的黏膜传播效率较低。病毒必须突破物理屏障才能感染黏膜 CD4+T 细胞。最初，低水平的病毒复制发生在黏膜 CD4+T 细胞中，但在几天内，高水平的复制发生在派尔集合淋巴结、肠道固有层和肠系膜淋巴结。了解 HIV 传播的早期事件可能为 HIV 疫苗的开发提供有价值的信息。供体中的病毒准种通过受体中的遗传瓶颈传播，因此在低风险环境中，感染通常由单个创始病毒建立。在亚型 A 和 C 的黏膜传播中，早期传播的病毒在 V1-V4 结构域的特定位置上编码的 gp120 具有较少数量的 N 连接糖基化位点，相对于供体准种中的典型慢性复制分离株。这些 N 连接糖基化位点缺失所获得的传播优势尚不清楚。使用原发性 α₄β₇/CD4+T 细胞和基于流式细胞术的稳态结合测定法，我们表明，去除与传播相关的 N 连接糖基化位点会导致 gp120 对整合素-α₄β₇的特异性反应性大大增加。尽管在许多 gp120 中未发现高亲和力，但在我们分析的早期传播 gp120 中观察到高亲和力整合素 α₄β₇。高亲和力是由 gp120 V1/V2 编码的序列介导的。α₄β₇ 反应性也受到位于 C3/V4 中的 N 连接糖基化位点的影响。这些结果表明，传播后发生的遗传瓶颈可能经常涉及到对 α₄β₇+/CD4+T 细胞的有效感染的相对要求。早期传播的 gp120 进一步通过与 CD4 相互作用的亲和力效应的依赖性来区分，这表明这些 gp120 具有不常见的结构特征，这些特征不存在于许多从慢性复制病毒中衍生的特征良好的 gp120 中。了解表征早期传播 gp120 的结构特征可能有助于设计有效的基于 gp120 的亚单位疫苗。
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