CD101 function, T regulatory cells and HIV-1 acquisition risk

摘要 在过去的二十年里，确定与HIV-1感染相关的流行病学因素（例如，包括 血浆HIV-1 RNA水平、无保护性行为的频率和男性包皮环切术）提供了一个重要的背景 制定HIV-1预防干预措施（抗逆转录病毒药物、暴露前预防和男性医学 包皮环切术）以减缓这种感染的传播。此外，最近的研究已经确定了 宿主炎症和免疫激活作为HIV-1感染风险的调节剂，增加了新的HIV-1感染的可能性。 HIV-1预防干预措施可以针对这些因素。这些干预措施可包括有针对性的 增强新型疫苗或杀微生物剂效果的佐剂;或窄谱抗炎剂 预防HIV-1感染而不增加免疫抑制的其他副作用。但 宿主炎症影响HIV-1性获得的分子机制仍然很差 明白一些研究已经将细胞炎症标记物确定为HIV-1感染的风险因素， 而其他人报道了与保护免受HIV-1感染相关的炎症因子。这些数据 表明宿主炎症在改变HIV-1感染中的作用可能是复杂的。更好地理解 因此，这些分子机制对于正确识别新型HIV-1的靶点至关重要 预防干预措施不会无意中增加HIV-1感染的风险。 我们最近应用了一种全基因组测序方法，从多个非洲HIV-1血清不一致的 异性恋夫妇队列，并成功地确定，并复制，变异之间的新关联 在人类基因CD 101和增加HIV-1感染风险。先前已报道了CD 101表达 是调节宿主免疫反应的T调节细胞的重要调节因子。因此，这些变体提供 这是一个独特的机会，了解宿主炎症的调节如何调节HIV-1获得风险。 然而，我们不知道这些变异影响CD 101或T调节细胞功能的机制。 这些CD 101变体可以增强对T细胞应答的抑制，从而减少有益的宿主免疫应答。 炎症反应;或者它们可以减少T细胞抑制，导致细胞炎症增加， HIV-1靶细胞的积累。因此，更好地了解CD 101变异体如何影响HIV-1 获得性风险可能提供对连接宿主炎症反应的复杂分子途径的深入了解 HIV-1感染风险 我们建议使用来自最初用于识别该CD 101的同一存储库的存档样本 与HIV-1获得风险的遗传关联，以更好地了解这些已确定的变异如何影响整体 炎症和调节性T细胞功能。这些研究将提供重要的线索，进入关键分子 HIV-1感染风险的潜在因素。

ABSTRACT Over the last two decades, identification of epidemiologic factors associated with HIV-1 infection (e.g., including plasma HIV-1 RNA level, frequency of unprotected sex, and male circumcision) has provided a critical context for developing HIV-1 prevention interventions (anti-retroviral drugs, pre-exposure prophylaxis, and medical male circumcision) to slow the spread of this infection. Moreover, recent studies have identified molecular markers of host inflammation and immune activation as modulators of HIV-1 infection risk, raising the possibility that novel HIV-1 prevention interventions could be targeted at these factors. Such interventions could include targeted adjuvants to augment the effect of novel vaccines or microbicides; or narrow-spectrum anti-inflammatory agents to prevent HIV-1 infection without augmenting other adverse effects from immunosuppression. However, the molecular mechanisms by which host inflammation impacts sexual acquisition of HIV-1 remain poorly understood. Some studies have identified markers of cellular inflammation as risk factors for HIV-1 infection, while others have reported inflammatory factors associated with protection from HIV-1 infection. These data suggest that the role of host inflammation in modifying HIV-1 infection is likely complex. A better understanding of these molecular mechanisms is therefore of critical importance to properly identify targets for novel HIV-1 prevention interventions that won’t inadvertently increase risk of HIV-1 infection. We recently applied a whole genome sequencing approach to data from multiple African HIV-1 serodiscordant heterosexual couples cohorts and successfully identified, and replicated, a novel association between variants in the human gene CD101 and increased HIV-1 acquisition risk. CD101 expression had been previously reported to be an important regulator of T regulatory cells that regulate host immune responses. Thus, these variants offer a unique opportunity to understand how the regulation of host inflammation may modulate HIV-1 acquisition risk. However, we do not know the mechanism by which these variants impact CD101 or T regulator cell function. These CD101 variants could enhance suppression of T cell responses thereby reducing helpful host inflammatory responses; or they could reduce T cell suppression resulting in increased cellular inflammation and accumulation of HIV-1 target cells. Thus, an improved understanding of how CD101 variants impact HIV-1 acquisition risk may provide insight into the complex molecular pathways that link host inflammatory responses and HIV-1 acquisition risk. We propose to use archived samples from the same repository that were originally used to identify this CD101 genetic association with HIV-1 acquisition risk to better understand how these identified variants impact overall inflammation and regulatory T cell function. These studies will provide important clues into the key molecular factors underlying HIV-1 acquisition risk.