Department of Medicine, University of Pennsylvania School of Medicine, 522 Johnson Pavilion, 36th & Hamilton Walk, Philadelphia, PA 19104-6060, USA.
J Transl Med. 2011 Jan 27;9 Suppl 1(Suppl 1):S3. doi: 10.1186/1479-5876-9-S1-S3.
Entry coreceptor use by HIV-1 plays a pivotal role in viral transmission, pathogenesis and disease progression. In many HIV-1 infected individuals, there is an expansion in coreceptor use from CCR5 to include CXCR4, which is associated with accelerated disease progression. While targeting HIV-1 envelope interactions with coreceptor during viral entry is an appealing approach to combat the virus, the methods of determining coreceptor use and the changes in coreceptor use that can occur during disease progression are important factors that may complicate the use of therapies targeting this stage of HIV-1 replication. Indicator cells are typically used to determine coreceptor use by HIV-1 in vitro, but the coreceptors used on these cells can differ from those used on primary cell targets. V3 based genetic sequence algorithms are another method used to predict coreceptor use by HIV-1 strains. However, these algorithms were developed to predict coreceptor use in cell lines and not primary cells and, furthermore, are not highly accurate for some classes of viruses. This article focuses on R5X4 HIV-1, the earliest CXCR4-using variants, reviewing the pattern of coreceptor use on primary CD4+ lymphocytes and macrophages, the relationship between primary cell coreceptor use and the two principal approaches to coreceptor analysis (genetic prediction and indicator cell phenotyping), and the implications of primary cell coreceptor use by these strains for treatment with a new class of small molecule antagonists that inhibit CCR5-mediated entry. These are important questions to consider given the development of new CCR5 blocking therapies and the prognosis associated with CXCR4 use.
HIV-1 进入的核心受体使用在病毒传播、发病机制和疾病进展中起着关键作用。在许多 HIV-1 感染者中，核心受体的使用从 CCR5 扩展到包括 CXCR4，这与疾病进展加速有关。虽然在病毒进入过程中靶向 HIV-1 包膜与核心受体的相互作用是一种有吸引力的对抗病毒的方法，但确定核心受体使用的方法以及在疾病进展过程中核心受体使用的变化是可能使针对 HIV-1 复制这一阶段的治疗复杂化的重要因素。指示细胞通常用于体外测定 HIV-1 的核心受体使用，但这些细胞上使用的核心受体与原发性细胞靶标上使用的核心受体不同。基于 V3 的遗传序列算法是另一种用于预测 HIV-1 株核心受体使用的方法。然而，这些算法是为预测细胞系而不是原发性细胞上的核心受体使用而开发的，此外，对于某些病毒类别，它们并不非常准确。本文重点介绍 R5X4 HIV-1，即最早的 CXCR4 使用变体，综述了原发性 CD4+淋巴细胞和巨噬细胞上核心受体使用的模式、原发性细胞核心受体使用与两种主要核心受体分析方法（遗传预测和指示细胞表型分析）之间的关系，以及这些株系对新型小分子拮抗剂的治疗效果的影响，这些拮抗剂抑制 CCR5 介导的进入。鉴于新的 CCR5 阻断疗法的发展以及与 CXCR4 使用相关的预后，这些都是需要考虑的重要问题。
