Department of Experimental Medical Science, Section of Molecular Virology, Lund University, Lund, Sweden.
Retrovirology. 2010 Mar 22;7:23. doi: 10.1186/1742-4690-7-23.
HIV-1 is one of the fastest evolving pathogens, and is distinguished by geographic and genetic variants that have been classified into different subtypes and circulating recombinant forms (CRFs). Early in infection the primary coreceptor is CCR5, but during disease course CXCR4-using HIV-1 populations may emerge. This has been correlated with accelerated disease progression in HIV-1 subtype B. Basic knowledge of HIV-1 coreceptor tropism is important due to the recent introduction of coreceptor antagonists in antiretroviral therapy, and subtype-specific differences regarding how frequently HIV-1 CXCR4-using populations appear in late-stage disease need to be further investigated. To study how frequently CXCR4-using populations appear in late-stage disease among HIV-1 subtype A and CRF02_AG, we evaluated the accuracy of a recombinant virus phenotypic assay for these subtypes, and used it to determine the HIV-1 coreceptor tropism of plasma samples collected during late-stage disease in Guinea-Bissau. We also performed a genotypic analysis and investigated subtype-specific differences in the appearance of CXCR4 tropism late in disease.
We found that the recombinant virus phenotypic assay accurately predicted HIV-1 coreceptor tropism of subtype A and CRF02_AG. Over the study period (1997-2007), we found an increasing and generally high frequency of CXCR4 tropism (86%) in CRF02_AG. By sequence analysis of the V3 region of our samples we developed a novel genotypic rule for predicting CXCR4 tropism in CRF02_AG, based on the combined criteria of the total number of charged amino acids and net charge. This rule had higher sensitivity than previously described genotypic rules and may be useful for development of future genotypic tools for this CRF. Finally, we conducted a literature analysis, combining data of 498 individuals in late-stage disease, and found high amounts of CXCR4 tropism for all major HIV-1 subtypes (60-77%), except for subtype C (15%).
The increase in CXCR4 tropism over time suggests an evolving epidemic of CRF02_AG. The results of the literature analysis demonstrate the need for further studies investigating subtype-specific emergence for CXCR4-tropism; this may be particularly important due to the introduction of CCR5-antagonists in HIV treatment regimens.
HIV-1 是进化最快的病原体之一，具有地理和遗传变异，这些变异已被分为不同的亚型和循环重组形式（CRFs）。在感染早期，主要的核心受体是 CCR5，但在疾病过程中，可能会出现使用 CXCR4 的 HIV-1 群体。这与 HIV-1 亚型 B 中疾病进展的加速有关。由于最近在抗逆转录病毒治疗中引入了核心受体拮抗剂，因此了解 HIV-1 核心受体嗜性的基本知识非常重要，并且需要进一步研究在晚期疾病中出现使用 CXCR4 的 HIV-1 群体的频率与亚型特异性差异。为了研究在 HIV-1 亚型 A 和 CRF02_AG 中晚期疾病中出现使用 CXCR4 的群体的频率，我们评估了一种针对这些亚型的重组病毒表型测定的准确性，并使用该测定来确定在几内亚比绍晚期疾病期间采集的血浆样本中的 HIV-1 核心受体嗜性。我们还进行了基因分析，并研究了在疾病晚期出现 CXCR4 嗜性的亚型特异性差异。
我们发现重组病毒表型测定能够准确预测 HIV-1 亚型 A 和 CRF02_AG 的核心受体嗜性。在研究期间（1997-2007 年），我们发现 CRF02_AG 中 CXCR4 嗜性的频率逐渐升高且普遍较高（86％）。通过对我们样本的 V3 区进行序列分析，我们根据带电氨基酸总数和净电荷的综合标准，为 CRF02_AG 中预测 CXCR4 嗜性开发了一种新的基因规则。该规则比以前描述的基因规则具有更高的敏感性，并且可能对未来开发针对该 CRF 的基因工具有用。最后，我们进行了文献分析，将 498 名晚期疾病患者的数据结合在一起，发现所有主要 HIV-1 亚型（60-77％）的 CXCR4 嗜性均很高，除了亚型 C（15％）。
随着时间的推移，CXCR4 嗜性的增加表明 CRF02_AG 的流行正在发生变化。文献分析的结果表明，需要进一步研究 CXCR4 嗜性的出现与亚型特异性的关系；由于在 HIV 治疗方案中引入了 CCR5 拮抗剂，因此这一点尤为重要。
