HIV Pathogenesis Programme, Doris Duke Medical Research Institute, Nelson R. Mandela School of Medicine, University of KwaZulu-Natal, Durban, South Africa.
J Acquir Immune Defic Syndr. 2011 Nov 1;58(3):233-40. doi: 10.1097/QAI.0b013e318228667f.
Drug resistance poses a significant challenge for the successful application of highly active antiretroviral therapy (HAART) globally. Furthermore, emergence of HIV-1 isolates that preferentially use CXCR4 as a coreceptor for cell entry, either as a consequence of natural viral evolution or HAART use, may compromise the efficacy of CCR5 antagonists as alternative antiviral therapy.
We sequenced the pol gene of viruses from 45 individuals failing at least 6 months of HAART in Durban, South Africa, to determine the prevalence and patterns of drug-resistance mutations. Coreceptor use profiles of these viruses and those from 45 HAART-naive individuals were analyzed using phenotypic and genotypic approaches.
Ninety-five percent of HAART-failing patients had at least one drug-resistant mutation. Thymidine analog mutations (TAMs) were present in 55% of patients with 9% of individuals possessing mutations indicative of the TAM1 pathway, 44% had TAM2, whereas 7% had mutations common to both pathways. Sixty percent of HAART-failing subjects had X4/dual//mixed-tropic viruses compared with 30% of HAART-naïve subjects (P < 0.02). Genetic coreceptor use prediction algorithms correlated with phenotypic results with 60% of samples from HAART-failing subjects predicted to possess CXCR4-using (X4/dual/mixed viruses) versus 15% of HAART-naïve patients.
The high proportion of TAMs and X4/dual/mixed HIV-1 viruses among patients failing therapy highlight the need for intensified monitoring of patients taking HAART and the problem of diminished drug options (including CCR5 antagonists) for patients failing therapy in resource-poor settings.
耐药性是全球高效抗逆转录病毒治疗（HAART）成功应用的重大挑战。此外，HIV-1 分离株优先使用 CXCR4 作为细胞进入的共受体，无论是由于自然病毒进化还是 HAART 使用的结果，都可能损害 CCR5 拮抗剂作为替代抗病毒治疗的疗效。
我们对来自南非德班的 45 名至少接受 6 个月 HAART 治疗失败的个体的病毒 pol 基因进行了测序，以确定耐药突变的流行率和模式。使用表型和基因型方法分析了这些病毒以及 45 名未接受 HAART 的个体的共受体使用情况。
95%的 HAART 失败患者至少有一种耐药突变。胸苷类似物突变（TAMs）存在于 55%的患者中，其中 9%的个体具有 TAM1 途径的突变，44%的患者具有 TAM2，而 7%的患者具有两种途径的共同突变。60%的 HAART 失败患者与 30%的 HAART 未接受患者相比，具有 X4/双/混合嗜性病毒（P<0.02）。遗传共受体使用预测算法与表型结果相关，60%的 HAART 失败患者样本预测具有使用 CXCR4 的（X4/双/混合病毒），而 15%的 HAART 未接受患者具有这种情况。
在治疗失败的患者中，TAMs 和 X4/双/混合 HIV-1 病毒的高比例突出了需要加强对接受 HAART 治疗的患者的监测，以及在资源匮乏环境中，治疗失败患者可供选择的药物（包括 CCR5 拮抗剂）减少的问题。
