The role of viral diversity in HIV-1 drug resistance

描述（由申请人提供）：通过引入抗逆转录病毒治疗（ART）， HIV-1感染的死亡率大大降低。然而，由于存在耐药病毒，抗逆转录病毒治疗常常失败。耐药的发生是因为编码目标酶的基因发生突变的病毒变异。这些耐药病毒在治疗前存在的频率尚不清楚。在单个患者中，这些耐药突变的产生可能取决于初始病毒种群、突变频率、病毒适应度和选择压力。我们对耐药性的了解大部分来自对抗逆转录病毒治疗的强大选择压力下的病毒种群的调查。这些先前的研究清楚地表明，面对药物治疗，病毒继续复制往往导致耐药病毒。目前尚不清楚这些病毒是否通常在抗逆转录病毒治疗之前就存在，以及是否有因素有助于预测它们的存在。为了理解这些问题，我们建议分析来自非洲抗逆转录病毒治疗初始队列患者的样本。我们假设耐药病毒在药物治疗之前就已经存在。此外，我们预测，在编码逆转录酶（RT）和蛋白酶的pol/pro位点上具有更大基因型多样性的病毒群体将更有可能产生耐药病毒变体。在药物治疗前了解影响耐药病毒突变的频率和持久性的因素对改善艾滋病毒/艾滋病患者的临床护理具有重要意义。此外，抗逆转录病毒治疗开始在非洲广泛推广，但往往没有严格的临床监测或建议。通过这些研究，我们将深入了解抗逆转录病毒治疗在非洲取得成功的可能性，以及耐药HIV -1病毒“新”流行演变的可能性。

DESCRIPTION (provided by applicant): The mortality from HIV-1 infection has been greatly reduced by the introduction of antiretroviral treatment (ART). ART, however, often fails due to the existence of drug resistant viruses. Drug resistance occurs because of the presence of viral variants with mutations in the genes encoding the targeted enzymes. The frequency with which these drug resistant viruses preexist prior to treatment is unclear. Within an individual patient, the generation of these drug resistance mutations presumably depends upon the initial virus population, mutation frequency, viral fitness, and selection pressure. Much of our understanding of drug resistance comes from investigations of virus populations under strong selection pressure of ART. These previous studies have clearly demonstrated that continued viral replication in the face of drug therapy often leads to drug resistant viruses. It remains unclear whether these viruses typically exist prior to ART and whether there are factors that would help predict their existence. In order to understand these questions we propose to analyze samples from an ART naive cohort of patients in Africa. We hypothesize that drug resistant viruses will exist prior to drug therapy. In addition, we predict that virus populations with greater genotypic diversity in the pol/pro locus, which encodes the enzymes, reverse transcriptase (RT) and protease, targeted by ART, will have a greater likelihood of having drug resistant viral variants. Understanding the factors influencing the frequency and persistence of drug resistant viral mutants prior to drug therapy will be important for improving the clinical care of patients with HIV/AIDS. Furthermore, ART is beginning to be widely introduced in Africa often without rigorous clinical monitoring or advice. With these studies, we will gain insight into the likelihood of success with ART in Africa and the possibility of the evolution of a 'new' epidemic with drug resistant HIV -1 viruses.