Drug resistance mutations in the connection subdomain of the HIV-1 reverse transcriptase

人类免疫缺陷病毒1型(HIV-1)感染可以通过抗逆转录病毒药物控制。在大多数接受抗逆转录病毒治疗的患者中，病毒会发生变异，不再被药物抑制。耐药HIV-1的出现是导致患者失去药物疗效的主要因素之一。导致耐药性的突变已经被定义，并针对不同的药物类别。用于预测耐药性的基因分析通常用于指导HIV-1感染者的治疗决定。对于针对HIV-1逆转录酶(RT)的药物，常用的基因型试剂盒通常会分析逆转录酶560个氨基酸中前240个氨基酸的突变。这忽略了该酶其他区域突变的影响，这些突变在耐药性中具有潜在的重要作用。最近，抑制HIV-1RT核糖核酸酶H功能的突变被证明会导致对齐多夫定的高水平耐药性，这为超过240密码子的突变可以带来耐药性提供了先例。我们对核糖核酸酶H的一个不同区域的分析称为连接亚域，证明了在接受药物治疗的患者和药物未成熟的患者中高度流行的突变的存在。在这项研究中，我们将使用体外试验来确定这些突变对耐药性和病毒适合性的影响。我们还将确定这些突变产生耐药性的机制。最后，使用我们独特的数据库，包括20,000多个基因分型样本，我们将确定这些突变在患者中的作用。这项研究预计将确定在RT连接亚域中存在的临床意义上的突变。此外，这项研究将导致更准确的基因分析的发展，这将改善对艾滋病毒感染者的临床管理。

Human immunodeficiency virus type 1 (HIV-1) infections can be controlled with antiretroviral drugs. In the majority of patients on antiretroviral therapy the virus mutates and is no longer inhibited by the drug. The emergence of drug-resistant HIV-1 is one of the major factors that lead to loss of drug efficacy in patients. Mutations that confer drug resistance have been defined and are specific for different drug classes. Genotype assays that are used to predict drug resistance are routinely used to guide therapeutic decisions in the treatment of HIV-1 infected individuals. For drugs that target the HIV-1 reverse transcriptase (RT), commonly used genotype kits normally analyse mutations in the first 240 out of 560 amino acids of the reverse transcriptase. This ignores the impact of mutations in other regions of the enzyme, which are potentially important in drug resistance. Recently, mutations that inhibit ribonuclease H function of the HIV-1 RT have been shown to confer high-level resistance to zidovudine, providing the precendent that mutations beyond codon 240 can confer drug resistance. Our analysis of a different region to ribonuclease H called the connection subdomain has demonstrated the presence of mutations that are highly prevalent in drug-treated versus drug naive patients. In this study we will use in vitro assays to define the effect of these mutations on drug resistance and viral fitness . We will also determine the mechanism by which these mutations confer drug resistance. Finally, using our unique database consisting of over 20,000 genotyped samples , we will establish the role of these mutations in the patient. This study is anticipated to identify clinically significant mutations that are present in the RT connection subdomain. Additionally, this study will lead to the development of more accurate genotype assays which will improve the clinical management of HIV infected individuals.