DRUG ABUSE AND RESISTANCE TO ANTIRETROVIRAL THERAPY

抗逆转录病毒治疗的耐药性总是由耐药病毒变异体的选择引起的。 耐药基因型可以是预先存在的，通常作为少数克隆，在治疗开始之前，或者它可以出现由于持续的病毒复制，尽管治疗。 在这两种情况下，HIV-1生命周期中出现的耐药性突变的发展可能是一个随机事件，取决于感染个体中HIV-1群体中新突变的出现速度。 新突变的出现反过来将反映给定病毒变体的固有复制特性，以及促进特定病毒变体复制的宿主因素，如T细胞活化状态或共受体表达。 我们最近确定，一个宿主因素不经常被认为是增加病毒复制的来源，注射吸毒的频率，是积极和高度显着相关的HIV-1感染注射吸毒者的env基因的多样性。这种增加不是由于第二种病毒的感染，可能是由于阿片类药物诱导的病毒复制增强，这已在组织培养系统中观察到。这是可能的，这种增加的多样性将扩展到病毒基因以外的env，包括波尔。基于这些研究结果，我们假设，多药耐药突变体将更容易出现在注射吸毒者和美沙酮维持计划比在无药物对照组。 为了解决这一假设，我们将评估妇女跨部门艾滋病毒研究从40多名妇女收集的标本，以回答以下问题：1）是否在经常注射毒品的人的env基因中观察到的较高的病毒遗传多样性率也在pol基因中观察到？2)在经常注射毒品者中观察到的较高的遗传多样性率是否也在服用美沙酮的个人中观察到？3)注射吸毒史或美沙酮使用史是否导致HAART耐药发生率较高？ 这项研究的结果应该有重要意义的临床方法来控制阿片类药物成瘾和抗逆转录病毒治疗的HIV-1感染，药物感染的人群。

Resistance to antiretroviral therapy always results from selection for resistant viral variants. The resistance genotype can either be pre-existing, frequently as a minority clone, before the initiation of therapy or it can emerge due to ongoing viral replication that occurs despite therapy. In either case the development of a drug-resistance mutation arising during the HIV-1 life cycle is likely a random event, dependent on the rate at which new mutations arise generally in the HIV-1 population existing within an infected individual. The appearance of new mutations, in turn, will reflect intrinsic replicative properties of a given viral variant, as well as host factors, such as T cell activation state or co-receptor expression, that facilitate replication of specific viral variants. We have recently determined that one host factor not frequently considered as a source of increased viral replication, frequency of injection drug use, is positively and highly significantly associated with diversity in the env gene of HIV-1 infected injection drug users. This increase is not due to infection with a second virus and may be attributable to opiate-induced enhancement of viral replication, which has been observed in tissue culture systems. It is likely that this increased diversity will extend to viral genes other than env, including pol. Based on these findings we hypothesize that multi-drug resistant mutants will emerge more readily among injection drug users and those on methadone maintenance programs than in drug-free control subjects. To address this hypothesis we will evaluate specimens collected from over 40 women by the Women's Interagency HIV Study to answer the following questions: 1) Is the higher rate of viral genetic diversity observed in the env gene in frequent drug injectors also observed in the pol gene? 2) Is the higher rate of genetic diversity observed in frequent injection drug users also observed in individuals taking methadone? 3) Does a history of injection drug use or methadone use result in a higher incidence of resistance to HAART? The findings from this study should have important implications for the clinical approach to control of opiate addiction and antiretroviral therapy in the HIV-1- infected, drug-infected population.