DRUG ABUSE AND RESISTANCE TO ANTIRETROVIRAL THERAPY

对抗逆转录病毒治疗的耐药性总是由对耐药病毒变种的选择造成的。耐药基因可能是在治疗开始之前预先存在的，通常是少数克隆，也可能是由于尽管治疗仍在进行的病毒复制而出现的。在任何一种情况下，在艾滋病毒-1生命周期中出现的耐药突变的发展可能是一个随机事件，取决于在感染个体内存在的艾滋病毒-1群体中普遍出现新突变的速度。新突变的出现反过来将反映给定病毒变体的内在复制特性，以及促进特定病毒变体复制的宿主因素，如T细胞激活状态或共受体表达。我们最近确定了一个不经常被认为是病毒复制增加的来源的宿主因素，注射吸毒的频率，与HIV-1感染的注射吸毒者env基因的多样性呈正相关且高度显著。这一增加不是由于感染了第二种病毒，而可能是由于阿片剂诱导的病毒复制的增强，这在组织培养系统中已经观察到。这种增加的多样性很可能会延伸到env以外的病毒基因，包括pol.基于这些发现，我们推测，在注射吸毒者和美沙酮维持计划的受试者中，多药耐药突变将比非药物对照受试者更容易出现。为了解决这一假设，我们将评估女性机构间艾滋病毒研究收集的40多名女性的样本，以回答以下问题：1)在频繁注射毒品的人群中，env基因中观察到的病毒遗传多样性更高的比率是否也在pol1基因中观察到？2)经常注射吸毒者中观察到的更高的遗传多样性比率是否也在服用美沙酮的个体中观察到？3)注射吸毒史或美沙酮吸毒史是否导致对HAART的耐药性更高？这项研究的发现将对控制HIV-1感染和药物感染人群中阿片成瘾和抗逆转录病毒治疗的临床方法具有重要意义。

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.