DRUG ABUSE AND RESISTANCE TO ANTIRETROVIRAL THERAPY

对抗逆转录病毒治疗的耐药性总是源于对耐药病毒变体的选择。耐药基因型可以是在开始治疗之前就已经存在的，通常是少数克隆，也可以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HIV-1生命周期中产生的耐药性突变的发展都可能是随机事件，取决于受感染个体内存在的HIV-1群体中通常出现新突变的速度。反过来，新突变的出现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，注射吸毒频率这一宿主因素通常不被认为是病毒复制增加的来源，但它与感染HIV-1的注射吸毒者的环境基因多样性呈正相关且高度显著。这种增加不是由于感染了第二种病毒，而可能是由于在组织培养系统中观察到的阿片类药物诱导的病毒复制增强。这种增加的多样性很可能会扩展到除env以外的病毒基因，包括pol。基于这些发现，我们假设多重耐药突变体在注射吸毒者和美沙酮维持计划者中比在无药物对照者中更容易出现。为了解决这一假设，我们将评估由妇女跨机构艾滋病毒研究收集的40多名妇女的标本，以回答以下问题：1)频繁注射药物的人在env基因中观察到的较高的病毒遗传多样性率是否也在pol基因中观察到？2)在频繁注射吸毒人群中观察到的较高的遗传多样性是否也在服用美沙酮的人群中观察到？3)注射用药史或美沙酮用药史是否会导致HAART耐药率升高？这项研究的结果应该对HIV-1感染、药物感染人群中控制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.