Does reduced DNA repair capacity play a role in HIV infection and progression in the lymphocytes of opiate addicts?
Does reduced DNA repair capacity play a role in HIV infection and progression in the lymphocytes of opiate addicts?
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DOI：
10.1097/00126334-200210012-00008
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发表时间：
2002-10-01
影响因子：
3.6
通讯作者：
Donahoe, RM
中科院分区：
文献类型：
--
作者：
Madden, JJ;Wang, YC;Donahoe, RM
体内和体外使用阿片类药物可降低人外周血淋巴细胞修复由产生单链加合物的物理和化学诱变剂引起的DNA损伤的能力。这种修复的减少导致个体细胞的遗传损伤增加，如通过细胞遗传学损伤测量的，包括姐妹染色单体交换和微核形成。这种损伤增加的预期后果也可以通过宿主细胞突变率和细胞凋亡率的增加来确定。这种遗传损伤增加的影响可以预期对感染这些淋巴细胞的HIV-1或猿免疫缺陷病毒具有重大后果。例如，长期以来已知DNA损伤剂诱导慢病毒生长和繁殖，并且已经发现在淋巴细胞的紫外线处理后，这对于HIV-1是真实的。然而，迄今为止，还没有人充分探讨宿主突变率增加对艾滋病毒生长和维持的影响。最近的报道已经证明了病毒突变在诸如对高效抗逆转录病毒疗法（HAART）的抗性等关键生理过程中的作用。除了病毒基因组中随机突变的影响外，HIV-1转录酶和蛋白酶中的特定突变导致突变病毒的积累增加和HAART的逐渐失败。因此，宿主细胞突变率的变化是否也能预测药物治疗敏感性的变化还有待检验。这也引发了一个问题，即艾滋病毒感染的吸毒者中较高的病毒突变率是否可能是这一人群中神经艾滋病发病率较高的基础。我们可以推测，成瘾者体内病毒异质性的增加，会产生攻击神经组织的能力更强、在那里复制的亲和力更高的突变体。
Opiate use in vivo and in vitro reduces the ability of human peripheral lymphocytes to repair DNA damage caused by both the physical and chemical mutagens that produce single-strand adducts. This decrease in repair leads to increased genetic damage to the individual cell as measured by cytogenetic damage, including sister chromatid exchanges and formation of micronuclei. The expected consequences of this increase in damage can also be established by increases in host cell mutation rate and rate of apoptosis. The effect of this increase in genetic damage can be expected to have significant consequences for HIV-1 or simian immunodeficiency virus infecting those lymphocytes. For example, DNA damaging agents have long been known to induce lentiviral growth and propagation, and this has been found to be true for HIV-1 following ultraviolet light treatment of lymphocytes. However, to date, no one has fully explored the consequences of increased host mutation rate on HIV growth and maintenance. Recent reports have demonstrated the role of viral mutation in such key physiologic processes as resistance to highly active antiretroviral therapy (HAART). Beyond the effects of random mutations in the viral genome, specific mutations in the HIV-1 transcriptase and protease lead to increased accumulation of mutant viruses and the gradual failure of HAART. It therefore remains to be tested whether changes in host cell mutation rate will also predict changes in susceptibility to drug therapy. This also leads to questions about whether the higher rate of viral mutation in HIV-infected drug addicts might be the basis for higher rates of neuroAIDS in this population. It would be attractive to Speculate that the increase in the heterogeneity of the virus in addicts produces mutants with a greater capacity to attack neuronal tissue and a high affinity to replicate there.