Prakash O, Rodriguez V E, Tang Z Y, Zhou P, Coleman R, Dhillon G, Shellito J E, Nelson S
Laboratory of Molecular Oncology, Alton Ochsner Medical Foundation, New Orleans, LA 70121, USA.
Alcohol Clin Exp Res. 2001 Mar;25(3):450-6.
A number of hematological abnormalities are associated with both human immunodeficiency virus type 1 (HIV-1) infection and alcohol abuse. There is little information on how alcohol abuse might further influence the survival and growth of hematopoietic progenitors in HIV-infected individuals in the presence of immune system abnormalities and anti-HIV drugs. Because there is evidence that viral transactivator Tat itself can induce hematopoietic suppression, in this study we examined the role of ethanol as a cofactor in transgenic mice that expressed HIV-1 Tat protein.
Tat transgenic mice and nontransgenic littermates were given ethanol (20% v/v) and the anti-HIV drug 3'-azido-3'-deoxythymidine (AZT; 1 mg/ml) in drinking water. Immunosuppression in mice was induced by weekly intraperitoneal injections of anti-CD4 antibody. Hematopoiesis was examined by erythroid colony forming unit (CFU-E) and granulocyte/macrophage colony-forming unit (CFU-GM) assays of the bone marrow progenitor cells.
Administration of ethanol for 7 weeks resulted in a 50% decrease in the proliferative capacity of CFU-E- and CFU-GM-derived progenitors from transgenic mice compared with that of ethanol-treated nontransgenic controls. Similar decreases also were observed in transgenic mice treated with AZT or a combination of AZT and ethanol. Furthermore, ethanol and AZT were significantly more toxic to the granulopoietic progenitors (40-50% inhibition) than to the erythropoietic progenitors (10-20% inhibition) in Tat transgenic mice. Although a 10 day exposure of Tat transgenic and nontransgenic mice to a combination of ethanol and AZT had no suppressive effect on the erythropoietic and granulopoietic progenitor cells, there was a marked decrease (40-60%) in CFU-GM in mice made immunodeficient by CD4+ T-lymphocyte depletion. The ethanol-treated Tat transgenic mice but not the nontransgenic litter-mates also showed a significant decrease (25%) in CFU-GM.
Our in vivo study strongly suggests that ethanol ingestion in HIV-1-infected individuals, particularly those on antiretroviral drugs, might increase bone marrow toxicity and contribute to HIV-1-associated hematopoietic impairment.
多种血液学异常与1型人类免疫缺陷病毒（HIV-1）感染及酒精滥用均有关联。关于在存在免疫系统异常和抗HIV药物的情况下，酒精滥用如何进一步影响HIV感染个体中造血祖细胞的存活和生长，相关信息较少。因为有证据表明病毒反式激活因子Tat本身可诱导造血抑制，所以在本研究中，我们在表达HIV-1 Tat蛋白的转基因小鼠中研究了乙醇作为辅助因子的作用。
给Tat转基因小鼠和非转基因同窝小鼠饮用含乙醇（20% v/v）和抗HIV药物3'-叠氮-3'-脱氧胸苷（AZT；1 mg/ml）的水。通过每周腹腔注射抗CD4抗体诱导小鼠免疫抑制。通过对骨髓祖细胞进行红系集落形成单位（CFU-E）和粒细胞/巨噬细胞集落形成单位（CFU-GM）测定来检测造血情况。
与经乙醇处理的非转基因对照相比，给转基因小鼠给予乙醇7周导致CFU-E和CFU-GM来源的祖细胞增殖能力降低50%。在用AZT或AZT与乙醇联合处理的转基因小鼠中也观察到类似的降低。此外，在Tat转基因小鼠中，乙醇和AZT对粒细胞生成祖细胞的毒性（抑制40 - 50%）明显大于对红细胞生成祖细胞的毒性（抑制10 - 20%）。尽管让Tat转基因和非转基因小鼠暴露于乙醇和AZT组合10天对红细胞生成和粒细胞生成祖细胞没有抑制作用，但在因CD4 + T淋巴细胞耗竭而免疫缺陷的小鼠中，CFU-GM显著降低（40 - 60%）。经乙醇处理的Tat转基因小鼠而非非转基因同窝小鼠的CFU-GM也显著降低（25%）。
我们的体内研究强烈表明，HIV-1感染个体，尤其是那些服用抗逆转录病毒药物的个体，摄入乙醇可能会增加骨髓毒性，并导致与HIV-1相关的造血功能损害。
