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Inhibition of Hematopoietic Progenitor Cell Proliferation by Ethanol in Human Immunodeficiency Virus Type 1 Tat‐Expressing Transgenic Mice
Author(s) -
Prakash Om,
Rodriguez Vicente E.,
Tang ZhenYa,
Zhou Peng,
Coleman Roy,
Dhillon Gundeep,
Shellito Judd E.,
Nelson Steve
Publication year - 2001
Publication title -
alcoholism: clinical and experimental research
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.267
H-Index - 153
eISSN - 1530-0277
pISSN - 0145-6008
DOI - 10.1111/j.1530-0277.2001.tb02234.x
Subject(s) - progenitor cell , haematopoiesis , transgene , genetically modified mouse , biology , immunology , virology , microbiology and biotechnology , stem cell , pharmacology , biochemistry , gene
Background: 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. Methods: 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. Results: 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 littermates also showed a significant decrease (25%) in CFU‐GM. Conclusion: 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.