Inhibition of hematopoietic progenitor cell proliferation by ethanol in human immunodeficiency virus type 1 tat-expressing transgenic mice.
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 litter-mates also showed a significant decrease (25%) in CFU-GM.


CONCLUSIONS
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.
Prakash
O
O
Laboratory of Molecular Oncology, Alton Ochsner Medical Foundation, New Orleans, LA 70121, USA. oprakash@ochsner.org
Rodriguez
V E
VE
Tang
Z Y
ZY
Zhou
P
P
Coleman
R
R
Dhillon
G
G
Shellito
J E
JE
Nelson
S
S
D000818:Animals; D019380:Anti-HIV Agents / Q000494:pharmacology*; D015496:CD4-Positive T-Lymphocytes / Q000187:drug effects* / Q000378:metabolism; D002455:Cell Division / Q000187:drug effects; D002492:Central Nervous System Depressants / Q000494:pharmacology*; D015672:Erythroid Precursor Cells / Q000187:drug effects / Q000378:metabolism; D000431:Ethanol / Q000494:pharmacology*; D015696:Gene Products, tat / Q000187:drug effects* / Q000378:metabolism; D006410:Hematopoiesis / Q000187:drug effects*; D006412:Hematopoietic Stem Cells / Q000187:drug effects* / Q000378:metabolism; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D010446:Peptide Fragments / Q000187:drug effects* / Q000378:metabolism; D015215:Zidovudine / Q000494:pharmacology*; D054322:tat Gene Products, Human Immunodeficiency Virus
D019380:Anti-HIV Agents; D002492:Central Nervous System Depressants; D015696:Gene Products, tat; D010446:Peptide Fragments; D054322:tat Gene Products, Human Immunodeficiency Virus; C422951:tat peptide (48-60), Human immunodeficiency virus 1; D000431:Ethanol; D015215:Zidovudine