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(Journal of Leukocyte Biology. 2001;70:592-600.)
© 2001 by Society for Leukocyte Biology

A defect in HIV-1 transgenic murine macrophages results in deficient nitric oxide production

Department of Medical Microbiology and Immunology, University of Alberta, Edmonton, Alberta, Canada

Correspondence: Peter Dickie, 1-40 HMRC, University of Alberta, Edmonton, AB T6G 2S2, Canada. E-mail: peter.dickie{at}ualberta.ca

HIV transgenic mice bearing multiple copies of a noninfectious (gag/pol) proviral DNA were tested for the systemic production of nitric oxide (NO). Serum levels of NO metabolites were reduced about 50% in HIV transgenic mice compared with nontransgenic sibling mice. This difference persisted when NO production was induced with peritoneal injections of bacterial endotoxin (LPS). Peritoneal inflammatory macrophages, but not resident peritoneal macrophages, derived from HIV-1 transgenic mice and activated in vitro with LPS and IFN- (or tumor necrosis factor and IFN-) also produced about 50% less NO than did macrophages harvested from nontransgenic littermates. Isogenic, transgenic mice bearing mutated nef or vpr genes had normal serum levels of NO metabolites and their macrophages produced normal levels of NO when stimulated. An explanation for the reduced NO response of HIV[Vpr+Nef+] macrophages was not apparent from measured levels of iNOS expression, viral gene expression, or arginase activity in activated macrophages. Inhibition of nitric oxide synthase (NOS) isoforms with L-NAME or aminoguanidine blocked time-dependent increases in HIV gene expression in activated macrophages cultured ex vivo. Inhibition with L-NAME occurred despite high levels of NO generated by iNOS, and exogenously supplied NO induced HIV gene expression only weakly, suggesting that cNOS had the greater influence on proviral gene induction. This system is presented as a model of HIV-1 proviral gene expression and dysfunction in macrophages.

Key Words: transcription • arginase • TNF- • NOS • Nef • Vpr

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