Regulation of nitric oxide synthase activity in human immunodeficiency virus type 1 (hiv-1)-infected monocytes: Implications for hiv-associated neurological disease

Michael I. Bukrinsky, Hans S.L.M. Nottet, Helena Schmidtmayerova, Larisa Dubrovsky, Clinton R. Flanagan, Mark E. Mullins, Stuart A. Lipton, Howard E. Gendelman

Research output: Contribution to journalArticle

302 Scopus citations

Abstract

Mononuclear phagocytes (monocytes, macrophages, and dendritic cells) play major roles in human immunodeficiency virus (HIV) persistence and disease pathogenesis. Macrophage antigen presentation and effector cell functions are impaired by HIV-1 infection. Abnormalities of macrophage effector cell function in bone marrow, lung, and brain likely result as a direct consequence of cellular activation and HIV replication. To further elucidate the extent of macrophage dysfunction in HIV-1 disease, a critical activation-specific regulatory molecule, nitric oxide (NO), which may contribute to diverse pathology, was studied. Little, if any, NO is produced by uninfected human monocytes. In contrast, infection with HIV-1 increases NO" production to modest, but significant levels (2-5 µM). Monocyte activation (with lipopolysaccharide, tumor necrosis factor a, or through interactions with astroglial cells) further enhances NO" production in HIV-infected cells, whereas its levels are diminished by interleukin 4. These results suggest a possible role for NO in HIV-associated pathology where virus-infected macrophages are found. In support of this hypothesis, RNA encoding the inducible NO synthase (iNOS) was detected in postmortem brain tissue from one pediatric AIDS patient with advanced HIV encephalitis. Corresponding iNOS mR.NA was not detected in brain tissue from five AIDS patients who died with less significant brain disease. These results demonstrate that HIV-1 can influence the expression of NOS in both cultured human monocytes and brain tissue. This newly described feature of HIV-macrophage interactions suggests previously unappreciated mechanisms of tissue pathology that result from productive viral replication.

Original languageEnglish (US)
Pages (from-to)735-745
Number of pages11
JournalJournal of Experimental Medicine
Volume181
Issue number2
DOIs
StatePublished - Feb 1 1995

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology

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