A critical role of nitric oxide in human immunodeficiency virus type 1-induced hyperresponsiveness of cultured monocytes

Bukrinsky, M., Schmidtmayerova, H., Zybarth, G., Dubrovsky, L., Sherry, B., Enikolopov, G. (1996) A critical role of nitric oxide in human immunodeficiency virus type 1-induced hyperresponsiveness of cultured monocytes. Molecular Medicine, 2 (4). pp. 460-468. ISSN 1076-1551

URL: http://www.ncbi.nlm.nih.gov/pubmed/8827716

Abstract

Human immunodeficiency virus type 1 (HIV-1) infection leads to a general exhaustion of the immune system. Prior to this widespread decline of immune functions, however, there is an evident hyperactivation of the monocyte/macrophage arm. Increased levels of cytokines and other biologically active molecules produced by activated monocytes may contribute to the pathogenesis of HIV disease both by activating expression of HIV-1 provirus and by direct effects on cytokine-sensitive tissues, such as lung or brain. In this article, we investigate mechanisms of hyperresponsiveness of HIV-infected monocytes. Materials and Methods: The study was performed on monocyte cultures infected in vitro with a monocyte tropic strain HIV-1(ADA). Cytokine production was induced by stimulation of cultures with lipopolysaccharides (LPS) and measured by ELISA. To study involvement of nitric oxide (NO) in the regulation of cytokine expression, inhibitors of nitric oxide synthase (NOS) or chemical donors of NO were used. Results: We demonstrate that infection with HIV-1 in vitro primes human monocytes for subsequent activation with LPS, resulting in increased production of proinflammatory cytokines tumor necrosis factor (TNF) and interleukin 6 (IL-6). This priming effect can be blocked by Ca2+-chelating agents and by the NOS inhibitor L-NMMA, but not by hemoglobin. It could be reproduced on uninfected monocyte cultures by using donors of NO, but not cGMP, together with LPS. Conclusions: NO, which is expressed in HIV-1-infected monocyte cultures, induces hyperresponsiveness of monocytes by synergizing with calcium signals activated in response to LPS stimulation. This activation is cGMP independent. Our findings demonstrate the critical role of NO in HIV-1-specific hyperactivation of monocytes.

Item Type: Paper
Uncontrolled Keywords: INTERFERON-GAMMA HIV-INFECTION INHIBITION MACROPHAGES EXPRESSION ACTIVATION SYNTHASE LIPOPOLYSACCHARIDE REPLICATION CYTOKINES
Subjects: diseases & disorders > viral diseases > HIV
bioinformatics > genomics and proteomics > small molecules > nitric oxide
CSHL Authors:
Communities: CSHL labs > Enikopolov lab
Depositing User: Matt Covey
Date Deposited: 20 Dec 2013 16:03
Last Modified: 20 Dec 2013 16:03
PMCID: PMC2230172
URI: http://repository.cshl.edu/id/eprint/29140

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