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A Critical Role of Nitric Oxide in Human Immunodeficiency Virus Type 1-Induced Hyperresponsiveness of Cultured Monocytes

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Abstract

Background

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 monocytetropic strain HTV-1ADA. 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.

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Acknowledgments

The authors wish to thank K. Manogue for critical reading of the manuscript and helpful comments, and A. Cerami for continued encouragement and support. This work was supported in part by the AmFAR Grant 02059-15-RGR (MB) and by funds from The Picower Institute for Medical Research.

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Authors and Affiliations

  1. The Picower Institute for Medical Research, 350 Community Drive, Manhasset, New York, 11030, USA

    Michael Bukrinsky, Helena Schmidtmayerova, Gabriele Zybarth, Larisa Dubrovsky & Barbara Sherry

  2. Institute of Virology, Slovak Academy of Sciences, Bratislava, Slovakia

    Helena Schmidtmayerova

  3. Cold Spring Harbor Laboratory, Cold Spring Harbor, New York, USA

    Grigori Enikolopov

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  1. Michael Bukrinsky
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  2. Helena Schmidtmayerova
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Bukrinsky, M., Schmidtmayerova, H., Zybarth, G. et al. A Critical Role of Nitric Oxide in Human Immunodeficiency Virus Type 1-Induced Hyperresponsiveness of Cultured Monocytes. Mol Med 2, 460–468 (1996). https://doi.org/10.1007/BF03401905

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