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The Critical Role of p38 MAP Kinase in T Cell HIV-1 Replication

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Abstract

Background

Replication of HIV-1 in human T lymphocytes requires the activation of host cellular proteins. This study identifies p38 mitogen-activated protein kinase (MAPK) as one such kinase necessary for HIV-1 replication in T cells.

Materials and Methods

Primary human T lymphocytes were infected with the LAI strain of HTV-1 and Jurkat cells were infected with the RF strain of HIV-1. HIV replication was measured by reverse transcriptase activity. Cellular expression of endogenous p38 MAPK protein was analyzed using immunoprecipitation. Blockade of p38 MAPK expression was achieved using anti-sense oligonucleotides to p38 MAPK and the guanylhydrazone compound CNI-1493, an inhibitor of p38 MAPK activation.

Results

HTV-1 infection of both primary human T lymphocytes and a T cell line rapidly activated the cellular p38 MAPK pathway, which remained activated for the duration of the culture. Addition of phosphothioated antisense oligonucleotides to p38 MAPK specifically inhibited viral replication. Blockade of p38 MAPK activation by addition of CNI-1493 also inhibited HIV-1 viral replication of primary T lymphocytes in a dose- and time-dependent manner. Stimulation of p38 MAPK activation did not occur with the addition of heat-inactivated virus, suggesting that viral internalization, and not just membrane binding, is necessary for p38 MAPK activation.

Conclusions

These results indicate that activation of the p38 MAPK cascade is critical for HIV-1 replication in primary T lymphocytes, and that blockade of this signal transduction pathway may be a novel therapeutic approach to the treatment of HIV-1 infection.

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Acknowledgments

We thank Ms. Dee Prieto for excellent secretarial support. Part of this work was presented at the meeting Molecular Basis of Sepsis, October 8–11, 1996, at Woods Hole, MA. This work was supported by NIH grants DK49283 and NIH A138245 and by institutional funding from The Picower Institute for Medical Research.

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Authors and Affiliations

  1. The Picower Institute for Medical Research, Manhasset, New York, USA

    Pamela S. Cohen, Helena Schmidtmayerova, Jameel Dennis, Larisa Dubrovsky, Barbara Sherry, Haichao Wang, Michael Bukrinsky & Kevin J. Tracey

  2. Laboratory of Biomedical Science, Department of Surgery, North Shore University Hospital, Manhasset, New York, USA

    Jameel Dennis & Kevin J. Tracey

  3. Department of Emergency Medicine, North Shore University Hospital, Manhasset, New York, USA

    Haichao Wang

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

    Helena Schmidtmayerova

Authors
  1. Pamela S. Cohen
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  2. Helena Schmidtmayerova
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  4. Larisa Dubrovsky
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Correspondence to Kevin J. Tracey.

Additional information

Communicated by R. Bucala.

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Cohen, P.S., Schmidtmayerova, H., Dennis, J. et al. The Critical Role of p38 MAP Kinase in T Cell HIV-1 Replication. Mol Med 3, 339–346 (1997). https://doi.org/10.1007/BF03401812

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