Suppression of HIV-1 viral replication and cellular pathogenesis by a novel p38/JNK kinase inhibitor

Karuppiah Muthumani, Scott A. Wadsworth, Nathanael S. Dayes, Daniel S. Hwang, Andrew Y. Choo, Harindra R. Abeysinghe, John Siekierka, David B. Weiner

Research output: Contribution to journalArticle

31 Citations (Scopus)

Abstract

Objective: To analyze a novel compound, which inhibits serine-threonine protein kinase p38, for its possible bioactivity against HIV-1 infection. Methods: Proteins involved in cellular signal transduction pathways represent a novel class of host therapeutic targets for infectious diseases. In this regard the serine/ threonine kinase p38 MAPK, a member of the mitogen-activated protein (MAP) kinase superfamily of signal transduction molecules may play an important role in HIV-1 infection. We analyzed the ability of this compound (RWJ67657) to inhibit HIV replication in primary T cells and monocytes. Cellular expression of phosphop38MAPK was studied by Western blot analysis. Blockade of HIV infection induced apoptosis was measured by Annexin V staining. Results: p38 inhibitor RWJ67657 was effective in inhibiting HIV-1 replication in both T-cell and monocyte cell lines, irrespective of the coreceptor used by the virus for entry into the cell. Importantly, both reverse transcriptase and protease resistant escape mutant viruses were effectively suppressed by RWJ67657. In addition, the tested compounds block HIV-induced T-cell apoptosis, a critical means of T-cell depletion linked to AIDS progression. Conclusion: Several steps in the HIV-1 virus life cycle appear to depend on cellular activation, including activation of the p38 pathway. Without activation virus replication is thought to be blocked due to incomplete reverse transcription and a lack of proviral DNA integration. The data collectively illustrate that inhibition of the p38 pathway can affect HIV-1 replication. Interruption of HIV infection by p38 inhibitors underscores the value of exploring antiviral drugs that target host cellular proteins.

Original languageEnglish
Pages (from-to)739-748
Number of pages10
JournalAIDS
Volume18
Issue number5
DOIs
StatePublished - 26 Mar 2004

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MAP Kinase Kinase 4
HIV-1
HIV Infections
T-Lymphocytes
Protein-Serine-Threonine Kinases
Monocytes
Signal Transduction
HIV
Apoptosis
Viruses
Virus Internalization
Annexin A5
RNA-Directed DNA Polymerase
p38 Mitogen-Activated Protein Kinases
Virus Replication
Mitogen-Activated Protein Kinases
Life Cycle Stages
Reverse Transcription
Antiviral Agents
Communicable Diseases

Keywords

  • Apoptosis
  • Cytokines
  • HIV-1
  • Viral replication
  • p38MAPK/JNK inhibitor

Cite this

Muthumani, K., Wadsworth, S. A., Dayes, N. S., Hwang, D. S., Choo, A. Y., Abeysinghe, H. R., ... Weiner, D. B. (2004). Suppression of HIV-1 viral replication and cellular pathogenesis by a novel p38/JNK kinase inhibitor. AIDS, 18(5), 739-748. https://doi.org/10.1097/00002030-200403260-00004
Muthumani, Karuppiah ; Wadsworth, Scott A. ; Dayes, Nathanael S. ; Hwang, Daniel S. ; Choo, Andrew Y. ; Abeysinghe, Harindra R. ; Siekierka, John ; Weiner, David B. / Suppression of HIV-1 viral replication and cellular pathogenesis by a novel p38/JNK kinase inhibitor. In: AIDS. 2004 ; Vol. 18, No. 5. pp. 739-748.
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Muthumani, K, Wadsworth, SA, Dayes, NS, Hwang, DS, Choo, AY, Abeysinghe, HR, Siekierka, J & Weiner, DB 2004, 'Suppression of HIV-1 viral replication and cellular pathogenesis by a novel p38/JNK kinase inhibitor', AIDS, vol. 18, no. 5, pp. 739-748. https://doi.org/10.1097/00002030-200403260-00004

Suppression of HIV-1 viral replication and cellular pathogenesis by a novel p38/JNK kinase inhibitor. / Muthumani, Karuppiah; Wadsworth, Scott A.; Dayes, Nathanael S.; Hwang, Daniel S.; Choo, Andrew Y.; Abeysinghe, Harindra R.; Siekierka, John; Weiner, David B.

In: AIDS, Vol. 18, No. 5, 26.03.2004, p. 739-748.

Research output: Contribution to journalArticle

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AU - Wadsworth, Scott A.

AU - Dayes, Nathanael S.

AU - Hwang, Daniel S.

AU - Choo, Andrew Y.

AU - Abeysinghe, Harindra R.

AU - Siekierka, John

AU - Weiner, David B.

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Muthumani K, Wadsworth SA, Dayes NS, Hwang DS, Choo AY, Abeysinghe HR et al. Suppression of HIV-1 viral replication and cellular pathogenesis by a novel p38/JNK kinase inhibitor. AIDS. 2004 Mar 26;18(5):739-748. https://doi.org/10.1097/00002030-200403260-00004