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Peptide-based Identification of Functional Motifs and their Binding Partners
14:28

Peptide-based Identification of Functional Motifs and their Binding Partners

Published on: July 1, 2013

Human immunodeficiency virus proteins induce the inhibitory cAMP/protein kinase A pathway in normal lymphocytes

B Hofmann1, P Nishanian, T Nguyen

  • 1Center for Interdisciplinary Research in Immunology and Disease, Johnson Comprehensive Cancer Center, University of California, Los Angeles 90024-1747.

Proceedings of the National Academy of Sciences of the United States of America
|July 15, 1993
PubMed

Insights

Human immunodeficiency virus (HIV) proteins impair T lymphocyte proliferation by activating the protein kinase A (PKA) pathway. This leads to increased cAMP, biochemical changes, and T cell anergy, hindering immune response.

Area of Science:

  • Immunology
  • Molecular Biology
  • Virology

Background:

  • Normal T lymphocyte proliferation is crucial for effective immune responses.
  • Human immunodeficiency virus (HIV) infection is known to impair T lymphocyte function.
  • The precise mechanisms underlying HIV-induced T cell dysfunction require further elucidation.

Purpose of the Study:

  • To investigate the molecular mechanisms by which HIV proteins impair T lymphocyte proliferation.
  • To identify key signaling pathways involved in HIV-induced T cell anergy.
  • To explore the role of cyclic adenosine monophosphate (cAMP) and protein kinase A (PKA) in this process.

Main Methods:

  • Assessed the induction of protein tyrosine kinases and PKA pathway in CD4+ and CD8+ T cells upon HIV protein exposure.
  • Measured intracellular cAMP levels in T lymphocytes.
  • Utilized agents like cholera toxoid and 8-bromo-cAMP to modulate cAMP/PKA activity.
  • Evaluated the activity of protein kinase C (PKC) upon stimulation.
  • Tested the effect of cAMP-reducing agents on HIV-induced T cell impairment.

Main Results:

  • HIV proteins actively impair T lymphocyte proliferation through induction of protein tyrosine kinases.
  • HIV-induced impairment is linked to the activation of the inhibitory PKA pathway, accompanied by increased intracellular cAMP.
  • Elevated cAMP/PKA activity leads to biochemical changes that inhibit phytohemagglutinin-stimulated T-lymphocyte proliferation.
  • External agents that increase cAMP/PKA activity mimicked HIV's inhibitory effect on proliferation.
  • HIV exposure decreased membrane-associated PKC activity, a proliferation promoter.
  • Agents reducing cAMP generation restored T-lymphocyte proliferation, neutralizing HIV's effect.

Conclusions:

  • HIV-induced augmentation of cAMP/PKA activity is a key mechanism contributing to T lymphocyte anergy.
  • This pathway disruption significantly impacts the proliferative capacity of T cells during HIV infection.
  • Targeting the cAMP/PKA pathway may offer therapeutic strategies to restore T cell function in HIV-infected individuals.

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