Differential Induction of interleukin-10 in Monocytes by HIV-1 Clade B and Clade C Tat Proteins

J Biol Chem. 2010 Jun 11;285(24):18319-25. doi: 10.1074/jbc.M110.120840. Epub 2010 Apr 8.

Abstract

The clade B human immunodeficiency virus, type 1 (HIV-1) Tat (trans-acting regulatory protein) induces interleukin-10 (IL-10) production in monocytes. IL-10, an anti-inflammatory cytokine, down-regulates proinflammatory cytokines and suppresses the immune response, leading to a rapid progression from HIV-1 infection to AIDS. Nine clades of HIV-1 are responsible for the majority of infections worldwide. Recent studies demonstrate that different HIV-1 clades have biological differences in relation to transmission, replication, and disease progression. In this study, we show that the cysteine to serine mutation at position 31, found in >90% of HIV-1 clade C Tat proteins, results in a marked decrease in IL-10 production in monocytes compared with clade B Tat. Additionally, the C31S mutation found in C Tat is responsible for the inability of these Tat proteins to produce high IL-10 levels in monocytes due to its inability to induce intracellular calcium flux through L-type calcium channels. Moreover, we show that p38alpha/p38beta and phosphoinositide 3-kinase are crucial to Tat-induced IL-10 production. These findings provide further evidence that HIV-1 clades differ in their biological properties that may impact HIV-1 pathogenesis and disease progression.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Amino Acid Sequence
  • Cytokines / metabolism
  • Enzyme Inhibitors / pharmacology
  • Flow Cytometry / methods
  • HIV-1 / metabolism*
  • Humans
  • Inflammation
  • Interleukin-10 / metabolism*
  • Leukocytes, Mononuclear / cytology
  • Mitogen-Activated Protein Kinase 11 / metabolism*
  • Mitogen-Activated Protein Kinase 14 / metabolism*
  • Molecular Sequence Data
  • Monocytes / virology*
  • Mutation
  • Sequence Homology, Amino Acid
  • tat Gene Products, Human Immunodeficiency Virus / metabolism*

Substances

  • Cytokines
  • Enzyme Inhibitors
  • tat Gene Products, Human Immunodeficiency Virus
  • Interleukin-10
  • Mitogen-Activated Protein Kinase 11
  • Mitogen-Activated Protein Kinase 14