Nuclear trafficking of the HIV-1 pre-integration complex depends on the ADAM10 intracellular domain

Virology. 2014 Apr;454-455:60-6. doi: 10.1016/j.virol.2014.02.006. Epub 2014 Feb 22.

Abstract

Previously, we showed that ADAM10 is necessary for HIV-1 replication in primary human macrophages and immortalized cell lines. Silencing ADAM10 expression interrupted the HIV-1 life cycle prior to nuclear translocation of viral cDNA. Furthermore, our data indicated that HIV-1 replication depends on the expression of ADAM15 and γ-secretase, which proteolytically processes ADAM10. Silencing ADAM15 or γ-secretase expression inhibits HIV-1 replication between reverse transcription and nuclear entry. Here, we show that ADAM10 expression also supports replication in CD4(+) T lymphocytes. The intracellular domain (ICD) of ADAM10 associates with the HIV-1 pre-integration complex (PIC) in the cytoplasm and immunoprecipitates and co-localizes with HIV-1 integrase, a key component of PIC. Taken together, our data support a model whereby ADAM15/γ-secretase processing of ADAM10 releases the ICD, which then incorporates into HIV-1 PIC to facilitate nuclear trafficking. Thus, these studies suggest ADAM10 as a novel therapeutic target for inhibiting HIV-1 prior to nuclear entry.

Keywords: ADAM10; ADAM15; CD4(+) T lymphocytes; HIV-1 integrase; HIV-1 pre-integration complex (PIC); HIV-1 replication; Macrophages; γ-Secretase.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • ADAM Proteins / metabolism*
  • ADAM10 Protein
  • Active Transport, Cell Nucleus*
  • Amyloid Precursor Protein Secretases / metabolism*
  • Cells, Cultured
  • DNA, Viral / metabolism
  • HIV-1 / physiology*
  • Host-Pathogen Interactions*
  • Humans
  • Immunoprecipitation
  • Macromolecular Substances / metabolism*
  • Membrane Proteins / metabolism*
  • Protein Binding
  • Protein Structure, Tertiary
  • Viral Proteins / metabolism
  • Virus Integration*

Substances

  • DNA, Viral
  • Macromolecular Substances
  • Membrane Proteins
  • Viral Proteins
  • Amyloid Precursor Protein Secretases
  • ADAM Proteins
  • ADAM10 Protein
  • ADAM10 protein, human