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

Mark A. Endsley, Anoma D. Somasunderam, Guangyu Li, Numan Oezguen, Varatharasa Thiviyanathan, James L. Murray, Donald H. Rubin, Thomas W. Hodge, William A. O'Brien, Briana Lewis, Monique R. Ferguson

Research output: Contribution to journalArticle

6 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)60-66
Number of pages7
JournalVirology
Volume454-455
Issue number1
DOIs
StatePublished - Apr 1 2014

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Keywords

  • ADAM10
  • ADAM15
  • CD4 T lymphocytes
  • HIV-1 integrase
  • HIV-1 pre-integration complex (PIC)
  • HIV-1 replication
  • Macrophages
  • γ-Secretase

ASJC Scopus subject areas

  • Virology

Cite this

Endsley, M. A., Somasunderam, A. D., Li, G., Oezguen, N., Thiviyanathan, V., Murray, J. L., Rubin, D. H., Hodge, T. W., O'Brien, W. A., Lewis, B., & Ferguson, M. R. (2014). Nuclear trafficking of the HIV-1 pre-integration complex depends on the ADAM10 intracellular domain. Virology, 454-455(1), 60-66. https://doi.org/10.1016/j.virol.2014.02.006