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

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{sup +} 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. - Highlights: • Nuclear trafficking of the HIV-1 pre-integration complex depends on ADAM10. • ADAM10 associates with HIV-1 integrase in the pre-integration complex. • HIV-1 replication depends on the expression of ADAM15 and γ-secretase. • Silencing ADAM15 or γ-secretase expression inhibits nuclear import of viral cDNA. • ADAM10 is importantmore » for HIV-1 replication in human macrophages and CD4{sup +} T lymphocytes.« less
Authors:
 [1] ;  [1] ;  [2] ;  [3] ;  [4] ;  [5] ;  [6] ;  [7] ;  [8] ;
  1. Department Internal Medicine, Division of Infectious Diseases, University of Texas Medical Branch, 301 University Blvd, Galveston, TX 77555 (United States)
  2. Department of Internal Medicine, Quillen College of Medicine, East Tennessee State University, Johnson City, TN 37614 (United States)
  3. Department of Pathology and Immunology, Microbiome Center, Texas Children's Hospital, Houston, TX 77030 (United States)
  4. Institute of Molecular Medicine, University of Texas Health Science Center, Houston, TX 77030 (United States)
  5. GeneTAG Technology, Inc., 3155 Northwoods Place, Norcross, GA 30071 (United States)
  6. Research Medicine, VA Tennessee Valley Healthcare System, 1310 24th Ave. South, Nashville, TN 37212 (United States)
  7. (United States)
  8. Pre-clinical and Antiviral Research, Tamir Biotechnology, Inc., 12625 High Bluff Dr., Suite 113, San Diego, CA 92130 (United States)
Publication Date:
OSTI Identifier:
22435025
Resource Type:
Journal Article
Resource Relation:
Journal Name: Virology; Journal Volume: 454-455; Other Information: Copyright (c) 2014 Elsevier Science B.V., Amsterdam, The Netherlands, All rights reserved.; Country of input: International Atomic Energy Agency (IAEA)
Country of Publication:
United States
Language:
English
Subject:
60 APPLIED LIFE SCIENCES; AIDS VIRUS; COMPLEXES; CYTOPLASM; HUMAN POPULATIONS; IMPORTS; LIFE CYCLE; LYMPHOCYTES; MACROPHAGES; SUPPORTS; TRANSCRIPTION