title: Nuclear trafficking of the HIV-1 pre-integration complex depends on the ADAM10 intracellular domain.
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.
authors.affiliation: Department Internal Medicine, Division of Infectious Diseases, University of Texas Medical Branch, 301 University Blvd, Galveston, TX 77555, USA. Electronic address: maendsle@utmb.edu.
authors.forename: Mark A
authors.initials: MA
authors.lastname: Endsley
authors.affiliation: Department Internal Medicine, Division of Infectious Diseases, University of Texas Medical Branch, 301 University Blvd, Galveston, TX 77555, USA. Electronic address: asomasun@utmb.edu.
authors.forename: Anoma D
authors.initials: AD
authors.lastname: Somasunderam
authors.affiliation: Department of Internal Medicine, Quillen College of Medicine, East Tennessee State University, Johnson City, TN 37614, USA. Electronic address: LIG001@mail.etsu.edu.
authors.forename: Guangyu
authors.initials: G
authors.lastname: Li
authors.affiliation: Department of Pathology & Immunology, Microbiome Center, Texas Children׳s Hospital, Houston, TX 77030, USA. Electronic address: numan.oezguen@bcm.edu.
authors.forename: Numan
authors.initials: N
authors.lastname: Oezguen
authors.affiliation: Institute of Molecular Medicine, University of Texas Health Science Center, Houston, TX 77030, USA. Electronic address: Varatharasa.Thiviyanathan@uth.tmc.edu.
authors.forename: Varatharasa
authors.initials: V
authors.lastname: Thiviyanathan
authors.affiliation: GeneTAG Technology, Inc., 3155 Northwoods Place, Norcross, GA 30071, USA. Electronic address: jmurray100@yahoo.com.
authors.forename: James L
authors.initials: JL
authors.lastname: Murray
authors.affiliation: Research Medicine, VA Tennessee Valley Healthcare System, 1310 24th Ave. South, Nashville, TN 37212, USA; Departments of Medicine, Pathology, Microbiology & Immunology, Vanderbilt University School of Medicine, 1161 21st Ave South, Nashville, TN 37232, USA. Electronic address: don.h.rubin@vanderbilt.edu.
authors.forename: Donald H
authors.initials: DH
authors.lastname: Rubin
authors.affiliation: Pre-clinical and Antiviral Research, Tamir Biotechnology, Inc., 12625 High Bluff Dr., Suite 113, San Diego, CA 92130, USA. Electronic address: twhodge3@gmail.com.
authors.forename: Thomas W
authors.initials: TW
authors.lastname: Hodge
authors.affiliation: Department Internal Medicine, Division of Infectious Diseases, University of Texas Medical Branch, 301 University Blvd, Galveston, TX 77555, USA; Clinical Development Medical Affairs, Virology, Boehringer Ingelheim, 900 Ridgebury Rd., Ridgefield, CT 06877, USA; Department of Internal Medicine, Division of Infectious Diseases, Emory University School of Medicine, 100 Woodruff Circle, Atlanta, GA 30322, USA. Electronic address: william.obrien@boehringer-ingelheim.com.
authors.forename: William A
authors.initials: WA
authors.lastname: O'Brien
authors.affiliation: Department Internal Medicine, Division of Infectious Diseases, University of Texas Medical Branch, 301 University Blvd, Galveston, TX 77555, USA. Electronic address: br3lewis@utmb.edu.
authors.forename: Briana
authors.initials: B
authors.lastname: Lewis
authors.affiliation: Department Internal Medicine, Division of Infectious Diseases, University of Texas Medical Branch, 301 University Blvd, Galveston, TX 77555, USA. Electronic address: mrfergus@utmb.edu.
authors.forename: Monique R
authors.initials: MR
authors.lastname: Ferguson
mesh_terms: D051722:ADAM Proteins / Q000378:metabolism*; D000072197:ADAM10 Protein; D021581:Active Transport, Cell Nucleus; D053829:Amyloid Precursor Protein Secretases / Q000378:metabolism*; D002478:Cells, Cultured; D004279:DNA, Viral / Q000378:metabolism; D015497:HIV-1 / Q000502:physiology*; D054884:Host-Pathogen Interactions; D006801:Humans; D047468:Immunoprecipitation; D046911:Macromolecular Substances / Q000378:metabolism*; D008565:Membrane Proteins / Q000378:metabolism*; D011485:Protein Binding; D017434:Protein Structure, Tertiary; D014764:Viral Proteins / Q000378:metabolism; D016662:Virus Integration
chemical_list: D004279:DNA, Viral; D046911:Macromolecular Substances; D008565:Membrane Proteins; D014764:Viral Proteins; D053829:Amyloid Precursor Protein Secretases; D051722:ADAM Proteins; D000072197:ADAM10 Protein; C491236:ADAM10 protein, human
keywords: ADAM10; ADAM15; CD4(+) T lymphocytes; HIV-1 integrase; HIV-1 pre-integration complex (PIC); HIV-1 replication; Macrophages; γ-Secretase
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