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

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

Author information

1
Department Internal Medicine, Division of Infectious Diseases, University of Texas Medical Branch, 301 University Blvd, Galveston, TX 77555, USA. Electronic address: maendsle@utmb.edu.
2
Department Internal Medicine, Division of Infectious Diseases, University of Texas Medical Branch, 301 University Blvd, Galveston, TX 77555, USA. Electronic address: asomasun@utmb.edu.
3
Department of Internal Medicine, Quillen College of Medicine, East Tennessee State University, Johnson City, TN 37614, USA. Electronic address: LIG001@mail.etsu.edu.
4
Department of Pathology & Immunology, Microbiome Center, Texas Children׳s Hospital, Houston, TX 77030, USA. Electronic address: numan.oezguen@bcm.edu.
5
Institute of Molecular Medicine, University of Texas Health Science Center, Houston, TX 77030, USA. Electronic address: Varatharasa.Thiviyanathan@uth.tmc.edu.
6
GeneTAG Technology, Inc., 3155 Northwoods Place, Norcross, GA 30071, USA. Electronic address: jmurray100@yahoo.com.
7
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.
8
Pre-clinical and Antiviral Research, Tamir Biotechnology, Inc., 12625 High Bluff Dr., Suite 113, San Diego, CA 92130, USA. Electronic address: twhodge3@gmail.com.
9
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.
10
Department Internal Medicine, Division of Infectious Diseases, University of Texas Medical Branch, 301 University Blvd, Galveston, TX 77555, USA. Electronic address: br3lewis@utmb.edu.
11
Department Internal Medicine, Division of Infectious Diseases, University of Texas Medical Branch, 301 University Blvd, Galveston, TX 77555, USA. Electronic address: mrfergus@utmb.edu.

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

PMID:
24725932
PMCID:
PMC4018752
DOI:
10.1016/j.virol.2014.02.006
[Indexed for MEDLINE]
Free PMC Article
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