title: TIM-family proteins inhibit HIV-1 release.
abstract: Accumulating evidence indicates that T-cell immunoglobulin (Ig) and mucin domain (TIM) proteins play critical roles in viral infections. Herein, we report that the TIM-family proteins strongly inhibit HIV-1 release, resulting in diminished viral production and replication. Expression of TIM-1 causes HIV-1 Gag and mature viral particles to accumulate on the plasma membrane. Mutation of the phosphatidylserine (PS) binding sites of TIM-1 abolishes its ability to block HIV-1 release. TIM-1, but to a much lesser extent PS-binding deficient mutants, induces PS flipping onto the cell surface; TIM-1 is also found to be incorporated into HIV-1 virions. Importantly, TIM-1 inhibits HIV-1 replication in CD4-positive Jurkat cells, despite its capability of up-regulating CD4 and promoting HIV-1 entry. In addition to TIM-1, TIM-3 and TIM-4 also block the release of HIV-1, as well as that of murine leukemia virus (MLV) and Ebola virus (EBOV); knockdown of TIM-3 in differentiated monocyte-derived macrophages (MDMs) enhances HIV-1 production. The inhibitory effects of TIM-family proteins on virus release are extended to other PS receptors, such as Axl and RAGE. Overall, our study uncovers a novel ability of TIM-family proteins to block the release of HIV-1 and other viruses by interaction with virion- and cell-associated PS. Our work provides new insights into a virus-cell interaction that is mediated by TIMs and PS receptors.
authors.affiliation: Department of Molecular Microbiology and Immunology, Bond Life Sciences Center, University of Missouri, Columbia, MO 65211;
authors.forename: Minghua
authors.initials: M
authors.lastname: Li
authors.affiliation: Virus-Cell Interaction Section, HIV Drug Resistance Program, National Cancer Institute-Frederick, Frederick, MD 21702;
authors.forename: Sherimay D
authors.initials: SD
authors.lastname: Ablan
authors.affiliation: Department of Molecular Microbiology and Immunology, Bond Life Sciences Center, University of Missouri, Columbia, MO 65211;
authors.forename: Chunhui
authors.initials: C
authors.lastname: Miao
authors.affiliation: Department of Molecular Microbiology and Immunology, Bond Life Sciences Center, University of Missouri, Columbia, MO 65211;
authors.forename: Yi-Min
authors.initials: YM
authors.lastname: Zheng
authors.affiliation: Department of Molecular Microbiology and Immunology, Bond Life Sciences Center, University of Missouri, Columbia, MO 65211;
authors.forename: Matthew S
authors.initials: MS
authors.lastname: Fuller
authors.affiliation: Department of Immunotherapy, SugarCone Biotech LLC, Holliston, MA 01746; and.
authors.forename: Paul D
authors.initials: PD
authors.lastname: Rennert
authors.affiliation: Department of Microbiology, University of Iowa, Iowa City, IA 52245.
authors.forename: Wendy
authors.initials: W
authors.lastname: Maury
authors.affiliation: Department of Molecular Microbiology and Immunology, Bond Life Sciences Center, University of Missouri, Columbia, MO 65211;
authors.forename: Marc C
authors.initials: MC
authors.lastname: Johnson
authors.affiliation: Virus-Cell Interaction Section, HIV Drug Resistance Program, National Cancer Institute-Frederick, Frederick, MD 21702;
authors.forename: Eric O
authors.initials: EO
authors.lastname: Freed
authors.affiliation: Department of Molecular Microbiology and Immunology, Bond Life Sciences Center, University of Missouri, Columbia, MO 65211; liushan@missouri.edu.
authors.forename: Shan-Lu
authors.initials: SL
authors.lastname: Liu
mesh_terms: D015496:CD4-Positive T-Lymphocytes / Q000502:physiology* / Q000821:virology; D002462:Cell Membrane / Q000378:metabolism / Q000821:virology; D055785:Gene Knockdown Techniques; D057809:HEK293 Cells; D015658:HIV Infections / Q000378:metabolism* / Q000821:virology; D015497:HIV-1 / Q000254:growth & development / Q000378:metabolism*; D006367:HeLa Cells; D000072596:Hepatitis A Virus Cellular Receptor 1; D000072597:Hepatitis A Virus Cellular Receptor 2; D006801:Humans; D019169:Jurkat Cells; D008562:Membrane Glycoproteins / Q000235:genetics / Q000378:metabolism*; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism*; D010718:Phosphatidylserines / Q000378:metabolism; D034741:RNA, Small Interfering / Q000235:genetics; D011991:Receptors, Virus / Q000235:genetics / Q000378:metabolism*; D014771:Virion / Q000254:growth & development / Q000378:metabolism; D014779:Virus Replication / Q000502:physiology
chemical_list: C491143:HAVCR1 protein, human; C448908:HAVCR2 protein, human; D000072596:Hepatitis A Virus Cellular Receptor 1; D000072597:Hepatitis A Virus Cellular Receptor 2; D008562:Membrane Glycoproteins; D008565:Membrane Proteins; D010718:Phosphatidylserines; D034741:RNA, Small Interfering; D011991:Receptors, Virus; C512411:TIMD4 protein, human