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Proc Natl Acad Sci U S A. 2014 Sep 2;111(35):E3699-707. doi: 10.1073/pnas.1404851111. Epub 2014 Aug 18.

TIM-family proteins inhibit HIV-1 release.

Author information

1
Department of Molecular Microbiology and Immunology, Bond Life Sciences Center, University of Missouri, Columbia, MO 65211;
2
Virus-Cell Interaction Section, HIV Drug Resistance Program, National Cancer Institute-Frederick, Frederick, MD 21702;
3
Department of Immunotherapy, SugarCone Biotech LLC, Holliston, MA 01746; and.
4
Department of Microbiology, University of Iowa, Iowa City, IA 52245.
5
Department of Molecular Microbiology and Immunology, Bond Life Sciences Center, University of Missouri, Columbia, MO 65211; liushan@missouri.edu.

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.

PMID:
25136083
PMCID:
PMC4156686
DOI:
10.1073/pnas.1404851111
[Indexed for MEDLINE]
Free PMC Article

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