TIM-family proteins inhibit HIV-1 release

Minghua Li, Sherimay D. Ablan, Chunhui Miao, Yi Min Zheng, Matthew S. Fuller, Paul D. Rennert, Wendy Maury, Marc C. Johnson, Eric O. Freed, Shan Lu Liu

Research output: Contribution to journalArticlepeer-review

64 Scopus citations

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 mono-cyte-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 virionand cell-associated PS. Our work provides new insights into a viruscell interaction that is mediated by TIMs and PS receptors.

Original languageEnglish (US)
Pages (from-to)E3699-E3707
JournalProceedings of the National Academy of Sciences of the United States of America
Volume111
Issue number35
DOIs
StatePublished - Sep 2 2014
Externally publishedYes

ASJC Scopus subject areas

  • General

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