TIM-family proteins inhibit HIV-1 release

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

doi:10.1073/pnas.1404851111

Cited by 72 publications

(89 citation statements)

References 55 publications

(78 reference statements)

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“…It has been reported that Tim-3 is a key regulator of the exhausted antigen-specific CD4+ and CD8+ T cells that arise in both humans and mice during chronic viral infections, such as HIV, hepatitis C virus (HCV), hepatitis B virus, and lymphocytic choriomeningitis virus (LCMV) and in cancer [18][19][20]. However, the role of Tim-3 in RCC remains unknown.…”

Section: Discussionmentioning

confidence: 99%

Tim-3 expression represents dysfunctional tumor infiltrating T cells in renal cell carcinoma

Cai

et al. 2015

World J Urol

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Section: Discussionmentioning

confidence: 99%

Tim-3 expression represents dysfunctional tumor infiltrating T cells in renal cell carcinoma

Cai

et al. 2015

World J Urol

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“…Plasmid DNAs were prepared using a miniprep DNA isolation kit (Qiagen) and were confirmed by DNA sequence analysis. The TIM-1-expressing vector pClneo-F-TIM-1 was kindly provided by Shan-Lu Liu (45). To express TIM-3, the TIM-3 cDNA (RDC0670; R&D Systems) was digested with HindIII and SmaI and inserted into the pShuttle-CMV vector (Addgene) digested with HindIII and EcoRV.…”

Section: Methodsmentioning

confidence: 99%

TIM-1 Promotes Hepatitis C Virus Cell Attachment and Infection

Wang

Qiao

Hou

et al. 2017

J Virol

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Human TIM and TAM family proteins were recently found to serve as phosphatidylserine (PS) receptors which promote infections by many different viruses, including dengue virus, West Nile virus, Ebola virus, Marburg virus, and Zika virus. In the present study, we provide substantial evidence demonstrating that TIM-1 is important for efficient infection by hepatitis C virus (HCV). The knockdown of TIM-1 expression significantly reduced HCV infection but not HCV RNA replication. Likewise, TIM-1 knockout in Huh-7.5 cells remarkably lowered HCV cell attachment and subsequent HCV infection. More significantly, the impairment of HCV infection in the TIM-1 knockout cells could be restored completely by ectopic expression of TIM-1 but not TIM-3 or TIM-4. Additionally, HCV infection and cell attachment were inhibited by PS but not by phosphatidylcholine (PC), demonstrating that TIM-1-mediated enhancement of HCV infection is PS dependent. The exposure of PS on the HCV envelope was confirmed by immunoprecipitation of HCV particles with a PS-specific monoclonal antibody. Collectively, these findings demonstrate that TIM-1 promotes HCV infection by serving as an attachment receptor for binding to PS exposed on the HCV envelope.IMPORTANCE TIM family proteins were recently found to enhance infections by many different viruses, including several members of the Flaviviridae family. However, their importance in HCV infection has not previously been examined experimentally. The TIM family proteins include three members in humans: TIM-1, TIM-3, and TIM-4. The findings derived from our studies demonstrate that TIM-1, but not TIM-3 or TIM-4, promotes HCV infection by functioning as an HCV attachment factor. Knockout of the TIM-1 gene resulted in a remarkable reduction of HCV cell attachment and infection. PS-containing liposomes blocked HCV cell attachment and subsequent HCV infection. HCV particles could also be precipitated with a PS-specific monoclonal antibody. These findings suggest that TIM-1 and its binding ligand, PS, may serve as novel targets for antiviral intervention. KEYWORDS hepatitis C virus, TIM-1, attachment, infection, receptor, TIM-3, TIM-4 H epatitis C virus (HCV) is an enveloped RNA virus containing a 9.6-kb singlestranded RNA genome of positive polarity (1). It is the prototype member of the Hepacivirus genus in the Flaviviridae family (2, 3). The viral RNA genome consists of a long open reading frame (ORF), encoding a single polyprotein, and untranslated regions (UTRs) at both the 5= and 3= ends. Upon translation, the viral polyprotein precursor is cleaved by cellular peptidases and the viral NS2/NS3 metalloprotease and NS3/4A serine protease into 10 individual structural and nonstructural (NS) proteins, designated core (C), envelope proteins 1 and 2 (E1 and E2), p7, NS2, NS3, NS4A, NS4B, NS5A, and NS5B (4). The structural proteins C, E1, and E2 are essential for the formation of HCV particles (5). The NS3 to NS5B proteins are the minimal set of viral proteins required for HCV RNA replication, although a...

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“…Hence, low TIM-3 expression by CD4 + T cells in INRs may drive excessive T h 1 immunity and persistent immune activation. Furthermore, binding of galectin-9 to TIM-3 on CD4 + T cells reduced the susceptibility of these cells to infection by HIV [27,28]. In contrast, the TIM-3 + CD4 + cell B A C Figure 5 Galectin-9 and TIM-3 expression on CD4 + T cells of healthy controls, HIV IRs and HIV INRs.…”

Section: Discussionmentioning

confidence: 99%