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Benjamin Chen

  • ASSOCIATE PROFESSOR Medicine, Infectious Diseases
  • ASSOCIATE PROFESSOR Pharmacology and Systems Therapeutics
  • ASSOCIATE PROFESSOR Microbiology
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Education

  • B.A.S., Stanford University

  • Ph.D., The Rockefeller University

  • M.D., Weill Medical College of Cornell University

  • Whitehead Institute for Biomedical Research, Massachusetts Institute of Technology

Biography

    The Bejamin K. Chen Laboratory studies the fundamental mechanisms of HIV assembly and transmission between cells. During infection of human cells with HIV-1, the causative agent of AIDS, each viral protein interacts with and utilizes cellular factors to propagate the infection. We are interested in the molecular interactions that occur between virus and host during viral assembly and transmission. To produce virus particles, one protein called Gag coordinates HIV assembly so that it occurs at a specific time and location. In infected T cells we find that assembly is triggered to occur when T cells contact one another, a phenomenon that greatly enhances propagation of HIV from cell to cell. The adhesive structures that form between infected and uninfected cells have been called virological synapses. We are working to understand how viral assembly and transmission are coordinated to facilitate HIV dissemination. Our studies are designed to uncover key cellular factors and events in assembly and transmission during HIV infection. An understanding of virological synapse-mediated transfer will aid in the development of new drug, vaccine and microbicide approaches.

    In The News
    Transfer of HIV Between T Cells Captured on Video
    Mount Sinai researchers and colleagues have for the first time captured on video the transfer of human immunodeficiency virus (HIV) from infected to uninfected T cells.
    Find out more here

Awards

  • 2007 -
    Irma T. Hirschl Monique Weill-Caulier Career Scientist Award

  • 2007 -
    Burroughs Wellcome Fund Investigator in the Pathogenesis of Infectious Diseases

  • 2000 - 2003
    National Research Service Award, National Institute for Allergy and Infectious Disease
    National Institutes of Health

  • 1990 -
    Graduation with Distinction in Philosophy
    Stanford University

  • 1990 -
    Graduation with Honors in Biological Sciences
    Stanford University

Research

Current Students: MD/PhD: Armando Delportillo (MIC), PREP Med: Sudeh Izadamehr, PREP: Chati Zony

Postdoctoral Fellows: Wolfgang Huebner, Ping Chen, Benjamin Dale                                                               

Summary of Research Studies:
Mechanisms of HIV cell-cell transmission. Recent studies have revealed that the efficiency of HIV dissemination is greatly facilitated by cell contact between infected and uninfected T cells. Infected T cells have been found to form adhesive contacts with uninfected CD4+ T cells. These contacts are called virological synapses (VS) because of some similarity to other adhesive structures in the immune system call immunological synapses. These structures require viral Env proteins to be expressed on the cell surface where they interact with CD4 on target cells. Using infectious fluorescent virus systems we are able to quantify and visualize the amount of viral transfer that occurs through VS. In vitro we find that these can be over 10,000-fold more efficient at transferring viral antigen from cell to cell. High resolution, real-time confocal microscopy allows us to directly visualize the changes in cellular distribution of viral protein that occur during VS formation. We find that the VS causes the massive transfer of ! viral particles into target T cells through an endocytic route that is still largely uncharacterized. The VS-mediated viral transfer can be resistant to patient antibodies that are capable of neutralizing homologous cell free virus. Our ongoing studies are directed at understanding the cellular mechanisms that regulate VS transfer. We are also working to understand how transfer may provide an important mechanism to evade humoral immune responses. The work will help us understand how this mode of efficient viral dissemination may allow HIV to spread efficiently in vivo. Examining the role of cell-cell transmission of HIV in vivo HIV researchers have long sought a genetically tractable, economical alternative to the costly primate models for HIV infection.

In a recent breakthrough in the field, investigators are using mice with humanized immune systems as in vivo models for HIV infection. These mouse systems transplant human hematopoietic stem cells into immunodeficient mice and allow diverse lineages of human immunocytes to develop. Importantly, the human immune systems are highly susceptible to HIV and can support sustained HIV viral loads in animals that are challenged. In humanized mouse systems, we plan to study the T cell dynamics that allow HIV to spread within a living organism. To understand the dynamics of T cells in an organism we will investigate the trafficking, interactions and viral propagation of HIV infected T cells. Our aim is to understand how T cell migration and interactions contribute to HIV dissemination in vivo. Role of host factors in regulating HIV assembly and virological synapse function We are interested in understanding how the viral Gag protein is targeted to specific membranes where viral assembly occurs. Viral genetic studies have revealed that determinants in the MA domain of Gag interact with species-specific host factors to regulate assembly. Using genetic and biochemical approaches, we have been working to identify host cofactors that participate in regulation of assembly. We have identified factors that interact the matrix domain and are testing their role in assembly and virological synapse formation. Current studies are exploring the roles of small G proteins of the Rab family and ubiquitin in modulating HIV assembly, budding and cell-cell transfer. Understanding the cellular pathways that regulate assembly will allow us to design novel inhibitors to block viral assembly. 

For more information, please visit the Benjamin K. Chen Laboratory.

Publications

Hubner W, McNerney GP, Dale B, Chen P, Gordon R, Chuang FS, Li X, Asmuth DM, Huser T, Chen BK. Quantitative 3D Video Microscopy of HIV Transfer Across T cell Virological Synapses. Manuscript in review. 2009;.

Hubner W, Chen P, Delportillo A, Liu Y, Gordon R, Chen BK. Sequence of HIV-1 Gag localization and oligomerization monitored with continuous, live confocal imaging of a replication-competent, fluorescently tagged HIV-1 [PMID: 17728233]. Journal of Virology 2007; 81: 12596-12607.

Chen P, Chen BK, Spinelli M, Hubner W. Predominant mode of HIV transfer between T cells is mediated by sustained Env-dependent neutralization-resistant virological synapses [PMID: 17728240]. Journal of Virology 2007; 81(22): 12582-12592.

Chen P, Riviere K, Hubner W, Chen BK, Liu Y. Chimeric HIV-1 containing SIV matrix exhibit enhanced assembly in murine cells and replicate in a cell type dependent manner in human T cells [PMID: 16563454]. Virology 2006; 349: 1-12.

Chen BK, Rousso I, Shim S, Kim PS. Efficient assembly of an HIV/MLV Gag-chimeric virus in murine cells [PMID: 11742097]. Proceedings of the National Academy of Sciences, U S A 2001; 98: 15239-15244.

Del Portillo A, Tripodi J, Najfeld V, Wodarz D, Levy DN, Chen BK. Multiploid inheritance of HIV-1 during cell-to-cell infection. Journal of virology 2011 Jul; 85(14).

Dale BM, McNerney GP, Thompson DL, Hubner W, de Los Reyes K, Chuang FY, Huser T, Chen BK. Cell-to-cell transfer of HIV-1 via virological synapses leads to endosomal virion maturation that activates viral membrane fusion. Cell host & microbe 2011 Dec; 10(6).

Durham ND, Yewdall AW, Chen P, Lee R, Zony C, Robinson JE, Chen BK. Neutralization resistance of virological synapse-mediated HIV-1 Infection is regulated by the gp41 cytoplasmic tail. Journal of virology 2012 Jul; 86(14).

Alvarez RA, Hamlin RE, Monroe A, Moldt B, Hotta MT, Rodriguez Caprio G, Fierer DS, Simon V, Chen BK. HIV-1 Vpu antagonism of tetherin inhibits antibody-dependent cellular cytotoxic responses by natural killer cells. Journal of virology 2014 Mar;.

Industry Relationships

Physicians and scientists on the faculty of the Icahn School of Medicine at Mount Sinai often interact with pharmaceutical, device and biotechnology companies to improve patient care, develop new therapies and achieve scientific breakthroughs. In order to promote an ethical and transparent environment for conducting research, providing clinical care and teaching, Mount Sinai requires that salaried faculty inform the School of their relationships with such companies.

Dr. Chen did not report having any of the following types of financial relationships with industry during 2012 and/or 2013: consulting, scientific advisory board, industry-sponsored lectures, service on Board of Directors, participation on industry-sponsored committees, equity ownership valued at greater than 5% of a publicly traded company or any value in a privately held company. Please note that this information may differ from information posted on corporate sites due to timing or classification differences.

Mount Sinai's faculty policies relating to faculty collaboration with industry are posted on our website at http://icahn.mssm.edu/about-us/services-and-resources/faculty-resources/handbooks-and-policies/faculty-handbook. Patients may wish to ask their physician about the activities they perform for companies.

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