Antivirals, Cell Adhesion, Cell Motility, Cytoskeleton, HIV/AIDS, Image Analysis, Imaging, Immune Deficiency, Immunology, Infectious Disease, Integrins, Lymphocytes, Lysosomes/endosome, Macrophage, Migration, Molecular Biology, Protein Trafficking & Sorting, RNA Transport & Localization, Retrovirus, Synapses, T Cells, Trafficking, Two-Photon Imaging, Vaccine Development, Viruses and Virology
Biophysics and Systems Pharmacology [BSP], Immunology [IMM], Microbiology [MIC]
BAS, Stanford University
MD, Weill Medical College of Cornell University
PhD, The Rockefeller University
, Whitehead Institute for Biomedical Research, Massachusetts Institute of Technology
Avant Garde Award in HIV/AIDS research
National Institute of Drug Abuse, NIH
Irma T. Hirschl Monique Weill-Caulier Career Scientist Award
Burroughs Wellcome Fund Investigator in the Pathogenesis of Infectious Diseases
National Research Service Award, National Institute for Allergy and Infectious Disease
National Institutes of Health
Graduation with Honors in Biological Sciences
Graduation with Distinction in Philosophy
Current Students: MD/PhD: Chati Zony, Graduate: Natasha Durham, Kenneth Law, Hongru Li
Postdoctoral Fellows: Ray Alvarez, Anthony Esposito, Lili Wang
Research Faculty: Ping Chen, Talia Swartz
Summary of Research Studies:
Mechanisms of HIV cell-cell transmission
The efficiency of HIV spread in culture is greatly facilitated by cell contact between infected and uninfected CD4+ T cells. Infected T cells form adhesive contacts with uninfected CD4+ T cells. These contacts are called virological synapses (VS) because of similarity to other adhesive structures in the immune system call immunological synapses. VS require viral Env proteins to be expressed on the cell surface where they interact with CD4 on target cells. Using infectious, fluorescent virus clones we are able to quantify and visualize the amount of viral transfer that occurs through VS. Live, video rate confocal microscopy allowed us to visualize the changes in cellular distribution of the viral protein Gag that occurs during VS formation. We found that the VS causes the efficient transfer of viral particles into target T cells through an endocytic route that is still being characterized. We are working to understand the viral signals that allow virus assembly to be recruited to the VS and the cellular signaling pathways the work in both the VS donor and target cells.
Neutralization Resistance of VS
The VS-mediated viral infection can be resistant to patient antibodies that are capable of neutralizing homologous cell free virus. We are working to understand how the VS provides a mechanism for HIV to evade humoral immune responses. We found that the cytoplasmic tail of the Env glycoprotein, which is plays an important role in regulating fusion activity of Env, plays a role in the resistance of cell-cell infection to neutralization. We are testing a model whereby the conformational regulation of Env during VS formation is what makes cell-cell transmission more resistant to neutralization. We are studying patient neutralizing responses, and cloning B cells from patients to characterize potent cell-cell neutralizing activities.
Role of cell-cell transmission in vivo
We have been studying humanized mouse models to better understand how this mode of efficient viral dissemination contributes to viral spread in vivo. To overcome the inability of HIV to replicate in mouse cells, researchers have exploited mouse xenograft models that engraft human immune systems into immunocompromised mice. These mouse systems transplant human hematopoietic stem cells into immunodeficient mice and allow diverse lineages of human immune cells 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 are using whole animal imaging and intravital microscopy to understand how T cell migration and synapse formation contribute to HIV spread within a living organism.
For more information, please visit the Benjamin K. Chen Laboratory.
Swartz TH, Esposito AM, Durham ND, Hartmann BM, Chen BK. P2X-Selective Purinergic Antagonists Are Strong Inhibitors of HIV-1 Fusion during both Cell-to-Cell and Cell-Free Infection. Journal of virology 2014 Oct; 88(19).
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 Jun; 88(11).
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).
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).
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).
Chen P, Chen BK, Mosoian A, Hays T, Ross MJ, Klotman PE, Klotman ME. Virological synapses allow HIV-1 uptake and gene expression in renal tubular epithelial cells. Journal of the American Society of Nephrology : JASN 2011 Mar; 22(3).
Hübner W, McNerney GP, Chen P, Dale BM, Gordon RE, Chuang FY, Li XD, Asmuth DM, Huser T, Chen BK. Quantitative 3D video microscopy of HIV transfer across T cell virological synapses. Science (New York, N.Y.) 2009 Mar; 323(5922).
Hübner W, Chen P, Del Portillo A, Liu Y, Gordon RE, Chen BK. Sequence of human immunodeficiency virus type 1 (HIV-1) Gag localization and oligomerization monitored with live confocal imaging of a replication-competent, fluorescently tagged HIV-1. Journal of virology 2007 Nov; 81(22).
Chen P, Hübner W, Spinelli MA, Chen BK. Predominant mode of human immunodeficiency virus transfer between T cells is mediated by sustained Env-dependent neutralization-resistant virological synapses. Journal of virology 2007 Nov; 81(22).
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