The Molecular Immunoengineering Section (MIS) at the Vaccine Research Center aims to conceive novel vaccine concepts that elicit broad and potent protective immune responses against influenza virus and provide a mechanistic principle for designing vaccines for other hypervariable pathogens such as coronaviruses and HIV-1. MIS is dedicated to advancing vaccine immunogen design beyond structure-based protein engineering by combining concepts and principles from multiple disciplines, including, but not limited to, immunobiology, biochemistry, biophysics, nanotechnology, and computational biology. The mission of the MIS is to define the fundamental rules behind vaccine-elicited immunity. Our interests span from basic immunology and virology to translational sciences with the goal of advancing vaccine concepts that would radically improve immune responses to vaccines. Our work involves various biochemical, biophysical, structural, immunological, and computational techniques and tools. MIS efforts include development of “supraseasonal” and “pre-pandemic” influenza vaccine candidates, “mosaic” antigen display technology, high-throughput high-definition virus neutralization assay systems, and animal models that recapitulate key aspects of human responses to influenza, such as immunological imprinting, preexisting immunity, antibody specificity and repertoire, immunodominance, and pathogenesis. MIS is also integrated with the VRC’s Influenza Program by serving as the lead of the Vaccine Concepts team. The Influenza Program involves multiple VRC Sections and Programs with the goal of advancing candidate vaccines from bench to clinic.

My work at the NIH concentrates on two aspects of HIV infection: the control of HIV-infection by the immunologic mechanism and the description of the changes in the CD4 T cell  transcriptome caused by HIV-infection.  In collaboration with individuals at the VRC, the California Institute of Technology and the Ragon Institute I am responsible for a clinical trial in which an AAV vector carries the coding sequence for VRC07, a potent broadly neutralizing Ab, into muscle cells of HIV-infected individuals on effective anti-retroviral therapy. In some individuals production of VRC07 occurred at ug/ml serum quantities for over 3 years. Although this level of VRC07 is not protective, this study shows that it is possible to side-step some of the difficulties in producing an immunogen capable of inducing a broadly neutralizing antibody by using a viral vector to transduction muscle cells.  I have also established methods to identify and sort live HIV-infected CD4 T cells. Unlike matrix proteins, envelope proteins are fully mature when transported to the surface of CD4 T cells.  By using fluorescently labeled broadly neutralizing antibodies that bind HIV envelope protein expressed on the surface of CD4 T cells, it is possible to use index sorting to identify live HIV-infected CD4 T cells.  The transcriptomes of these cells are then characterized using RNA seq. We have used these methods to characterize the transcriptomes from HIV-infected peripheral CD4 T cells and in ACH2 cells transitioning from “latent-infection” to “active-infection”. These studies have allowed us to correlate markers of disease progression such as CD4 down regulation, viral RNA concentrations and viral RNA splice patterns, with activation of NF-B pathway and increased HIV-RNA transcription.  We are currently using these methods to identify and characterize the longitudinal effect of SHIV infection on the CD4 T cell transcriptome of individual SHIV infected CD4 T cells from rhesus macaque lymph nodes.