Computational Biology & Bioinformatics

PHD in Computational Biology & Bioinformatics

Program Principles & Goals

The PhD Program in Computational Biology & Bioinformatics (CBB) is an integrative, multi-disciplinary training program that encompasses the study of biology using computational and quantitative methods. In and out of the classroom, students learn to apply the tools of statistics, mathematics, computer science and informatics to biological problems. The vibrant and innovative Duke research in these fields provides exciting interactions between biological and computational scientists. Because the Program in Computational Biology and Bioinformatics is based in the Duke Center for Genomic and Computational Biology, it offers a unique opportunity for students to become one of tomorrow's leaders in the genome sciences.

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Meet A Faculty Member

  • Professor in Surgery
    Dr. Tomaras' research program focuses primarily on understanding host-pathogen interactions in HIV. Understanding both the cellular and humoral response to HIV infection and determining the mechanisms of viral immune evasion are key components of our research program.
     
    We study a cellular immune response to HIV involving noncytolytic CD8 T cells that mediate suppression of HIV replication by targeting virus gene expression. The precise mediators involved in this inhibition are currently unknown, but discovery of their identity and knowledge of their mechanism will be beneficial for novel HIV therapeutic and vaccine design.
     
    We also study humoral responses to HIV that involve understanding the generation and maintenance of HIV specific antibodies, both neutralizing and nonneutralizing. We are particularly focused on the viral genetic elements responsible for virus escape from neutralizing antibodies throughout the course of infection and the role of these mutations in altering virus fitness.
     
    For binding antibodies (non-neutralizing), we are studying the types of antibodies that are elicited by HIV infection and by candidate HIV vaccines to help decipher their functional role in vivo. Integral to our study of both the cellular and humoral responses to HIV infection is the analysis of the viral genome as it adapts to the changing immune pressure.
    Dr. Tomaras' overall research program is to understand the cellular and humoral immune response to HIV-1 infection and vaccination that are involved in protection from HIV-1. The research in the Tomaras laboratory centers around three main projects involving 1) antiviral CD8+ T cell responses in HIV-1 infection and post vaccination, 2) mucosal and systemic antibody responses to infection and vaccination in both non-human primates and humans and 3) the ontogeny of neutralizing antibodies in HIV-1 infection. Her laboratory is also within the Duke Human Vaccine Institute (http://humanvaccine.duke.edu/modules/Tomaras/index.php?id=1).
    Antiviral CD8+ T Cell Responses. CD8+ T cell immune responses to HIV involve noncytolytic CD8 T cells that mediate suppression of HIV replication. During human acute HIV-1 infection and acute SIV infection in non-human primates, CD8+ T cell responses have been associated with the initial control of viremia. A detailed understanding of the properties of CD8+ T cells that correlate with virologic control will inform vaccine development by focusing on strategies that elicit functional cellular responses. In this regard, it is critical to determine the phenotypic and functional properties of CD8+ T cells that can mediate viral suppression. We have developed a robust and high throughput multi-clade virus inhibition assay for the measurement of functional CD8 T cell activity to decipher the mechanisms of virus inhibition that include both lytic and nonlytic mechanism. We identified that CD8+ T cell mediated virus inhibition, like other memory CD8+ T cells, can use epigenetics to control expression of inhibitory molecules so that they can control molecules released to target infected CD4+ T cells. Studying the role of epigenetics in CD8+ T cell mediated virus inhibition is an innovative concept that will likely uncover pathways for induction of highly functional CD8+ T cells. Insights into the induction of these CD8+ T cell responses are central to understanding how to precisely target this population of cells by vaccination. We found that CD8+ T cell antiviral activity from vaccinees and virus controllers were defined by CD107a and MIP-1β expression and that CD8+ T cell from all memory stages of differentiation exhibit antiviral activity, including transitional memory CD8+ T cells. Our data define attributes of an antiviral CD8+ T cell response that may be optimized in the search for an efficacious HIV-1 vaccine. Current work aims to probe the specific CD8 T cell populations that are responsible for mediating HIV-1 inhibition and the contribution of soluble factors during acute infection, in natural virus controllers, and post vaccination.
    Mucosal and Systemic Antibodies. A window of opportunity for immune responses to extinguish HIV-1 exists from the moment of transmission through establishment of the latent pool of HIV-1-infected cells. A critical time to study the initial immune responses to the transmitted/founder virus is the eclipse phase of HIV-1 infection. We have shown that the first detectable antibody response is in the form of HIV-1 virion-Ab complexes and the initial free antibody response is targeted only to the gp41 portion of the HIV-1 envelope. This body of work provided a deeper understanding of the initial B cell response to HIV infection that has allowed subsequent work to focus on why the humoral response is targeted initially to gp41 and not other potentially protective epitopes. Moreover, this work is leading to more detailed analyses of the ontogeny of the initial B cell response and whether this pathway to an ineffectual antibody response impedes the elicitation of more protective responses. This is critical for defining what a vaccine must do differently from natural infection in stimulating the B cell response. We are currently working to understand the functional significance of systemic and mucosal HIV-1 specific IgM, IgG subclasses and IgA. As part of our analysis of candidate HIV-1 vaccine trials, the RV144 efficacy trial, and non-human primate studies we are working to define the potential humoral correlates of protection and define the contributions of different types of non-neutralizing (HIV-1 inhibitory) antibodies.
    Heterologous Neutralizing Antibodies. Identification of broadly neutralizing antibody specificities in HIV-1 infection will allow an understanding of what antibody specificities the human immune system is capable of making that can neutralize or eliminate diverse strains of HIV-1. We identified that 2F5-like antibodies can develop in chronic HIV-1 infection and can mediate neutralization breadth. As a result of this work, we continued to investigate the nature of the HIV-1 viruses that were most sensitive to HIV-1 gp41 MPER mediated neutralization. We identified a single amino acid substitution in gp41 that leads to prolonged MPER exposure with implications for vaccine design. For potential envelope based vaccine strategies, a greater understanding of the evolution of the HIV envelope under selective pressure is critical in understanding and predicting vaccine efficacy.

Anna Lowegard

3rd year CBB Student Bruce Donald Lab
May 2
Dr. Erik Soderblom and Dr. Will Thompson, Duke Proteomics and Metabolomics
GCB Academy

Mass Spectrometry Based Proteomic and Metabolomic Data Analysis Strategies

May 3
Carla Shatz, PhD, David Staff Jordon Director of Stanford Bio-X, Stanford University
Ruth K. Broad Foundation Seminar Series on Neurobiology and Disease

Saving the synapse: developmental critical periods and Alzheimer's disease

May 10
Dejian Ren, PhD, Associate Professor of Biology, University of Pennsylvania
Duke Neurobiology

TBD-Dejian Ren, PhD