Assistant Professor

Associate Director of Research, Duke Human Vaccine Institute

Co-Director Molecular Virology Core, Center for AIDS Research

Departments of Surgery, Immunology, Molecular Genetics and Microbiology

Program in Computational Biology and Bioinformatics
gdt@duke.edu

Dr. Tomaras' overall research program is to understand the cellular and humoral immune response to HIV-1 infection and determine the mechanisms of viral immune evasion. Detailed understanding of the dynamics of the host-pathogen interaction during infection will contribute to a greater understanding of why the host immune response fails to contain virus replication. The research in our laboratory centers around three main projects involving antiviral CD8 cell responses, HIV neutralizing antibodies and mucosal and system antibody responses during acute HIV-1 infection and vaccination.

Our laboratory studies a cellular immune response to HIV involving noncytolytic CD8 T cells that mediate suppression of HIV replication by targeting virus gene expression.  Noncytolytic CD8 T cell mediated suppression correlates with a healthier clinical state and is found in exposed uninfected individuals, thus is a potentially important vaccine elicited immune response.  Although highly sought after, the precise mediators of noncytolytic CD8+ suppression are unknown.  Noncytolytic CD8 suppression occurs during the time of virus gene expression and we have recently uncovered that a major target is the initiation of virus transcription.  Ongoing studies are building upon these findings to determine if noncytolytic CD8 suppression is directly involved in proviral latency, a transcriptionally silent state.  In addition, we are studying the characteristics of a virus that is more resistant to CD8 suppression, identified by screening genetically related pairs of viruses for their sensitivity to CD8 suppression and then creating further resistance through in vitro selection. Current work aims to reveal the viral genetic elements involved in CD8 T cell suppression.  In addition, we have developed a robust and high throughput virus suppression assay for the measurement of functional CD8 T cell activity during HIV-1 infection and as the result of vaccination.

A better understanding of the timing for the development of antibody responses, specifically the characterization of the antibody isotypes and antigen specificity, are important for understanding how HIV may influence adaptive B cell immunity. 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-1virion-Ab complexes.  We are currently working to understand the functional significance of the early HIV-1 specific IgM, IgG (IgG1, IgG2, IgG3, IgG4) and IgA (both mucosal and systemic) in acute HIV-1 infection and with candidate HIV-1 vaccines.

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 have recently identified that 2F5 like antibodies can develop in chronic HIV-1 infection and can mediate neutralization breadth.  HIV-1 can rapidly escape from neutralizing antibodies during natural infection.  Recent studies highlight both the potential strength of specific monoclonal antibody therapies for decreasing viral load and the need to understand virus escape in this setting.  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.  We are particularly interested in the role of

Env mutations in altering virus fitness.