The progression of acute and persistent viral infections is governed, in part, by the ability of CD4 and CD8 T cells to eliminate virus-infected cells or effectively retard viral replication. This is especially important for persistent viruses uch as HIV, CMV, or HCV that are never cleared by the immune system. This proposal describes experiments designed to understand a central control mechanism guiding T cell differentiation and function. Foxo transcription factors are differentially regulated by physiological conditions such as oxidative stress, abundance of growth factors (such as insulin), nutrient availability, or inflammation. Integrating this information, they promote or restrict programs of gene expression that govern cellular survival, quiescence, DNA repair, and metabolism, and they directly control highly specialized functions including: the IL-7 receptor, CTLA-4, and Icos. In particular, preliminary data presented demonstrate that Foxo transcription factors control the expansion and activation status of CD8 cytotoxic T cells post-infection. In addition, the absence of Foxo1 promotes the appearance of CD4 central memory precursor cells, and CD4 follicular helper cells able to produce IL-21. These results combined with the observation that HIV elite controller patients have a deficit in Foxo3 activity, reveal the central and profound influence that this transcription factor module exerts on the immune system. We propose an in depth analysis of Foxo1 and Foxo3 transcription factors in the progression and clearance of virus infections, and a large-scale analysis of their control over the programming of gene expression. The results will have direct implications for the progression of long co-evolved viral diseases such as HIV, Herpes, and Hepatitis C virus.

Public Health Relevance

The outcome of virus infections can be highly variable within the population, and this is especially important for persistent viruses such as HIV and Hepatitis C virus. Obesity, stress, and inflammation all impact the course of infectious disease. Foxo transcription factors constitute a very highly connected signal transduction node that exists in al cells but has been specialized in lymphocytes and myeloid cells to govern differentiation and function. Their activity is regulated by inflammation, oxidative stress, nutrient availability, and growth factors to control survival, quiescence, and bioenergetics. Using genetics, next generation sequencing and cellular analysis, the proposed experiments will probe the manner with which Foxo factors control the clearance of acute and persistent viruses.

National Institute of Health (NIH)
National Institute of Allergy and Infectious Diseases (NIAID)
Research Project (R01)
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Cellular and Molecular Immunology - A Study Section (CMIA)
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Kelly, Halonna R
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University of California San Diego
Other Basic Sciences
Schools of Medicine
La Jolla
United States
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Roupé, Karl Markus; Veerla, Srinivas; Olson, Joshua et al. (2014) Transcription factor binding site analysis identifies FOXO transcription factors as regulators of the cutaneous wound healing process. PLoS One 9:e89274
Michelini, Rodrigo Hess; Doedens, Andrew L; Goldrath, Ananda W et al. (2013) Differentiation of CD8 memory T cells depends on Foxo1. J Exp Med 210:1189-200