Research

Research

HIV Evasion of Innate Immunity

HIV life cycle

One of the focuses in the lab is to understand how HIV exploits host factors to evade innate immune detection. Viral nucleic acids introduced into cells or synthesized during infection trigger cytosolic sensors of innate immunity to produce antiviral cytokines, such as type I interferons (IFN). Some viruses evade immune sensing. Although HIV introduces genomic RNA and then generates a variety of DNA products in the cytosol through reverse transcription, HIV infection of T cells and macrophages does not trip these alarms. How HIV avoids activating innate immune sensors of foreign nucleic acids is unknown. Few copies of HIV DNA integrate in a cell during infection, leaving behind some HIV DNA in the cytosol. Unintegrated HIV DNA is believed to be cleared by host enzymes. We recently found that the cytosolic exonuclease TREX1 suppressed interferon triggered by HIV (Yan 2010 Nature Immunology). We are interested in characterizing mechanism(s) by which the innate immune recognition of HIV is regulated. We hope to develop novel antiretroviral therapeutics that is based on enhancing innate immunity.

Innate Immunity and Antiviral Responses

WT and Trex1

We recently uncovered a novel cell-intrinsic signaling pathway that was initiated by dysregulation of the lysosome, and that induced an interferon-independent activation of antiviral genes (Hasan 2012 Nature Immunology). We are interested in how biogenesis of cellular organelles impacts innate immune responses. We are also interested in novel ways to stimulate broad-spectrum antiviral response.

Pathogenesis of Autoimmune Disease

Aicardi-Goutieres syndrome (AGS)

Another area of interest in our lab is to understand the pathogenesis of human autoimmune diseases. Mutations in human TREX1 gene are associated with Aicardi-Goutieres syndrome (AGS), a severe neurological brain disease often found in infant and young children, familial chilblain lupus (FCL) and systemic lupus erythematosus (SLE). Trex1−/− mice develop autoimmune noninfectious inflammatory myocarditis and often die of heart failure. Studies of Trex1−/− mice suggested that DNA derived from DNA replication debris or endogenous retroelements maybe the underlying cause of autoimmunity. We are interested in investigating how our cells regulate innate immune detection of self nucleic acids and what are the molecular and clinical consequences when things go awry. We hope to develop useful biomarkers and treatments for related human autoimmune diseases.