Assistant Professor Microbiology
Assistant Professor Medicine, Infectious Diseases
Mount Sinai School of Medicine
Kinetics of innate immune responses control HIV/AIDS disease
Humans possess multi-layered defenses against invading pathogens. One of the earliest antiviral defense mechanism is the induction of interferon (IFN) synthesis. "Danger" sensing systems, such as Toll like receptors, RIG-I like receptors, and NOD like receptors converge in activating the synthesis of type I interferon (IFN). IFNs curb viral replication by a variety of mechanisms, including the shut down of protein synthesis and the degradation of foreign nucleic acids. Since dendritic cells (DCs) are instrumental in mediating the transition from innate to adaptive immunity, pathogenic viruses often dysregulate DC activation and type I IFN production in order to evade these first lines of defense.
We hypothesize that HIV manipulates the very early kinetics of human innate immune responses by interfering with DC function leading to inhibition of type I IFN production in DCs. Since HIV is predicted to require DC to T-cell transfer for the efficient initial spread, we anticipate that one or more of the HIV proteins impede the events leading to DC maturation and IFN production while migration is preserved. We developed a number of assays to study the manipulation of innate immunity by pathogenic RNA viruses such as Dengue, Influenza and Newcastle Disease. We propose now to use these experimental platforms to test whether primary cells from HIV infected patients selected based on their exceptional clinical outcome (control of HIV/AIDS in the absence of treatment, termed "HIV control") differ in their innate response profiles from cells derived from normal progressors or HIV- controls upon exposure to Dengue, Influenza and Newcastle Disease viruses.
Information generated in this pilot proposal will help understand how HIV strains elude innate immunity in the majority of humans. This will be critical for a) defining the correlate of immunity and protection in HIV infection and b) developing more efficient HIV vaccines.