RAMYA GOPAL, SREEKUMAR BALAN & VLADIMIR ROUDKO
Plasmacytoid dendritic cells (pDCs) are innate immune cells that are specialized to produce interferon-alpha (IFNα) and participate in activating adaptive immune responses. Although IFNα inhibits HIV-1 (HIV) replication in vitro, pDCs may act as inflammatory and immunosuppressive dendritic cells (DCs) rather than classical antigen-presenting cells during chronic HIV infection in vivo, contributing more to HIV pathogenesis than to protection.
Improved understanding of HIV-pDC interactions may yield potential new avenues of discovery to prevent HIV transmission, to blunt chronic immune activation and exhaustion, and to enhance beneficial adaptive immune responses.
pDCs sense viral nucleic acids through endosomal Toll-like receptor (TLR) 7/9 to produce type I interferon (IFN) and to differentiate into potent antigen presenting cells (APC). Engagement of TLR7/9 in early endosomes appears to trigger the IRF7 pathway for IFN production whereas engagement in lysosomes seems to trigger the NF-κB pathway for maturation into APC. We have shown that HIV-1 localizes predominantly to early endosomes, not lysosomes, and mainly stimulate IRF7 rather than NF-κB signaling pathways in pDC. We further demonstrated that HIV virions may be re-directed to lysosomes for NF-κB signaling by either pseudotyping HIV with influenza hemagglutinin envelope or modification of CD4 mediated-intracellular trafficking. These data suggest that HIV envelope-CD4 receptor interactions drive pDC activation toward an immature IFN producing phenotype rather than differentiation into a mature dendritic cell phenotype.
Currently, Ramya, Sreekumar and Vladimir are investigating molecular mechanisms of viral sensing by pDCs to better understand how certain viruses stimulate pDCs to become predominantly interferon-producing cells, whereas other viruses stimulate pDCs to become antigen presenting cells.