Toll-Like Receptor (TLR) Signaling Enables Cyclic GMP-AMP Synthase (cGAS) Sensing of HIV-1 Infection in Macrophages
Mohammad Adnan Siddiqui, Masahiro Yamashita
Abstract
Innate immune activation is a hallmark of HIV-1 pathogenesis. Thus, it is critical to understand how HIV-1 infection elicits innate immune responses. In this work, we show that HIV-1 infection of macrophages leads to a robust type I interferon (IFN) production only when a second signaling event is initiated by a coexisting immunostimulatory molecule. Our results show that HIV-1 infection alone is not sufficient for triggering a strong IFN response. We find that bacterial membrane components, which are recognized by endosomal innate sensors, enable production of elevated levels of IFNs and significant upregulation of interferon-stimulated genes upon HIV-1 infection. This IFN response is dependent on viral DNA synthesis and prevented by a stable capsid, pointing to an essential role for a DNA sensing molecule. These observations provide new insights into how different innate immune recognition pathways synergize during HIV-1 infection and determine the outcome of innate responses.