Activation of type I interferon production in human immune cells by cell-to-cell transmission of HIV-1 - ABSTRACT Type I interferon (IFN) is an important cytokine that not only functions as host innate immune response against infection but also regulates inflammation and immunopathogenesis process. IFN production mediated by cGAS/STING signaling pathway, which senses cytosol DNA, is one of fundamental systems found in a variety of viral infections. However, mechanisms of how HIV-1 infection induces production of IFN in immune cells has been incompletely understood for decades. Clinical studies have demonstrated elevated IFN activity in people living with HIV-1. In similar, persistent IFN expressions were found in HIV/AIDS animal models. However, in vitro studies using cell-free HIV-1 viruses reported poor induction of IFN production triggered by cGAS/STING signaling pathway. Interestingly, in a pilot study, we found that HIV-1 cell associated infection, a mode of viral transmission through direct cell to cell contact that yields rapid virion transfer and much efficient replication, activated IFN expression by triggering cGAS-STING signaling pathway in cultured MT2 cells. Therefore, in this study, we hypothesize that cell-to-cell transmission of HIV-1 activates productions of IFNs and inflammatory cytokines by inducing cGAS/STING pathways. We have developed two cell based models to study cell-to-cell transmission of HIV-1 independent of cell free virus infection in both cultured and primary human immune cells.We propose to test our hypothesis by two specific aims. Aim 1. To investigate whether HIV-1 cell-to-cell transmission activates IFN production by inducing cGAS/STING/IRF-3 pathway. We will investigate and confirm the activation of this pathway specifically by cell associated infection. We will further verify that cGAS is the sensor of this pathway activation and identify factors that triggers this activation under unique virological and cellular environments during cell associated trasmission of HIV-1. Aim 2. To investigate whether HIV- 1 cell-to-cell transmission triggers cGAS/STING/NF-κB pathway. We will examine changes in status of this signaling pathway activation after cell-to-cell transmission of HIV-1. We will also investigate if cell associated infection reactivates HIV-1 in latency through upregulating NF-κB. Understanding the role of HIV- 1 cell-to-cell transmission in the activation of IFN with well characterized signaling pathways will represent a new way to fulfill our understanding in the pathogenesis of HIV infection as well as providing a potential guide to therapeutic approaches. This study will also provide great opportunity of research collaborations and extensive learning experience for students at ACPHS.
