HIV-1 infection by cell-to-cell transmission induces human innate immune response.
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Issue Date
2023-07
Authors
Sanchez, Anthony '23
Degree
Advisor
Shi, Binshan
Committee Members
Singh, Vir
LaRocca, Timothy J.
Yager, Eric
LaRocca, Timothy J.
Yager, Eric
Journal Title
Journal ISSN
Volume Title
Abstract
HIV-1 can spread from infected cells to intact cells frequently through close cellular contact in human lymphoid tissues/organs. Compared to cell free virus infection, HIV-1 cell-to-cell transmission yields a significantly higher multiplicity of infection and requires both cellular membrane and skeleton changes, however the impact of HIV-1 cell-to-cell transmission to host innate immune response, particularly the IFN initiation by cGAS-STING pathways, has not been reported previously. In this study, it was found that HIV-1 GFP+ (∆env) virus in infected MT2 cells could transmit to uninfected MT2 cells and other immune cells predominantly by cell-to-cell transmission. The infection by cell-to-cell transmission of HIV-1 started to increase 12 hours and peaked at 36 hours after coculture of infected donor MT2 cells and uninfected recipient cells. Syncytia was observed in HIV-1 cell-to-cell transmitted MT2 cells by using fluorescence microscopy. In addition, the flow cytometry result indicated cell morphology and structure changes in MT2 cells after HIV-1 cell-to-cell transmission. Importantly, in HIV-1 GFP+ infected MT2 cells, phosphorylation of both STING and IRF3 proteins were detected at 36 hours post infection, which was virus infection dosage dependent. The nuclear translocation of phosphorylated IRF3 was also identified. Furthermore, transcriptional upregulation of IFNB1 was confirmed by a real time PCR experiment. These data strongly demonstrated HIV-1 cell-to-cell transmission in MT2 cells triggered cGAS-STING pathway and activated IFN gene expression. Meanwhile, the influence of host cell autophagy process to HIV-1 cell-to-cell transmission was also studies. It was found that the induction of autophagy by rapamycin mildly inhibited HIV-1 cell-to-cell transmission; while autophagy inhibitors 3MA, Baf. A and chloroquine also blocked HIV-1 cell-to-cell transmission, except E64D/ pepstatin which inhibits final proteolytic stage of autophagy. Together, our results have provided compelling evidence that HIV-1 cell-to-cell transmission activates IFN and interacts with autophagy system, which might have significant impact on HIV-1 pathogenesis through the host innate immune response and inflammatory signaling.
Citation
Sanchez A. HIV-1 infection by cell-to-cell transmission induces human innate immune response. Ann Arbor (MI): Proquest LLC; 2023. 76 p.
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