Type-1 inflammatory imprinting and programmed responsiveness to CD40L enhance Siglec-1-dependent HIV-1...

Dendritic cells (DC) play a central role in host immunity as they carry environmental cues from sites of infection to the lymphatics, where they subsequently direct appropriate adaptive immune responses. Importantly, this process is exploited by pathogens such as HIV-1, which utilize DC to efficiently facilitate HIV-1 trans-infection of CD4⁺ T cells. In this study, we show that monocyte-derived DC matured under type-1 proinflammatory conditions, either through exposure to soluble mediators of type-1 immunity or through bystander activation of cytotoxic T cells, display enhanced trans-infection capacity, while prostaglandin E2 exposure diminishes this trait. This heightened trans-infection activity involves DC upregulation of sialic acid binding immunoglobulin-like lectin-1 (Siglec-1/CD169) surface expression and a distinct responsiveness to the CD4⁺ T helper cell signal CD40L. The upregulated expression of Siglec-1 increases HIV-1 surface binding potential on these proinflammatory DC, while CD40L/CD40 signaling uniquely induces the formation of pronounced morphologic extensions and the release of the chemokine CCL20, together increasing CD4+ T cell access and susceptibility to HIV-1 infection. Overall, this study demonstrates that the nature of environmental signals received by monocyte-derived DC during maturation and the character of their subsequent responsiveness to CD40L-expressing T helper cells dictates their ability to facilitate HIV-1 trans-infection.