Abstract
Myeloid dendritic cells (mDCs) contribute to both HIV pathogenesis and elicitation of antiviral immunity. Understanding how mDC responses to stimuli shape HIV infection outcomes will inform HIV prevention and treatment strategies. The long double-stranded RNA (dsRNA) viral mimic, polyinosinic polycytidylic acid (polyIC, PIC) potently stimulates DCs to focus Th1 responses, triggers direct antiviral activity in vitro, and boosts anti-HIV responses in vivo. Stabilized polyICLC (PICLC) is being developed for vaccine adjuvant applications in humans, making it critical to understand how mDC sensing of PICLC influences HIV infection. Using the monocyte-derived DC (moDC) model, we sought to describe how PICLC (vs. other dsRNAs) impacts HIV infection within DCs and DC-T cell mixtures. We extended this work to in vivo macaque rectal transmission studies by administering PICLC with or before rectal SIVmac239 (SIVwt) or SIVmac239ΔNef (SIVΔNef) challenge. Like PIC, PICLC activated DCs and T cells, increased expression of α4β7 and CD169, and induced type I IFN responses in vitro. The type of dsRNA and timing of dsRNA exposure differentially impacted in vitro DC-driven HIV infection. Rectal PICLC treatment similarly induced DC and T cell activation and pro- and anti-HIV factors locally and systemically. Importantly, this did not enhance SIV transmission in vivo. Instead, SIV acquisition was marginally reduced after a single high dose challenge. Interestingly, in the PICLC-treated, SIVΔNef-infected animals, SIVΔNef viremia was higher, in line with the importance of DC and T cell activation in SIVΔNef replication. In the right combination anti-HIV strategy, PICLC has the potential to limit HIV infection and boost HIV immunity.
Highlights
Myeloid dendritic cells orchestrate immune responses to infections at mucosal sites
In order to assess the importance of DC function in mucosal HIV acquisition in vivo and potentially identify a role for PICLC-mediated Myeloid dendritic cells (mDCs) maturation in tipping the balance between protection and transmission, we examined how PICLC impacts rectal SIV transmission in macaques, a model which recapitulates the role of mDCs in HIV infection [5]
PICLC continues to be developed for use in vivo, yet little information exists on its impact on in vitro DC and DC-T cell biology to help guide development
Summary
Myeloid dendritic cells (mDCs) orchestrate immune responses to infections at mucosal sites. Immature mDCs isolated from blood [8], immature monocyte-derived DCs (moDCs) that are used to model mDCs in vitro [9,10,11,12], and Langerhans cells (LCs) [13] can all capture HIV They efficiently transfer infectious particles to CD4+ T cells across the DC-T cell infectious synapse in trans while immature moDCs (iDCs) become productively infected at a low level, supplying virus to T cells in cis [2,3,4,5,6, 8,9,10,11,12]. Cis transfer is thought to contribute especially to long-term viral transmission [11, 12, 14, 15]
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