HIV-1 exploits innate signaling by TLR8 and DC-SIGN for productive infection of dendritic cells

Pattern-recognition receptors (PRRs) elicit antiviral immune responses to human immunodeficiency virus type 1 (HIV-1). Here we show that HIV-1 required signaling by the PRRs Toll-like receptor 8 (TLR8) and DC-SIGN for replication in dendritic cells (DCs). HIV-1 activated the transcription factor NF-kappa B through TLR8 to initiate the transcription of integrated provirus by RNA polymerase II (RNAPII). However, DC-SIGN signaling was required for the generation of full-length viral transcripts. Binding of the HIV-1 envelope glycoprotein gp120 to DC-SIGN induced kinase Raf-1-dependent phosphorylation of the NF-kappa B subunit p65 at Ser276, which recruited the transcription-elongation factor pTEF-b to nascent transcripts. Transcription elongation and generation of full-length viral transcripts was dependent on pTEF-b-mediated phosphorylation of RNAPII at Ser2. Inhibition of either pathway abrogated replication and prevented HIV-1 transmission. Thus, HIV-1 subverts crucial components of the immune system for replication that might be targeted to prevent infection and disseminatio

Memory Th1 Cells Are Protective in Invasive <i>Staphylococcus aureus</i> Infection

<div><p>Mechanisms of protective immunity to <i>Staphylococcus aureus</i> infection in humans remain elusive. While the importance of cellular immunity has been shown in mice, T cell responses in humans have not been characterised. Using a murine model of recurrent <i>S</i>. <i>aureus</i> peritonitis, we demonstrated that prior exposure to <i>S</i>. <i>aureus</i> enhanced IFNγ responses upon subsequent infection, while adoptive transfer of <i>S</i>. <i>aureus</i> antigen-specific Th1 cells was protective in naïve mice. Translating these findings, we found that <i>S</i>. <i>aureus</i> antigen-specific Th1 cells were also significantly expanded during human <i>S</i>. <i>aureus</i> bloodstream infection (BSI). These Th1 cells were CD45RO⁺, indicative of a memory phenotype. Thus, exposure to <i>S</i>. <i>aureus</i> induces memory Th1 cells in mice and humans, identifying Th1 cells as potential <i>S</i>. <i>aureus</i> vaccine targets. Consequently, we developed a model vaccine comprising staphylococcal clumping factor A, which we demonstrate to be an effective human T cell antigen, combined with the Th1-driving adjuvant CpG. This novel Th1-inducing vaccine conferred significant protection during <i>S</i>. <i>aureus</i> infection in mice. This study notably advances our understanding of <i>S</i>. <i>aureus</i> cellular immunity, and demonstrates for the first time that a correlate of <i>S</i>. <i>aureus</i> protective immunity identified in mice may be relevant in humans.</p></div