Chronic immune activation is a multifactorial process driven by many cell types, including conventional DCs (cDCs), pDCs, T cells, or NK cells. DCs recognizing HIV or microbial components through TLRs or other pattern recognition receptors secrete IFN-α and inflammatory cytokines, inducing activation of other cell types (e.g., NK cells). Activated NK cells can lyse virally infected cells directly or through ADCC. Inhibitors of the TLR pathway or of cytokine signaling can be used to tune down the inflammatory response. For example, chloroquine (14) and short oligonucleotides (ODNs) block activation of endosomal TLR. Rapamycin inhibits mammalian target of rapamycin (mTOR) signaling, necessary for recruitment of MyD88 to TLRs (16). STAT decoys can inhibit the transcriptional program induced in target cells by inflammatory cytokines. Synthetic mimetics of defensins, peptides with antimicrobial activity, could be used to protect gut epithelium from bacterial invasion and enhance anti-HIV immune responses. TRAF6, TNF receptor–associated factor 6; IRAK1, IL-1 receptor–associated kinase 1.