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Epidemiologic data suggest an association between depot medroxyprogesterone acetate (DMPA), a progesterone-based hormonal contraceptive, and increased risk of HIV acquisition and transmission. DMPA is highly effective and is among the most commonly used form of hormonal contraception in areas of high HIV prevalence. Thus, defining the biological mechanisms that contribute to the potential negative synergy between DMPA and HIV is key and may facilitate the identification of alternative contraceptive strategies. Proposed mechanisms include thinning or disruption of the cervicovaginal epithelial barrier, induction of mucosal inflammation, interference with innate and adaptive soluble and cellular immune responses, and/or alterations in the vaginal microbiome. DMPA may also indirectly increase the risk of HIV by promoting genital herpes or other sexually transmitted infections. However, there is a paucity of rigorous in vitro, animal model and clinical data to support these potential mechanisms highlighting the need for future research.

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Immunoreceptor tyrosine-based activation motifs (ITAMs) are signaling domains located within the cytoplasmic tails of many transmembrane receptors and associated adaptor proteins that mediate immune cell activation. ITAMs also have been identified in the cytoplasmic tails of some enveloped virus glycoproteins. Here, we identified ITAM sequences in three mammalian reovirus proteins: 2, 2, and 2. We demonstrate for the first time that 2 is phosphorylated, contains a functional ITAM, and activates NF-B. Specifically, 2 and NS recruit the ITAM-signaling intermediate Syk to cytoplasmic viral factories and this recruitment requires the 2 ITAM. Moreover, both the 2 ITAM and Syk are required for maximal 2 activation of NF-B. A mutant virus lacking the 2 ITAM activates NF-B less efficiently and induces lower levels of the downstream antiviral cytokine beta interferon (IFN-␤) than does wild-type virus despite similar replication. Notably, the consequences of these 2 ITAM effects are cell type specific. In fibroblasts where NF-B is required for reovirus-induced apoptosis, the 2 ITAM is advantageous for viral spread and enhances viral fitness. Conversely, in cardiac myocytes where the IFN response is critical for antiviral protection and NF-B is not required for apoptosis, the 2 ITAM stimulates cellular defense mechanisms and diminishes viral fitness. Together, these results suggest that the cell type-specific effect of the 2 ITAM on viral spread reflects the cell type-specific effects of NF-B and IFN-␤. This first demonstration of a functional ITAM in a nonenveloped virus presents a new mechanism for viral ITAM-mediated signaling with likely organ-specific consequences in the host.