Antiretroviral therapy (ART) efficiently suppresses HIV replication but immune activation and low CD4 T cell counts often persist. The underlying mechanism of this ART-resistant pathogenesis is not clear. We observed that levels of plasma extracellular vesicles (pEV) are strongly elevated in HIV infection and do not decline during ART. Surprisingly, these vesicles contained the viral accessory proteins Nef and Vpu, which are assumed to be not expressed under efficient ART, as well as pro-inflammatory effectors, including activated ADAM17. HIV pEV were characterized by the presence of activated αvβ3 and absence of CD81 and Tsg101. Correlating with immune activation, peripheral monocytes ingested large amounts of pEV, giving rise to an increased population of CD1c(+) CD14(+) cells that secreted inflammatory cytokines. Importantly, the pro-inflammatory content, particularly ADAM17 activity, correlated with low T cell counts. Preliminary evidence suggested that HIV pEV derived from peripheral mononuclear cells and from an unknown myeloid cell population. In summary we propose an important role of pro-inflammatory pEV in chronic HIV infection due to ongoing viral Nef activity.

Syndecan-2, a transmembrane heparan sulfate proteoglycan, is a critical mediator in the tumorigenesis of colon carcinoma cells. We explored the function of syndecan-2 in melanoma, one of the most invasive types of cancers, and found that the expression of this protein was elevated in tissue samples from both nevus and malignant human melanomas but not in melanocytes of the normal human skin tissues. Similarly, elevated syndecan-2 expression was observed in various melanoma cell lines. Overexpression of syndecan-2 enhanced migration and invasion of melanoma cells, whereas the opposite was observed when syndecan-2 levels were knocked down using small inhibitory RNAs. Syndecan-2 expression was enhanced by fibroblast growth factor-2, which is known to stimulate melanoma cell migration; however, α-melanocyte-stimulating hormone decreased syndecan-2 expression and melanoma cell migration and invasion in a melanin synthesis-independent manner. Furthermore, syndecan-2 overexpression rescued the migration defects induced by α-melanocyte-stimulating hormone treatment. Together, these data strongly suggest that syndecan-2 plays a crucial role in the migratory potential of melanoma cells.

The innate immune defense of mammalian hosts relies on its capacity to detect invading pathogens and then directly eliminate them or help guide adaptive immune responses. Recognition of microbial DNA and RNA by pattern recognition receptors (PRRs) is central to the detection of pathogens by initiating cytokine-mediated innate immunity. In contrast, disturbance of this pathogen surveillance system can result in aberrant innate immune activation, leading to proinflammatory or autoimmune diseases. Among the many important PRRs are proteins of the retinoic acid-inducible gene-I (RIG-I)-like receptor (RLR) family as well as cyclic GMP-AMP synthase (cGAS), which detect viral RNA and DNA, respectively, within the host cell. Intriguingly, recent evidence has shown that “unmasked,” misprocessed, or mislocalized host-derived RNA or DNA molecules can also be recognized by RLRs or cGAS, thereby triggering antiviral host defenses or causing inflammation. Here, we review recent advances of endogenous nucleic acid recognition by RLRs and cGAS during viral infection and systemic proinflammatory/autoimmune disorders.