Extracellular signaling is a mechanism that higher eukaryotes have evolved to facilitate organismal homeostasis. Recent years have seen an emerging interest in the role of secreted microvesicles, termed extracellular vesicles (EV) or exosomes in this signaling network. EV contents can be modified by the cell in response to stimuli, allowing them to relay information to neighboring cells, influencing their physiology. Here we show that the tumor virus Kaposi’s Sarcoma-associated herpesvirus (KSHV) hijacks this signaling pathway to induce cell proliferation, migration, and transcriptome reprogramming in cells not infected with the virus. KSHV-EV activates the canonical MEK/ERK pathway, while not alerting innate immune regulators, allowing the virus to exert these changes without cellular pathogen recognition. Collectively, we propose that KSHV establishes a niche favorable for viral spread and cell transformation through cell-derived vesicles, all while avoiding detection.

Kaposi’s Sarcoma (KS) originates from endothelial cells and it is one of the most overt angiogenic tumors. In Sub-Saharan Africa, where HIV and the Kaposi Sarcoma-associated Herpes Virus (KSHV) are endemic, KS is the most common cancer overall, but model systems for disease study are insufficient. Here we report the development of a novel mouse model of KS where KSHV is retained stably and tumors are elicited rapidly. Tumor growth was sensitive to specific allosteric inhibitors (rapamycin, CCI-779, RAD001) of the pivotal cell growth regulator mTOR. Inhibition of tumor growth was durable up to 130 days and reversible. mTOR blockade reduced VEGF secretion and formation of tumor vasculature. Together, the results demonstrated that mTOR inhibitors exert a direct anti-KS effect by inhibiting angiogenesis and paracrine effectors, suggesting their application as a new treatment modality for KS and other cancers of endothelial origin.

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29 30 SARS-CoV-2 is constantly evolving. Prior studies have focused on high case-density locations, such 31 as the Northern and Western metropolitan areas in the U.S. This study demonstrates continued 32 SARS-CoV-2 evolution in a suburban Southern U.S. region by high-density amplicon sequencing of 33 symptomatic cases. 57% of strains carried the spike D614G variant. The presence of D614G was 34 associated with a higher genome copy number and its prevalence expanded with time. Four strains 35 carried a deletion in a predicted stem loop of the 3' untranslated region. The data are consistent with 36 community spread within the local population and the larger continental U.S. No strain had mutations 37 in the target sites used in common diagnostic assays. The data instill confidence in the sensitivity of 38 current tests and validate "testing by sequencing" as a new option to uncover cases, particularly those 39 not conforming to the standard clinical presentation of COVID-19. This study contributes to the 40 understanding of COVID-19 by providing an extensive set of genomes from a non-urban setting and 41 further informs vaccine design by defining D614G as a dominant and emergent SARS-CoV-2 isolate 42 in the U.S.