Tripartite motif-containing protein 5a (TRIM5a) is a cellular antiviral restriction factor that prevents early events in retrovirus replication. The activity of TRIM5a is thought to be limited to retroviruses as a result of highly specific interactions with capsid lattices. In contrast to this current understanding, we show that both human and rhesus macaque TRIM5a suppress replication of specific flaviviruses. Multiple viruses in the tick-borne encephalitis complex are sensitive to TRIM5a-dependent restriction, but mosquito-borne flaviviruses, including yellow fever, dengue, and Zika viruses, are resistant. TRIM5a suppresses replication by binding to the viral protease NS2B/3 to promote its K48-linked ubiquitination and proteasomal degradation. Importantly, TRIM5a contributes to the antiviral function of IFN-I against sensitive flaviviruses in human cells. Thus, TRIM5a possesses remarkable plasticity in the recognition of diverse virus families, with the potential to influence human susceptibility to emerging flaviviruses of global concern.

Kaposi's sarcoma (KS) is an AIDS-defining cancer caused by the KS-associated herpesvirus (KSHV). Unanswered questions regarding KS are its cellular ontology and the conditions conducive to viral oncogenesis. We identify PDGFRA(+)/SCA-1(+) bone marrow-derived mesenchymal stem cells (Pα(+)S MSCs) as KS spindle-cell progenitors and found that pro-angiogenic environmental conditions typical of KS are critical for KSHV sarcomagenesis. This is because growth in KS-like conditions generates a de-repressed KSHV epigenome allowing oncogenic KSHV gene expression in infected Pα(+)S MSCs. Furthermore, these growth conditions allow KSHV-infected Pα(+)S MSCs to overcome KSHV-driven oncogene-induced senescence and cell cycle arrest via a PDGFRA-signaling mechanism; thus identifying PDGFRA not only as a phenotypic determinant for KS-progenitors but also as a critical enabler for viral oncogenesis.

33Tripartite motif-containing protein 5a (TRIM5a) functions as a cellular antiviral restriction 34 factor with exquisite specificity towards the capsid lattices of retroviruses. The relative avidity 35 of TRIM5a binding to retrovirus capsids directly impacts primate species susceptibility to 36 infection, but the antiviral role of TRIM5a is thought limited to retroviruses. In contrast to this 37 current understanding, here we show that both human and rhesus TRIM5a possess potent 38 antiviral function against specific flaviviruses through interaction with the viral protease 39 (NS2B/3) to inhibit virus replication. Importantly, TRIM5a was essential for the antiviral 40 function of IFN-I against sensitive flaviviruses in human cells. However, TRIM5a was ineffective 41 against mosquito-borne flaviviruses (yellow fever, dengue, and Zika viruses) that establish 42 transmission cycles in humans following emergence from non-human primates. Thus, TRIM5a 43 is revealed to possess remarkable plasticity in recognition of diverse virus families, with 44 potential to influence human susceptibility to emerging flaviviruses of global concern. 45 46 47 Main 48Flaviviruses (family Flaviviridae) include 53 recognized virus species of which 40 are known to 49 cause disease in humans, with over 40% of the world's population at risk of flavivirus infection 50 annually 1 . These viruses have high potential for emergence into human populations as 51 witnessed historically through global emergence of dengue virus (DENV), West Nile virus 52 (WNV), and Zika virus (ZIKV). Additional (re)emerging viruses of considerable medical 53 importance include yellow fever virus (YFV), Japanese encephalitis virus (JEV) and members of 54 the tick-borne encephalitis virus (TBEV) serogroup. Flaviviruses share in common a positive-55 sense single-stranded RNA (ssRNA) genome encoding a single polyprotein that is cleaved by 56 host cell signalases 2 and the viral protease to generate three structural (capsid [C], pre-57 membrane [M] and envelope [E]) and seven nonstructural (NS) proteins (NS1, NS2A, NS2B, NS3, 58NS4A, NS4B and NS5) 3 . Two of the nonstructural proteins have enzymatic activity; the NS3 59 protein encodes the viral RNA helicase and together with its co-factor NS2B (NS2B/3) functions 60