TRIM5α restricts flavivirus replication by targeting the viral protease for proteasomal degradation.

Abstract

Tripartite motif-containing protein 5 (TRIM5) functions as a cellular antiviral restriction factor with exquisite specificity towards the capsid lattices of retroviruses. The relative avidity of TRIM5 binding to retrovirus capsids directly impacts primate species susceptibility to infection, but the antiviral role of TRIM5 is thought limited to retroviruses. In contrast to this current understanding, here we show that both human and rhesus TRIM5 possess potent antiviral function against specific flaviviruses through interaction with the viral protease (NS2B/3) to inhibit virus replication. Importantly, TRIM5 was essential for the antiviral function of IFN-I against sensitive flaviviruses in human cells. However, TRIM5 was ineffective against mosquito-borne flaviviruses (yellow fever, dengue, and Zika viruses) that establish transmission cycles in humans following emergence from non-human primates. Thus, TRIM5 is revealed to possess remarkable plasticity in recognition of diverse virus families, with potential to influence human susceptibility to emerging flaviviruses of global concern.