HPIV-2 V protein interferes with interaction between FTH1 and NCOA4 and inhibits NCOA4-mediated ferritin degradation, leading to the inhibition of iron release to the cytoplasm. This iron homeostasis modulation allows infected cells to avoid apoptotic cell death, resulting in effective growth of hPIV-2.

Hazara Nairovirus (HAZV) is a tri-segmented RNA virus most closely related to Crimean-Congo hemorrhagic fever virus, in the order Bunyavirales. The terminal roughly 20 nt of their genome ends are highly complementary, similar to those of other segmented negative-strand RNA viruses (sNSV), and act as promoters for RNA synthesis. These promoters contain two elements; the very termini of both strands (promoter element 1 (PE1)) are conserved and virus-specific, and are found bound to separate sites on the polymerase surface in crystal structures of promoter-polymerase complexes. The following sequences (PE2) are segment-specific with the potential to form dsRNA, and this latter aspect is also important for promoter activity. Nairovirus genome promoters differ from those of peribunya and arenaviruses in that they contain a short ss-region between the two regions of complementarity. Using a HAZV mini-genome system, we find the single-stranded nature of this region, as well as the potential of the following sequence to form dsRNA, are essential for reporter gene expression. Most unexpectedly, the sequence of the PE2 dsRNA appears to be equally important for promoter activity. These differences in sNSV PE2 promoter elements are discussed in the light of our current understanding of the initiation of RNA synthesis. IMPORTANCE A mini-genome system for HAZV, closely related to CCHFV, was used to study its genome replication. HAZV genome ends, like those of other sNSV such as peribunya- and arenaviruses, are highly complementary and serve as promoters for genome synthesis. These promoters are composed of two elements; the very termini of both 3’ and 5’ strands that are initially bound to separate sites on the polymerase surface in a sequence-specific fashion, and the following sequences with the potential to anneal, but whose sequence is not important. Nairovirus promoters differ from the other sNSV cited in that they contain a short ssRNA region between the two elements. The ss nature of this region is an essential element of this promoter, whereas its sequence is unimportant. The sequence of the following complementary region is unexpectedly also important, a possible rare example of sequence-specific dsRNA recognition.

Viruses have evolved various strategies to evade the host innate immune system. The relationship between nairoviruses and the interferon (IFN) system is poorly understood. We investigated whether and how nairoviruses antagonize host innate immunity using Hazara orthonairovirus (HAZV) as a surrogate model for Crimean-Congo hemorrhagic fever virus. HAZV nucleoprotein (N) was found to interact with the tripartite motif-containing protein 25 (TRIM25). The N-terminal region of N protein and the C-terminal region of TRIM25 are important for their interaction. Overexpression of N protein results in weakened interaction of TRIM25 with retinoic acid-inducible gene I (RIG-I). Furthermore, K63-linked polyubiquitination of RIG-I is inhibited in the presence of N protein. Our data collectively suggest that HAZV N protein interferes with the binding of TRIM25 to RIG-I and subsequent K63-linked polyubiquitination of RIG-I, which leads to inhibition of type I IFN production.