Resistance to complement-mediated lysis of parainfluenza virus 5-infected cells is acquired after transition from acute to persistent infection

A persistent infection (PI) with RNA viruses can extend virus shedding, prolong inflammation, and be a source of new viral variants. Since profound changes to innate immune pathways can occur in PI cells, it was important to test PI cells for changes in sensitivity to the complement (C') system, powerful innate immune pathways capable of lysing infected cells. Using parainfluenza virus 5 (PIV5) as a model system, we show that PI cells are nearly completely resistant to C'-mediated lysis, in stark contrast to high sensitivity of acute PIV5-infected cells to C' killing. A key finding was the upregulated expression in PI cells of two C' inhibitors: Vitronectin and complement factor H. These are important results with strong potential to inform therapeutics, given that polymorphisms in C' genes can correlate with severity of viral infections, and clinical trials are underway with new drugs that modulate C' responses.