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Abstract
Limited efficacy of current antivirals and antiviral-resistant mutations impairs anti-influenza treatment. Here, we evaluate the in vitro and in vivo antiviral effect of three defective interfering genes (DIG-3) of influenza virus. Viral replication is significantly reduced in cell lines transfected with DIG-3. Mice treated with DIG-3 encoded by jetPEI-vector, as prophylaxis and therapeutics against A(H7N7) virus, respectively, have significantly better survivals (80% and 50%) than control mice (0%). We further develop a dual-functional peptide TAT-P1, which delivers DIG-3 with high efficiency and concomitantly exerts antiviral activity by preventing endosomal acidification. TAT-P1/DIG-3 is more effective than jetPEI/DIG-3 in treating A(H7N7) or A(H1N1)pdm09-infected mice and shows potent prophylactic protection on A(H7N7) or A(H1N1)pdm09-infected mice. The addition of P1 peptide, which prevents endosomal acidification, can enhance the protection of TAT-P1/DIG-3 on A(H1N1)pdm09-infected mice. Dual-functional TAT-P1 with DIG-3 can effectively protect or treat mice infected by avian and seasonal influenza virus.
Highlights
Limited efficacy of current antivirals and antiviral-resistant mutations impairs anti-influenza treatment
Influenza defective interfering PB2 (DI-PB2), Defective interfering (DI)-PB1, and DI-PA genes with large internal deletion were generated from the backbone of A/WSN/ 1933(H1N1) virus using fusion PCR
When these plasmids of DI-PB2, DIPB1, and DI-PA were co-transfected or individually transfected into 293T and A549 cells, 7–8 log copies per well of each defective interfering genes (DIG) RNA was detected by RT-qPCR (Fig. 1b, c and Supplementary Fig. 1)
Summary
Limited efficacy of current antivirals and antiviral-resistant mutations impairs anti-influenza treatment. We evaluate the in vitro and in vivo antiviral effect of three defective interfering genes (DIG-3) of influenza virus. We further develop a dual-functional peptide TAT-P1, which delivers DIG-3 with high efficiency and concomitantly exerts antiviral activity by preventing endosomal acidification. Dual-functional TAT-P1 with DIG-3 can effectively protect or treat mice infected by avian and seasonal influenza virus. Though influenza DI virus (DIV) has been shown to be effective in vivo as a potential broad-spectrum antiviral with low risk for inducing resistance[13,14,15,16], there are several concerns of influenza DIV used as therapeutic agents. Dual-functional TAT-P1 could efficiently deliver DIG-3 by transfection into mouse lung cells to inhibit viral replication and directly inhibit viral replication by preventing endosomal acidification. We confirmed that DIG-3 delivered by TAT-P1 in mice further improved the survivals of avian A(H7N7) or human A(H1N1) virus-infected mice
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