Effective control of influenza A virus infection by boosting γδ-T-cell immunity with pamidronate (106.13)

Abstract Influenza remains a global threat to public health. There are few antiviral drugs for treating influenza and the emergence of antiviral resistance has further limited the available therapeutic options. Furthermore, antivirals are not invariably effective in severe influenza, such as that caused by H5N1 viruses. Thus, there is an urgent need to develop alternative therapeutic strategies. Pamidronate has been commonly used to treat osteoporosis by enhancing human Vγ9Vδ2-T-cell immunity. Using Rag2-/-γc-/- mice reconstituted with human peripheral mononuclear cells (huPBMCs) as a model, we demonstrate that the treatment of pamidronate decreases disease severity and/or mortality caused by human seasonal H1N1 and avian H5N1 influenza virus, and controls the lung inflammation and viral replication. Importantly, pamidronate has no such effects in influenza virus-infected Rag2-/-γc-/- mice reconstituted with Vγ9Vδ2-T-cell-depleted huPBMCs. Our results demonstrate that pamidronate can control human and avian influenza A virus infections through a Vγ9Vδ2-T-cell dependent mechanism in vivo. This study provides proof-of-concept of a novel therapeutic strategy for treating influenza by targeting the host rather than the virus, thereby reducing the opportunity for the emergence of drug-resistant viruses. This ‘new application of an old drug’ potentially offers a safe and readily available option for treating influenza.