We previously reported a natural antisense (AS) RNA as an important modulator of human interferon-Alpha1 (IFNA1) mRNA levels. Here, we identified the guinea pig (Cavia porcellus) IFNA1 gene to enable a proof-of-concept experiment to be performed to confirm that the AS-mRNA regulatory axis exerts in vivo control over innate immunity. We selected a guinea pig model system for influenza virus infection because guinea pigs encode a functional Mx1 gene, an important anti-viral effector in the type I interferon pathway. We identified 15 guinea pig IFNA1 gene candidates upon bioinformatic analysis and selected the three candidates with the highest sequence homology to Homo sapiens, Mus musculus and Marmota himalayana IFNA1. The anti-viral activity of guinea pig IFN-Alpha1 protein against influenza virus A/Puerto Rico/8/34- or endomyocarditis virus-infection was then determined for the three gene candidates. We identified cpIFNA1 as the candidate with the highest sequence homologies and best anti-viral effects. cpIFNA1 will enable us to perform a proof-of-concept experiment to verify that IFN-Alpha1 AS increases cpIFNA1 mRNA levels, resulting in inhibition of influenza virus proliferation in vivo.