Co-infection is a process by which a cell or organism already infected with a virus is then infected with a second, different virus (1, 2). The human coronavirus SARS-CoV-2 has resulted in the death of nearly 200,000 Americans in less than one year (3, 4); the upcoming influenza could potentially pose a problem with respect to co-infection with Influenza and SARS-CoV-2. We mined a published microarray dataset (5) to discover genes associated with viral co-infection in patients with a coronavirus infection. We found that genes of the HLA family, particularly HLA-DRB and HLA-A, were significantly differentially expressed in the blood of patients with human coronavirus infections, including HCoV-229E, HCoV OC43, HCoV NL63, and HCoV HKU1. Different viral co-infections, including Influenza A, Human Rhinovirus, Enterovirus, and Respiratory Syncytial Virus A co-infections were also associated with significant differential expression of HLA family genes in patient blood. Perturbation of HLA family gene expression appears to be a general feature of viral co-infection in humans.