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Marek's disease virus (MDV), an alphaherpesvirus, causes severe immunosuppression and T cell lymphomas in chickens, known as Marek's disease (MD), an economically important poultry disease primarily controlled by vaccination. Importantly, it also serves as a comparative model for studying herpesvirus-induced tumor formation in humans. MDV encodes more than 100 genes, most of which have unknown functions. MDV LORF1 is unique to serotype I MDV (MDV-1), lacking homologs in other herpesviruses, and has not been explored yet. To this end, an infectious bacterial artificial chromosome (BAC) harboring the complete genome of the MDV-1 very virulent strain Md5 was generated, and the rescued rMd5 maintained biological properties similar to the parental virus both in vitro and in vivo. Subsequently, rMd5ΔLORF1, a recombinant Md5 virus deficient in pLORF1 expression, was generated by a frameshift mutation in the LORF1 gene. Chickens infected with rMd5ΔLORF1 exhibited a lower mortality rate and delayed bursal atrophy than those infected with the parental rMd5 and the revertant virus (rMd5-reLORF1). Consistently, viral loads of rMd5ΔLORF1 were obviously lower than those of rMd5 or rMd5-reLORF1 in the bursa, but not in the spleen. Importantly, we found that pLORF1 deficiency impairs viral replication in bursal B cells. Furthermore, we showed that pLORF1 associated with the cellular membrane, interacted with MDV structural proteins, and exhibited punctate colocalization with tegument or capsid proteins in the cytoplasm. Taken together, this study demonstrates for the first time that the MDV-1 unique gene LORF1 is involved in MDV-induced bursal atrophy but not in tumor formation. Author summary: Marek's disease virus (MDV) is an extensively studied alphaherpesvirus since it is not only a causative agent of Marek's disease (MD), a highly contagious poultry neoplastic disease posing a significant economic impact on the poultry industry worldwide, but also a comparative model for studying human oncogenic viruses. Although MD has been effectively controlled by massive vaccination since 1969, the continuous emergence of higher virulent strains creates challenges for preventing future outbreaks due to vaccine failure. Therefore, the characterization of unknown genes related to MDV-induced tumor formation and/or immune suppression is of great importance. In this study, we showed for the first time that LORF1, a unique gene of serotype 1 MDV, appears to affect viral replication within the bursa, consequently influencing bursal atrophy. Our findings reveal an essential role of LORF1 in immune suppression, suggesting its potential as a target gene for the development of an MDV gene deletion vaccine. [ABSTRACT FROM AUTHOR]