Epstein–Barr virus (EBV) and Kaposi’s sarcoma-associated herpesvirus (KSHV), which are the only members of the gamma(γ) herpesviruses, are oncogenic viruses that significantly contribute to the development of various human cancers, such as Burkitt’s lymphoma, nasopharyngeal carcinoma, Hodgkin’s lymphoma, Kaposi’s sarcoma, and primary effusion lymphoma. Oncogenesis triggered by γ-herpesviruses involves complex interactions between viral genetics, host cellular mechanisms, and immune evasion strategies. At the genetic level, crucial viral oncogenes participate in the disruption of cell signaling, leading to uncontrolled proliferation and inhibition of apoptosis. These viral proteins can modulate several cellular pathways, including the NF-κB and JAK/STAT pathways, which play essential roles in cell survival and inflammation. Epigenetic modifications further contribute to EBV- and KSHV-mediated cancerogenesis. Both EBV and KSHV manipulate host cell DNA methylation, histone modification, and chromatin remodeling, the interplay of which contribute to the elevation of oncogene expression and the silencing of the tumor suppressor genes. Immune factors also play a pivotal role in the development of cancer. The γ-herpesviruses have evolved intricate immune evasion strategies, including the manipulation of the major histocompatibility complex (MHC) and the release of cytokines, allowing infected cells to evade immune detection and destruction. In addition, a compromised immune system, such as in HIV/AIDS patients, significantly increases the risk of cancers associated with EBV and KSHV. This review aims to provide a comprehensive overview of the genetic, epigenetic, and immune mechanisms by which γ-herpesviruses drive cancerogenesis, highlighting key molecular pathways and potential therapeutic targets.

Background: The interaction between HIV-1 and host immune cells, particularly macrophages, is crucial in understanding viral persistence and pathogenesis. This study aims to explore the impact of HIV-1 infection on macrophage microRNA (miRNA) expression profiles using a systems biology approach to uncover the potential role of miRNAs in modulating macrophage functionality and identify key miRNA targets that may serve as therapeutic avenues. Methods: PMA-differentiated THP-1 cells were used to model macrophage infection with HIV-1. A custom miRNA microarray was performed to identify dysregulated miRNAs following infection. miRTarBase was utilized for miRNA target identification, revealing gene targets associated with the dysregulated miRNAs. A protein-protein interaction (PPI) map of miRNA targets and their first interactors was constructed, with key nodes identified based on a calculated disease score, which considered degree, betweenness centrality, average shortest path length, and clustering coefficient. Gene Ontology molecular function analysis was also conducted on the identified targets. Results: The miRNA microarray identified 23 dysregulated miRNAs in HIV-1-infected macrophages, with 8 upregulated and 15 downregulated. Among these, the top 10 dysregulated miRNAs targeted over 2000 unique genes. PPI analysis revealed key nodes in the upregulated miRNA network, including APP , MYC , ESR2 , RAF1 , and HIST1H4A , while ZRANB1 , HSPA8 , TGOLN2 , HSPA5 , and BRD4 were prominent in the downregulated miRNA network. Notably, KRAS , CUL3 , TP53 , ESR1 , and PARP1 were influenced by both upregulated and downregulated miRNAs. Gene Ontology analysis indicated that the targeted genes were involved in processes such as protein and RNA binding, ATPase activity, and ribosomal function. Conclusions: HIV-1 infection induces significant dysregulation of miRNAs in macrophages, impacting a wide array of gene targets and molecular functions. These findings suggest that miRNA-mediated regulation may play a crucial role in HIV-1 pathogenesis within macrophages and present potential targets for miRNA-based therapeutic strategies.