Abstract: Objective To analyze the biological regulation and key proteins of brain tissue gene expression gene data in HIV-related neurocognitive disorder (HAND) patients, and to provide a new theoretical basis for HAND prevention and intervention. Methods Microarray gene chip data of brain tissue were downloaded from gene expression omnibus (GEO) public database including New York HAND patients (14 cases) and non-patients (7 cases), and the differential expression genes were imported into the analysis software gene-cloud of biotechnology informs (GCBI) experimental platform, GenClip 2.0 and Sytoscape 3.5.1. Exploring expression of protein interaction network, biological pathway, and the molecular mechanism of the development of HAND from the perspective of transcriptions. Results Compared with the control group, there were 780 (1.43%) differentially expressed genes between the two groups. The difference gene was mainly associated with immune response regulation, anti-infective, antiviral, cell signaling and synaptic transmission. LYN and RPS4Y1 genes are the key nodes of the protein-protein interaction network. DNM1, FLT1, NOTCH3, LYN, ISG15 and RPS4Y1 were the key expression genes. The DNM1, FLT1 and NOTCH3 genes were lower in the HAND group, while LYN, ISG15 and RPS4Y1 gene was highly expressed, and the difference was statistically significant (all P<0.05). Conclusions There were 780 differentially expressed genes in HAND patients and non-patients. LYN and RPS4Y1 genes are the core nodes of protein network and are highly expressed in brain tissue of HAND patients. The function mainly includes immune response, immune regulation, anti-infection, anti-virus and other biological functions.