HIV infection plays a role in accelerating aging. A mechanism known as cellular senescence has been previously recognized as a hallmark of aging. However, how HIV/SIV influences brain aging or how it affects the progression of neurological disorders relevant to cellular senescence is not well understood. In this study, the SIV-infected rhesus macaque model was used to characterize the contribution of SIV in the aging process of the brain. We performed in silico and in vitro experiments followed by in vivo studies. In addition, we developed a novel bioinformatic tool – MTD to facilitate the metatranscriptome analysis. Then, we further verify our findings by using MTD to perform data mining on the publicly shared raw data. We found that SIV replication is inhibited in senescent cells. Moreover, our results revealed the age disparities in brain cellular senescence response to SIV infection. During SIV infection, young animals are more prone to have cellular senescence in the brain, whereas old animals are more resistant to be induced to cellular senescence in the brain. We further found that old animals have enhanced antiviral function in senescent brain cells than young ones. Given that senescent cells in the brain contribute to cognitive decline and neurodegeneration, our findings indicate that they also play an important role in the acceleration of brain aging in SIV-infected young hosts and possibly contribute toward the development of HIV-associated neurocognitive disorders even with long-term antiretroviral therapy. Moreover, the association between abnormal behavior in rhesus macaques and SIV infection was studied by using the animal record database in TNPRC. Our study found that the SIV infection and Chinese-origin were two factors positively associated with the expression of abnormal behaviors in rhesus macaques.