The molecular basis for HIV-1 susceptibility in primary human monocyte-derived macrophages (MDMs) was previously evaluated by comparing the transcriptome of infected and bystander populations. Careful analysis of the data suggested that the ubiquitin ligase MDM2 acted as a positive regulator of HIV-1 replication in MDMs. In this study， MDM2 silencing through transcript-specific small interfering RNAs in MDMs induced a reduction in HIV-1 reverse transcription and integration along with an increase in the expression of p53-induced genes， including Experiments with Nutlin-3， a pharmacological inhibitor of MDM2 p53-binding activity， showed a similar effect on HIV-1 infection， suggesting that the observed restriction in HIV-1 production results from the release/activation of p53 and not the absence of MDM2 Knockdown and inhibition of MDM2 also both correlate with a decrease in the Thr592-phosphorylated inactive form of SAMHD1. The expression level of MDM2 and the p53 activation status are therefore important factors in the overall susceptibility of macrophages to HIV-1 infection， bringing a new understanding of signaling events controlling the process of virus replication in this cell type. Macrophages， with their long life span and their resistance to HIV-1-mediated cytopathic effect， might serve as viral reservoirs， contributing to virus persistence in an infected individual. Identification of host factors that increase the overall susceptibility of macrophages to HIV-1 might provide new therapeutic targets for the efficient control of viral replication in these cells and limit the formation of reservoirs in exposed individuals. In this study， we demonstrate the importance of p53 regulation by MDM2， which creates a cellular environment more favorable to the early steps of HIV-1 replication. Moreover， we show that p53 stabilization reduces virus infection in human macrophages， highlighting the important role of p53 in antiviral immunity.