Abstract Patients infected with human immunodeficiency virus‐1 (HIV‐1) have an increased incidence of B‐cell lymphoma, even though HIV‐1 does not infect B cells. The development of B‐cell lymphomas appears to be related to the action of the HIV‐1 transactivator protein (Tat), which is released from HIV‐infected cells and penetrates uninfected B cells, affecting host cell gene expression. Upon chronic HIV‐1 infection, Tat acts on the cells for a long time, probably allowing the cells to adapt to the presence of the viral protein. The aim of this work was to identify and study the mechanism of adaptation of cells to prolonged (chronic) exposure to HIV‐1 Tat. We performed a comparative analysis of cells expressing Tat under the action of either an inducible promoter or a constitutive promoter, allowing us to model acute and chronic Tat effects, respectively. We found that the acute action of Tat leads to the suppression of cell proliferation, probably due to the downregulation of genes associated with replication and protein synthesis. In the case of chronic action of Tat, cell proliferation was restored and the expression of genes associated with the implementation of protective (antiviral) functions of the cell was increased. Analysis using proteasome inhibitors showed that in the case of chronic action, intense Tat proteolysis occurred, which could be the main mechanism of B‐cell adaptation. Thus, B cells have a powerful mechanism to adapt to the entry of HIV‐1 Tat, the efficiency of which may determine the frequency of lymphomagenesis in HIV‐1‐infected patients.