The human immunodeficiency virus matrix protein p17 plays a critical role in many steps of the virus life cycle. In addition, p17 displays biological activities outside infected cells. Indeed, virus-neutralizing antibodies against p17 in plasma of infected patients correlate with slower disease progression, and p17 has been shown to interact with an as yet unidentified cell surface receptor expressed on peripheral blood B cells. The present study investigated intracellular signaling pathways triggered following this interaction. Using protein/DNA arrays, we show that p17 increases phosphorylation and the DNA-binding activity of CREB and c-Myc through the time- and dose-dependent activation of the cAMP/PKA and MEK/ERK signaling pathways. Interestingly, we found that both signaling pathways are synergistically activated upon co-stimulation through the CD19 receptor. As both CREB and c-Myc are involved in the regulation of cell proliferation, differentiation, and survival, our findings might suggest a potential mechanism of B cell lymphomagenesis during HIV-1 infection.