Abstract Infection with human immunodeficiency virus (HIV) compromises the immune system leaving infected individuals vulnerable to other pathologies including cancer. HIV-infected patients have an increased risk of cancer development as compared to the general population. Primary effusion lymphoma (PEL), a high-grade non-Hodgkin lymphoma with very poor prognosis, typically affects individuals infected with HIV in advanced stages of acquired immune deficiency syndrome (AIDS). While the use of anti-HIV drugs is associated with better prognosis, treating cancer in HIV-infected patients is often challenging due to potential drug interactions between anti-cancer agents and antiretroviral drugs. We demonstrate that inhibition of the exportin-1 (CRM1/XPO1) mediated nuclear protein transport by SINE compounds results in effective suppression of HIV replication, which was quantified by measuring virus-associated core antigen (p24) by ELISA. In addition by using MTT, assays, Annexin staining, FACS and immunoblot analysis we demonstrated that XPO1 inhibition induced cell cycle arrest and apoptosis in PEL cell lines (BC-1, BCBL-1, and JSC-1) at similar doses. SINE blocked the nuclear export of the late viral partially and unspliced RNA species encoding for the viral structural proteins. In BC-1 PEL cells inhibition of XPO1 resulted in the nuclear accumulation of p53 tumor suppressor protein as well as inhibition of NF-κB activity. In vivo, oral administration twice a week for 4 weeks, 20 mg/kg of the clinical SINE compound selinexor (currently in phase I/II clinical trials) led to a significant suppression of the BC-1 PEL growth in vivo. These findings provide a strong basis for inhibiting XPO1 as a novel strategy for the combined treatment of HIV and PEL or other AIDS-related cancers. Disclosures Tamir: Karyopharm: Employment. Kauffman:Karyopharm: Employment, Equity Ownership. Shacham:Karyopharm: Employment, Equity Ownership. Landesman:Karyopharm: Employment.