Proposed model of the pathogenesis of EBV-associated and EBV-unrelated lymphomas of HIV-infected patients. In a systemic background of immune suppression variably mitigated by cART, B lymphocytes are chronically activated by persistent antigenic stimulation, HIV virions bearing CD40L, HIV-released proteins (gp120, p17, Tat, etc), and various cytokines. Uncontrolled B-cell activation or EBV infection may upregulate CXCR2, an IL-8 receptor that may also serve as cellular receptor for HIV p17 and its variants. Triggering of CXCR2 by distinct p17 protein variants accumulated within nodal or extranodal lymphoid tissues may enhance B-cell clonogenicity and growth, thus increasing the likelihood of critical genetic alterations (chromosomal translocations involving c-MYC, Bcl-6 mutations, etc), which are also promoted by AID expression. In EBV-infected B cells, p17 variants may upregulate LMP-1, the major EBV oncoprotein, which further contributes to the development of EBV-associated lymphomas in this setting. In conditions of profound immune suppression, LMP-1 can be expressed by lymphoma cells, as it is the case of immunoblastic DLBCL, whereas the expression of this immunogenic EBV protein is silenced as immune escape mechanism in lymphomas associated with mild immunosuppression such as EBV-associated BL. HIV p17-mediated upregulation of LMP-1 may also contribute to the development of cHL in this setting.