A lymphomagenic role for HIV beyond immune suppression?

Abstract

Despite the immune reconstitution promoted by combined antiretroviral therapy (cART), lymphomas still represent the most common type of cancer in HIV-infected individuals. Cofactors related to immunodeficiency such as oncogenic viruses, chronic antigenic stimulation, and cytokine overproduction are thought to be the main drivers of HIV lymphomagenesis, although the current scenario does not convincingly explain the still-high incidence of lymphomas and the occurrence of peculiar lymphoma histotypes in HIV-infected patients under cART. Recent findings are challenging the current view of a mainly indirect role of HIV in lymphoma development and support the possibility that HIV may directly contribute to lymphomagenesis. In fact, mechanisms other than immune suppression involve biologic effects mediated by HIV products that are secreted and accumulate in lymphoid tissues, mainly within lymph node germinal centers. Notably, HIV-infected patients with lymphomas, but not those not affected by these tumors, were recently shown to carry HIV p17 protein variants with enhanced B-cell clonogenic activity. HIV p17 protein variants were characterized by the presence of distinct insertions at the C-terminal region of the protein responsible for a structural destabilization and the acquisition of novel biologic properties. These data are changing the current paradigm assuming that HIV is only indirectly related to lymphomagenesis. Furthermore, these recent findings are consistent with a role of HIV as a critical microenvironmental factor promoting lymphoma development and pave the way for further studies that may lead to the design of more effective strategies for an early identification and improved control of lymphomas in the HIV setting.

Figure 1

Main viral and molecular pathogenic pathways. Lymphomas in patients infected with HIV are heterogeneous, not only pathologically but also in terms of pathogenetic pathways and cellular derivation. The molecular pathway in HIV-associated BL involves activation of MYC (100% of cases), inactivation of p53 (50%-60% of cases), and infection by EBV (30%-50% of cases). Unclassifiable lymphomas with features intermediate between BL and DLBCL may occur. Molecular studies have shown rearrangements in BCL2 (and BCL6) and MYC genes. The molecular pathogenesis of HIV-associated centroblastic (CB) and immunoblastic (IB) DLBCL is complex and more heterogeneous. Infection with EBV occurs in 30% of DLBCL with CB morphology and 90% of DLBCL with IB and anaplastic (ALCL) morphology. Many EBV-positive IB DLBCLs express the EBV-encoded transforming protein LMP-1. There is an association between molecular changes in the BCL6 proto-oncogene and 20% of HIV-associated CB DLBCLs. Molecular studies of cells in PEL have shown no rearrangements in BCL1, BCL2, BCL6, and MYC genes. However, mutations in the BCL6 5′ noncoding region are common in PEL. In addition to consistent infection by KSHV, PELs are also commonly infected by EBV (80%). Regarding the molecular pathogenesis of PBL of the oral cavity type, EBV infection of the neoplastic clone has been frequently reported. In HIV-infected patients, nearly all cases of cHL are associated with EBV infection and express LMP-1.

Figure 2

HIV-released proteins within lymphoid follicles. Persistence of HIV-encoded proteins in the GC of lymphoid follicles in patients under cART. Histological sections from lymph node (A-C) and nasopharynx (D-E) were immunolabeled for the capsid p24 (B and D) and the matrix p17 (C,E) proteins. HIV p24 and p17 deposited in the GCs show similar distribution in the biopsy sites and display a dendritic pattern. Matrix p17 accumulates and persists within lymphoid tissues of HIV-infected patients in both lymph nodes and extranodal sites, where this protein may exert its pathogenic effects on B cells. Images were acquired with the Olympus Dot.Slide Virtual microscopy system, using an Olympus BX51 microscopy equipped with PLAN APO 2×/0.08 and UPLAN SApo 40×/0.95 objectives. Images were assembled using Adobe Photoshop 6 (Adobe Systems, San Jose, CA).

Figure 3

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.