Immune Activation: Contribution to AIDS-Associated Non-Hodgkin Lymphoma

Abstract

HIV infection is associated with a greatly elevated risk for the development of non-Hodgkin lymphoma (NHL), which while diminished, remains elevated in the highly active antiretroviral therapy (HAART) era. Chronic B cell activation, driven by contact with HIV virions, B cell-stimulatory cytokines, viruses (EBV, HPV, HCV), and by high levels of antigenic stimulation occurs in HIV infected persons, and it is seen at even higher levels in those who go on to develop AIDS-NHL. Evidence from multiple studies indicates that elevated serum levels of several B cell-stimulatory cytokines and biomarkers are seen preceding AIDS-NHL, as well as in immunocompetent persons that develop NHL. Phenotypic changes in circulating B cells also are seen preceding AIDS-NHL, including the expression of AICDA, and of cell-surface molecules and miRNA that are associated with activated B cells. HAART only partially normalizes the immune system of treated HIV+ persons as they still show clear evidence for ongoing inflammation and immune activation in, even those who show complete suppression of HIV viremia. Together, this provides ample evidence to support the notion that chronic activation of B cells contributes to the genesis of B cell lymphomas.

Extracellular vesicles as biomarkers for AIDS-associated non-Hodgkin lymphoma risk

“…Dysregulated IL-6 signaling can contribute to the progression of pathological conditions, including cancer ( 56 ). In this study, we were interested in measuring IL-6Rα in EVs as IL-6 levels are significantly elevated in HIV-infected individuals years prior to an AIDS-NHL diagnosis ( 2 , 7 , 57 ). The elevated levels of EVs bearing IL-6Rα in pre-AIDS-NHL cases may bind cell membranes through receptor-ligand interactions and induce signaling in recipient cells.…”

“…Other tumor subtypes are primary central nervous system lymphoma (PCNSL), plasmablastic lymphoma (PBL), and primary effusion lymphoma (PEL), which is seen less frequently ( 2 , 4 – 6 ). Individuals with chronic HIV infection may develop lymphomas that are heterogenous in nature due to different pathogenic mechanisms that include chronic exposure to antigen, genetic mutations, dysregulation and production of pro-inflammatory cytokines, and the loss of immunoregulation of co-infections with oncogenic viruses [i.e., Epstein-Barr Virus (EBV), Kaposi’s sarcoma-associated herpesvirus (KSHV) or Human Herpesvirus 8 (HHV-8)] ( 1 , 4 , 5 , 7 ). HIV infection may directly drive lymphomagenesis, which can be dictated by HIV viremia, the depth of CD4 nadir, the immunosuppressive state of the individual, and/or delayed ART treatment or interruptions in treatment ( 1 , 2 , 5 , 7 – 10 ).…”

HIV-associated lymphomas

“…• для ВИЧ-положительных пациентов с ПЦНС, не получающих АРТ, рекомендуется ее инициация до начала терапии по поводу лимфомы; • даже при плохом соматическом статусе пациента и плохо контролируемом течении ВИЧ-инфекции рекомендуется рассмотрение возможности начала лечения стандартными курсами программной химиотерапии высокоагрессивных лимфом; • для пациентов с плохим соматическим статусом и не являющихся в связи с этим кандидатами для начала химиотерапии рекомендуется только лучевая терапия в качестве инициальной терапии [33][34][35][36][37].…”

Reframing Burkitt lymphoma: virology not epidemiology defines clinical variants

“…Elevated expression of AID in peripheral blood lymphocytes was detected prior to the emergence of BL in HIV+ patients ( 90 ) suggesting that dysregulation of AID is an early step prior to the MYC translocation. This is critical point as it leads to a hypothesis that chronic immune activation, regardless of inciting agent (e.g., viral or parasite) can drive the MYC translocation ( 96 ).…”