Latent Membrane Protein 1 Deletion Mutants Accumulate in Reed-Sternberg Cells of Human Immunodeficiency Virus-Related Hodgkin's Lymphoma

Giusti, Massimo; Ponzoni, Maurilio; Caggiari, Laura; Lettini, Antonia Anna; Vago, Luca; Re, Vallì De; Gloghini, Annunziata; Zancai, Paola; Carbone, Antonino; Boiocchi, Mauro; Dolcetti, Riccardo

doi:10.1128/jvi.79.4.2643-2649.2005

Cited by 13 publications

(10 citation statements)

References 27 publications

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“…34 The accumulation of mutational events may probably be enhanced by processes such as somatic hypermutation and immunoglobulin class switching that are associated to the persistent condition of B-cell activation characterizing HIV-infected individuals. 34,35 An analogous mechanism may be hypothesized for the generation of BZLF1 promoter variants from an unmutated ancestor. The progressive accumulation of mutational events during latent infection, may generate EBV variants that are selected for their transforming potential and/or for their ability to escape immune defenses.…”

Section: Discussionmentioning

confidence: 99%

Characterization of variants in the promoter of EBV gene BZLF1 in normal donors, HIV-positive patients and in AIDS-related lymphomas

Martini

Capello

Serraino

et al. 2007

Journal of Infection

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Section: Discussionmentioning

confidence: 99%

Characterization of variants in the promoter of EBV gene BZLF1 in normal donors, HIV-positive patients and in AIDS-related lymphomas

Martini

Capello

Serraino

et al. 2007

Journal of Infection

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“…37,38 Thus, the clonal expansion of Hodgkin-and Reed-Sternberg cells in HIV-associated Hodgkin lymphoma probably shares several features of transformation with EBV-infected Hodgkin-and Reed-Sternberg cells arising in different conditions of immunosuppression like peripheral T-cell lymphomas, 39 B-chronic lymphocytic leukemia, 40,41 or EBVpositive diffuse large B-cell lymphoma of the elderly. 42 In concert with the particular composition of the microenvironment, we propose that HIV-related Hodgkin lymphoma associated with a high content of spindle-shaped macrophages and low CD4 þ T-cell content represents a unique subtype of classical Hodgkin lymphoma, which should be recognized by pathologists.…”

Section: Discussionmentioning

confidence: 99%

Spindle-shaped CD163+ rosetting macrophages replace CD4+ T-cells in HIV-related classical Hodgkin lymphoma

et al. 2013

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Combination antiretroviral therapy is highly effective in HIV infection, leading to decreased incidences of AIDSdefining neoplasms. However, HIV patients still have a 10-fold increased risk of developing classical Hodgkin lymphoma compared with the general population. As Hodgkin-and Reed-Sternberg cells represent only a minority in the tumor infiltrate, the aim of the present study was to characterize the microenvironment of HIV-related classical Hodgkin lymphoma and compare it with classical Hodgkin lymphoma cases of immunocompetent individuals. The major morphologic differences were the presence of necrotic foci and the absence of epithelioid cell formation in HIV-related Hodgkin lymphoma. We observed a significantly decreased number of CD4 þ T-cells and a significantly increased number of CD163 þ macrophages in HIVrelated Hodgkin lymphoma. Cases exhibiting a 'sarcomatoid' pattern of the reactive infiltrate exhibited significantly greater numbers of macrophages, associating the 'sarcomatoid' pattern to the presence of spindle-shaped macrophages. Whereas, rosetting of CD4 þ T-cells around Hodgkin-and Reed-Sternberg cells was frequently observed in classical Hodgkin lymphoma in immunocompetent persons; rosetting in a subset of HIV-related Hodgkin lymphoma cases appeared to involve cytoplasmic protrusions of spindle-shaped macrophages. HIV-related Hodgkin lymphoma, therefore, is characterized by unique morphologic features, which should be recognized by pathologists.

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“…EBV types (EBV1 and EBV2) were determined by amplification of strain-specific regions of EBNA3C and EBNA2 genes, as described [Sample et al, 1990;Hassan et al, 2006]. Del30, as well as the number of 33 bp tandem repeats in LMP1 C-ter region were characterized by PCR assays [Khanim et al, 1996;Guidoboni et al, 2005]. PCR products were electrophoresed through pre-cast 12% polyacrilamide gels in a GenePhor TM Electrophoresis System (Amersham Biosciences, Uppsala, Sweden), followed by silver staining.…”

Section: Pcr Amplifications and Dna Sequencingmentioning

confidence: 99%

“…C-ter LMP1 fragment [nucleotide positions 168,209-168,649; amino acids (aa), 225-366] was amplified by PCR with primers 1s 5 0 -CCACCTGCTCGTGAGTG-GAGC-3 0 and 1as 5 0 -CCACCGGAACCAGAAGAACCC-3 0 as described by Guidoboni et al [2005]. Reactions were carried out using High Fidelity Platinum Taq polymerase (Invitrogen, Carlsbad, CA).…”

Section: Pcr Amplifications and Dna Sequencingmentioning

confidence: 99%

“…Del30 variant was found only in 7.4% of the Argentine healthy population [Correa et al, 2004], while it was described in about 60% of Brazilian non-neoplastic cases [Hayashi et al, 1997]. Thus, it is not clear whether the high del30 frequency in EBV-related cancers merely reflects the geographical predominance of these variants or is rather due to special virus-host interactions leading to enhanced production and/or selection of LMP1 deletion mutants [Guidoboni et al, 2005]. To address this issue C-ter LMP1 region was examined in a group of immunocompetent EBVþ Hodgkin's lymphoma along with non-neoplastic controls from South America, assessing sequence variability throughout C-ter region in both deleted and wild type LMP1 EBV variants.…”

Section: Introductionmentioning

confidence: 99%

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Structural variability of the carboxy‐terminus of Epstein–Barr virus encoded latent membrane protein 1 gene in Hodgkin's lymphomas

Guiretti

Chabay

Valva

et al. 2007

Journal of Medical Virology

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Epstein-Barr virus (EBV) is implicated in the pathogenesis of several lymphoid and epithelial neoplasms. Latent membrane protein 1 (LMP1) is the major viral oncogene and it is controversial whether tumor LMP1 variants reflect their geographical predominance or are associated with enhanced oncogenic properties. This study aimed to analyze LMP1 molecular variability of 62 EBV+ Hodgkin's lymphomas and 22 non-neoplastic controls from Brazil and Argentina. EBV association was characterized by EBER-ISH, LMP1 immunohistochemistry and PCR assays for EBNA2 and 3C (typing), LMP1 30 bp deletion (del30) and number of 33 bp tandem repeats. LMP1 C-terminal sequencing was performed in 42 cases. EBV1 was the predominant strain in both geographical Hodgkin's lymphoma groups (average 82%). A higher frequency of del30 variant was observed in lymphomas (41/63) than in non-neoplastic controls (6/22) (OR 4.97, CI 95% 1.53-16.79; P = 0.005, chi(2) test). A large number (5-7) of 33 bp repeat units was characteristic of del30 LMP1 variants (P < 0.0001, Fisher's exact test). Sequence analysis showed a similar mutation spectrum to that described worldwide but none of the current classification schemes could be applied completely. A distinct structural pattern was observed in del30 variants, characterized by a large number of 33 bp repeat units and the presence of a 15 bp insertion encoding the JAK3 Box-1a motif (3/15 wt vs. 16/20 del30; P = 0.001, chi(2) test). The results suggest a pathogenic role for LMP1 del30 variants in Hodgkin's lymphoma from South America and point to particular virus-host molecular mechanisms, such as genomic instability in LMP1 carboxy-terminus, leading to enhanced production and selection of these deletion variants.

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Latent Membrane Protein 1 Deletion Mutants Accumulate in Reed-Sternberg Cells of Human Immunodeficiency Virus-Related Hodgkin's Lymphoma

Cited by 13 publications

References 27 publications

Characterization of variants in the promoter of EBV gene BZLF1 in normal donors, HIV-positive patients and in AIDS-related lymphomas

Characterization of variants in the promoter of EBV gene BZLF1 in normal donors, HIV-positive patients and in AIDS-related lymphomas

Spindle-shaped CD163+ rosetting macrophages replace CD4+ T-cells in HIV-related classical Hodgkin lymphoma

Structural variability of the carboxy‐terminus of Epstein–Barr virus encoded latent membrane protein 1 gene in Hodgkin's lymphomas

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