Role of HIV-1 matrix protein p17 variants in lymphoma pathogenesis

Dolcetti, Riccardo; Giagulli, Cinzia; He, Wangxiao; Selleri, Marina; Caccuri, Francesca; Eyzaguirre, Lindsay M.; Mazzuca, Pietro; Corbellini, Silvia; Campilongo, Federica; Marsico, Stefania; Giombini, Emanuela; Muraro, Elena; Rozera, Gabriella; Paoli, Paolo De; Carbone, Antonino; Capobianchi, Maria Rosaria; Ippolito, Giuseppe; Fiorentini, Simona; Blattner, William A.; Lu, Wuyuan; Gallo, Robert C.; Caruso, Arnaldo

doi:10.1073/pnas.1514748112

Cited by 63 publications

(117 citation statements)

References 32 publications

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“…B cells were negatively isolated from unstimulated PBMCs using the EasySep Human B Cell Enrichment Kit without CD34 Depletion (Stem Cell Technologies) and were cultured in complete RPMI-1640. Cells were activated with soluble 1 μg/mL CD40L (MEGACD40L; Enzo Life Sciences) and 10 ng/mL IL-4 (R&D Systems) for 5 d. HPLC-purified HIV-1 BH10 p17 was chemically synthesized via solid-phase peptide synthesis by W. Lu, Institute of Human Virology, University of Maryland School of Medicine, Baltimore, as reported previously (12).…”

Section: Methodsmentioning

confidence: 99%

“…It was recently reported that extracellular matrix protein p17 and particular genetic variants signal to B cells to enhance growth and induce chemotaxis (12,18,19). Moreover, proviral sequences for variant p17s that display B-cell growth-promoting activity can be found in HIV-NHL tissues, suggesting a role for variant p17s in lymphoma pathogenesis (12).…”

Section: Significancementioning

confidence: 99%

“…Moreover, proviral sequences for variant p17s that display B-cell growth-promoting activity can be found in HIV-NHL tissues, suggesting a role for variant p17s in lymphoma pathogenesis (12). In addition to its effects on B cells, p17 can induce angiogenesis/lymphangiogenesis in vitro and in vivo (20)(21)(22).…”

Section: Significancementioning

confidence: 99%

“…From this perspective, an intriguing possibility is that HIV itself may contribute to lymphomagenesis more directly through biological effects of HIV proteins (12,13). HIV-1 matrix p17, capsid p24, and envelope glycoprotein (gp) 120 accumulate and persist in lymphoid tissues for at least 1 y after cART, in the absence of viral replication (14).…”

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confidence: 99%

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Expression of HIV-1 matrix protein p17 and association with B-cell lymphoma in HIV-1 transgenic mice

Carroll

Lafferty

Marchionni

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

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HIV-1 infection is associated with increased risk for B-cell lymphomas. How HIV infection promotes the development of lymphoma is unclear, but it may involve chronic B-cell activation, inflammation, and/or impaired immunity, possibly leading to a loss of control of oncogenic viruses and reduced tumor immunosurveillance. We hypothesized that HIV structural proteins may contribute to lymphomagenesis directly, because they can persist long term in lymph nodes in the absence of viral replication. The HIV-1 transgenic mouse Tg26 carries a noninfectious HIV-1 provirus lacking part of the gag-pol region, thus constituting a model for studying the effects of viral products in pathogenesis. Approximately 15% of Tg26 mice spontaneously develop leukemia/lymphoma. We investigated which viral proteins are associated with the development of leukemia/lymphoma in the Tg26 mouse model, and performed microarray analysis on RNA from spleen and lymph nodes to identify potential mechanisms of lymphomagenesis. Of the viral proteins examined, only expression of HIV-1 matrix protein p17 was associated with leukemia/lymphoma development and was highly expressed in bone marrow before disease. The tumor cells resembled pro-B cells, and were CD19(+)IgM(-)IgD(-)CD93(+)CD43(+)CD21(-)CD23(-)VpreB(+)CXCR4(+) Consistent with the pro-B-cell stage of B-cell development, microarray analysis revealed enrichment of transcripts, including Rag1, Rag2, CD93, Vpreb1, Vpreb3, and Igll1 We confirmed RAG1 expression in Tg26 tumors, and hypothesized that HIV-1 matrix protein p17 may directly induce RAG1 in B cells. Stimulation of human activated B cells with p17 enhanced RAG1 expression in three of seven donors, suggesting that intracellular signaling by p17 may lead to genomic instability and transformation

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Section: Methodsmentioning

confidence: 99%

Section: Significancementioning

confidence: 99%

Section: Significancementioning

confidence: 99%

mentioning

confidence: 99%

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Expression of HIV-1 matrix protein p17 and association with B-cell lymphoma in HIV-1 transgenic mice

Carroll

Lafferty

Marchionni

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

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“…In fact, recent evidence indicates that HIV-encoded proteins endowed with peculiar biologic effects on B lymphocytes are secreted and accumulate in lymphoid tissues, mainly within lymph node germinal centers, where they may act as critical microenvironmental factors promoting lymphoma development. 7,8 Moreover, recent studies have shown that HIV viremia during highly active antiretroviral therapy is a predictor of HIV-associated lymphomas. Overall, these findings add further strength to the argument that HIV may directly contribute to lymphomagenesis.…”

Section: Introductionmentioning

confidence: 99%

A lymphomagenic role for HIV beyond immune suppression?

Dolcetti

Gloghini

Caruso

et al. 2016

Blood

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105

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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.

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Expression and prognostic significance of the PD‐1/PD‐L1 pathway in AIDS‐related non‐Hodgkin lymphoma

Zhao,

Cai,

Xiao

et al. 2024

Cancer Medicine

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ObjectiveImmune tolerance and evasion play a critical role in virus‐driven malignancies. However, the phenotype and clinical significance of programmed cell death 1 (PD‐1) and its ligands, PD‐L1 and PD‐L2, in aggressive acquired immunodeficiency syndrome (AIDS)‐related non‐Hodgkin lymphoma (AR‐NHL) remain poorly understood, particularly in the Epstein–Barr virus (EBV)‐positive subset.MethodsWe used in situ hybridization with EBV‐encoded RNA (EBER) to assess the EBV status. We performed immunohistochemistry and flow cytometry analysis to evaluate components of the PD‐1/PD‐L1/L2 pathway in a multi‐institutional cohort of 58 patients with AR‐NHL and compared EBV‐positive and EBV‐negative cases.ResultsThe prevalence of EBV+ in AR‐NHL was 56.9% and was associated with a marked increase in the expression of PD‐1/PD‐L1/PD‐L2 in malignant cells. Patients with AR‐NHLs who tested positive for both EBER and PD‐1 exhibited lower survival rates compared to those negative for these markers (47.4% vs. 93.8%, p = 0.004). Similarly, patients positive for both EBER and PD‐L1 also demonstrated poorer survival (56.5% vs. 93.8%, p = 0.043). Importantly, PD‐1 tissue‐expression demonstrated independent prognostic significance for overall survival in multivariate analysis and was correlated to elevated levels of LDH (r = 0.313, p = 0.031), increased PD‐1+ Tregs (p = 0.006), and robust expression of EBER (r = 0.541, p < 0.001) and PD‐L1 (r = 0.354, p = 0.014) expression.ConclusionsThese data emphasize the importance of PD‐1‐mediated immune evasion in the complex landscape of immune oncology in AR‐NHL co‐infected with EBV, and contribute to the diagnostic classification and possible definition of immunotherapeutic strategies for this unique subgroup.

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Role of HIV-1 matrix protein p17 variants in lymphoma pathogenesis

Cited by 63 publications

References 32 publications

Expression of HIV-1 matrix protein p17 and association with B-cell lymphoma in HIV-1 transgenic mice

Expression of HIV-1 matrix protein p17 and association with B-cell lymphoma in HIV-1 transgenic mice

A lymphomagenic role for HIV beyond immune suppression?

Expression and prognostic significance of the PD‐1/PD‐L1 pathway in AIDS‐related non‐Hodgkin lymphoma

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