Pivotal role of HIV and EBV replication in the long-term persistence of monoclonal gammopathy in patients on antiretroviral therapy

Ouedraogo, David Eric; Makinson, Alain; Vendrell, Jean-Pierre; Casanova, Marie-Laure; Nagot, Nicolas; Cezar, Renaud; Bolloré, Karine; Taaba, Yassine Al; Foulongne, Vincent; Badiou, Stéphanie; Viljoen, Johannes; Reynes, Jacques; Perre, Philippe Van de; Tuaillon, Édouard

doi:10.1182/blood-2012-12-470393

Cited by 18 publications

(14 citation statements)

References 23 publications

(29 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Kaposi sarcoma of the bone marrow or spleen, however, is rare and unlikely to be a major reason for hypo‐proliferative anaemia and other cytopenias. Plasma cell dyscrasias are increasingly appreciated in the backdrop of HIV infection and can contribute to cytopenias, rouleaux formation on peripheral blood smear, as well as monoclonal gammopathy of uncertain significance (Amara et al , ; Ouedraogo et al , ). Although not the focus of this review, it is worth noting that patients with well controlled HIV viraemia and lympho‐ and myelo‐proliferative malignancies, plasma cell dyscrasias and acute forms of leukaemia should be offered chemotherapy options like their HIV negative counterparts (Rubinstein et al , ).…”

Section: Direct Impact Of Tumours On Haematopoiesismentioning

confidence: 99%

Haematological manifestations of human immune deficiency virus infection

Vishnu

Aboulafia

2015

Br J Haematol

View full text Add to dashboard Cite

SummaryEarly in the human immunodeficiency virus (HIV) epidemic, infected patients presented to medical attention with striking abnormalities in each of the major blood cell lineages. The reasons for these derangements remain complex and multifactorial. HIV infects multipotent haematopoietic progenitor cells and establish latent cellular reservoirs, disturbs the bone marrow microenvironment and also causes immune dysregulation. These events lead to cytokine imbalances and disruption of other factors required for normal haematopoiesis. Activation of the reticulo-endothelial system can also result in increased blood cell destruction. The deleterious effects of medications, including first and second generation anti-retroviral agents, on haematopoiesis were well documented in the early years of HIV care; in the current era of HIV-care, the advent of newer and less toxic anti-retroviral drugs have had a more beneficial impact on haematopoiesis. Due to impaired regulation of the immune system and potential side effects of one or more anti-retroviral agents, there is also an increase in coagulation abnormalities such as thromboembolism, and less frequently, acquired disorders of coagulation including thrombotic thrombocytopenic purpura, immune thrombocytopenic purpura and acquired inhibitors of coagulation. In this article we review the epidemiology and aetiology of select non-oncological haematological disorders commonly seen in people living with HIV-acquired immune deficiency syndrome.

show abstract

Section: Direct Impact Of Tumours On Haematopoiesismentioning

confidence: 99%

Haematological manifestations of human immune deficiency virus infection

Vishnu

Aboulafia

2015

Br J Haematol

View full text Add to dashboard Cite

show abstract

“…Altogether the data presented in this study and our previous studies suggest that the EBV-dUTPase canalter the tumor microenvironment, based upon its novel functions as a PAMP, and immunopotentiate the pathophysiological effects towards tumor development. As shown in Figure 5, we propose that the infiltration of plasmablasts/plasma cells within the tumor microenvironment [74][75][76][77][78][79] results in the increased release of EBV-dUTPase from these cells due to lytic/ abortive-lytic replication of EBV [80][81][82]. Ligation of the EBV-dUTPase with TLR2 on CD14 + antigen presenting cells (APCs) and T-cells results in the activation of specific pathways (IL-6 and BIC/miR-155) that promote the proliferation/functioning of EBV-genome positive B-cells and simultaneously promote pathways (PD-1:PD-L1/L2; ICOS:ICOSL; IL-15/ IL-15R; IL-4I1; Egr-1 and PAG1) that modulate T-cell proliferation/function leading to T-cell tolerance/exhaustion.The outcome of these interactions between APCs and T-cells, via ligation/engagement of these pathways, in an environment in which effector T-cell proliferation and function are diminished coupled with an increased formation of a suppressive regulatory T-cell (Treg) population.…”

Section: Discussionmentioning

confidence: 91%

EBV-dUTPase Modulates Host Immune Responses Potentially Altering the Tumor Microenvironment in EBV-associated Malignancies

Mv¹

2016

Curr Res HIV/AIDS

View full text Add to dashboard Cite

While the use of long-term antiretroviral therapy (ART) has improved immune function and reduced the incidence of some malignancies in human immunodeficiency virus (HIV-1) infected patients, this is not the case for non-Hodgkin's lymphoma, an AIDS-defining cancer, and Hodgkin lymphoma, a non-AIDS defining cancer. Epstein-Barr virus (EBV) is an independent factor that adversely affects risk and/or survival among patients with Diffuse Large B cell Lymphoma (DLBCL) or classical Hodgkin lymphoma in immunocompetent patients as well as in HIV-1 infected individuals on ART. While cells infected with EBV in EBV-associated malignancies generally express one type of the latency programs, a small number of cells in these tumors are expressing EBV genes associated with lytic replication of the virus, which suggests that products from lytic or abortive-lytic replication may contribute to lymphomagenesis. However, the potential roles of these proteins in lymphomagenesis remain unclear. In this study we demonstrate that the EBV deoxyuridine triphosphate nucleotidohydrolase (dUTPase), an early protein produced during abortive/lytic EBV replication, is expressed in nasopharyngeal carcinoma (NPC) tumors in a mouse model of NPC, an EBV associated malignancy. Furthermore, screening of sera from 4 cohorts of patients diagnosed with AIDS, DLBCL, NPC and breast cancer (BC) by ELISA revealed an increase in IgG antibodies to the EBV-dUTPase in a subset of patients with AIDS, DLBCL and NPC relative to the controls. Finally, using an in vitro model of EBV infection we demonstrate that the EBV-dUTPase also inhibits T-cell function thus, allowing the proliferation of EBV immortalized B-cells. Altogether, our data support the premise that the EBV-dUTPase can modulate host immune responses and potentially alter the tumor microenvironment by promoting the survival/proliferation of immortalized B-cells, which may lead to lymphomagenesis.

show abstract

“…A consequence of such abnormal B cell activation is polyclonal hypergammaglobulinemia and abnormal autoantibody production. In some cases robust B cell activation may result in oligoclonal and monoclonal paraproteins . The natural history of these viral dependent monoclonal proteins and whether they signify an increased risk of HM in HIV remain unclear.…”

Section: Discussionmentioning

confidence: 99%

Retrospective study of the prevalence and progression of monoclonal gammopathy in HIV positive versus HIV negative patients

Jou

Gligich

Chan

et al. 2015

Hematological Oncology

View full text Add to dashboard Cite

The significance of HIV associated paraproteins and their risk of progression to hematological malignancies remains unclear. We compared the development of hematological malignancies among HIV+ (n = 266) and HIVÀ (n = 537) patients with monoclonal gammopathies. HIV+ and HIVÀ patients with a positive serum protein electrophoresis test (SPEP) were studied. HIV+ SPEP+ were more likely to have faint and oligoclonal paraproteins (F-SPEP) and less likely to have discrete bands (D-SPEP) compared to HIVÀ SPEP+. The incidence of hematological malignancies was significantly lower in the HIV+ compared to the HIVÀ (6.4% vs 15.4%, p < 0.0002). Upon subgroup analysis, the lower incidence of hematological malignancies was noted for HIV+ patients with F-SPEP but not for those with D-SPEP.

show abstract

Pivotal role of HIV and EBV replication in the long-term persistence of monoclonal gammopathy in patients on antiretroviral therapy

Cited by 18 publications

References 23 publications

Haematological manifestations of human immune deficiency virus infection

Haematological manifestations of human immune deficiency virus infection

EBV-dUTPase Modulates Host Immune Responses Potentially Altering the Tumor Microenvironment in EBV-associated Malignancies

Retrospective study of the prevalence and progression of monoclonal gammopathy in HIV positive versus HIV negative patients

Contact Info

Product

Resources

About