Molecular Biology of EBV in Relationship to HIV/AIDS-Associated Oncogenesis.

Herpesvirus-induced disease is one of the most lethal factors which leads to high mortality in HIV/AIDS patients. EBV, also known as human herpesvirus 4, can transform naive B cells into immortalized cells in vitro through the regulation of cell cycle, cell proliferation, and apoptosis. EBV infection is associated with several lymphoma and epithelial cancers in humans, which occurs at a much higher rate in immune deficient individuals than in healthy people, demonstrating that the immune system plays a vital role in inhibiting EBV activities. EBV latency infection proteins can mimic suppression cytokines or upregulate PD-1 on B cells to repress the cytotoxic T cells response. Many malignancies, including Hodgkin Lymphoma and non-Hodgkin's lymphomas occur at a much higher frequency in EBV positive individuals than in EBV negative people during the development of HIV infection. Importantly, understanding EBV pathogenesis at the molecular level will aid the development of novel therapies for EBV-induced diseases in HIV/AIDS patients.

Survival and predictors of death in people with HIV-associated lymphoma compared to those with a diagnosis of lymphoma in general population.

OBJECTIVES: to compare overall survival in HIV-associated lymphoma (HIV-L) and lymphoma raising in HIV-negative population (nHIV-L) and to identify predictors of increased risk of death. METHODS: All HIV+ patients with HIV-associated lymphoma (Hodgkin lymphoma, HL; non-Hodgkin Lymphoma, NHL) observed between 1.2000 and 12.2013 in the ICONA Foundation Study cohort or in three collaborating centres, and, as control group, nHIV-L individuals followed in one of the four collaborating centres over the same time period, were included. Survival estimates were calculated by use of Kaplan-Meier (KM) and multivariable Cox regression models. RESULTS: 1,331 pts were included (465 HIV-L, 866 nHIV-L): 909 (68%) NHL, 422 (32%) HL. 3 years-cumulative probability (95% confidence interval, CI) of death was higher in HIV-L compared to nHIV-L in NHL (38% (33-44) vs. 22% (19-26); p<0.001), and HL (22% [15-29] vs. 10% (6-13), p<0.001). Among HL, HIV was associated with an increased risk of death (hazard ratio [HR] = 2.37 [95% CI: 1.24-4.55], p = 0.009) independently of calendar year, age, gender, type of chemotherapy and stage; in NHL, HIV was no longer an independent predictor of death after controlling for rituximab use and IPI (HR = 1.26 (0.97-1.63), p = 0.08). CONCLUSIONS: Our analysis shows a reduced overall survival in HIV+ patients diagnosed with lymphoma compared to HIV-negative controls. Whereas in HIV people with HL, the increased risk of death was confirmed even after adjustment for main confounders, the association between HIV status and survival in NHL appears to be somewhat attenuated after controlling for more aggressive presentation and lower frequency of rituximab use in HIV-+ people.

HIV-1 matrix protein p17 promotes lymphangiogenesis and activates the endothelin-1/endothelin B receptor axis.

OBJECTIVE: AIDS-related lymphomas are high grade and aggressively metastatic with poor prognosis. Lymphangiogenesis is essential in supporting proliferation and survival of lymphoma, as well as tumor dissemination. Data suggest that aberrant lymphangiogenesis relies on action of HIV-1 proteins rather than on a direct effect of the virus itself. HIV-1 matrix protein p17 was found to accumulate and persist in lymph nodes of patients even under highly active antiretroviral therapy. Because p17 was recently found to exert a potent proangiogenic activity by interacting with chemokine (C-X-C motif) receptors 1 and 2, we tested the prolymphangiogenic activity of the viral protein. APPROACH AND RESULTS: Human primary lymph node-derived lymphatic endothelial cells were used to perform capillary-like structure formation, wound healing, spheroids, and Western blot assays after stimulation with or without p17. Here, we show that p17 promotes lymphangiogenesis by binding to chemokine (C-X-C motif) receptor-1 and chemokine (C-X-C motif) receptor-2 expressed on lymph node-derived lymphatic endothelial cells and activating the Akt/extracellular signal-regulated kinase signaling pathway. In particular, it was found to induce capillary-like structure formation, sprout formation from spheroids, and increase lymph node-derived lymphatic endothelial cells motility. The p17 lymphangiogenic activity was, in part, sustained by activation of the endothelin-1/endothelin receptor B axis. A Matrigel plug assay showed that p17 was able to promote the outgrowth of lymphatic vessels in vivo, demonstrating that p17 directly regulates lymphatic vessel formation. CONCLUSIONS: Our results suggest that p17 may generate a prolymphangiogenic microenvironment and plays a role in predisposing the lymph node to lymphoma growth and metastasis. This finding offers new opportunities to identify treatment strategies in combating AIDS-related lymphomas.

HHV-8 large T-cell lymphoma: an unusual malignancy amidst more common B-cell lymphomas in HIV-positive children treated at a single institution.

Non-Hodgkin lymphomas of B-cell origin are the most commonly encountered HIV-related lymphomas in adults and children. These lymphomas are often extranodal, involve the central nervous system or other sites, and have been found to behave in a more aggressive manner. We report an unusual case of a child with HHV-8-positive large T-cell lymphoma.

Alterations of negative regulators of cytokine signalling in immunodeficiency-related non-Hodgkin lymphoma.

We investigated immunodeficiency-related non-Hodgkin lymphoma for the presence of molecular alterations affecting negative regulators of the Janus family protein tyrosine kinase/signal transducer and activator of transcription pathway. Protein tyrosine phosphatase, non-receptor type 6/Src homology 2-containing tyrosine phosphatase-1 epigenetic silencing was recurrent in primary effusion lymphoma (100%), and diffuse large B-cell lymphoma (63%), with a higher prevalence in the non-germinal centre subtype, and was associated with the activation of the Janus family protein tyrosine kinase/signal transducer and activator of transcription 3 pathway. Suppressor of cytokine signalling (SOCS)1 and SOCS3 epigenetic silencing were occasionally detected, whereas SOCS1 was frequently mutated in diffuse large B-cell lymphoma and polymorphic post-transplant lymphoproliferative disorders, possibly as a cause of aberrant somatic hypermutation. However, the mutation profile of the coding region of the gene was different from that expected from the aberrant somatic hypermutation process, suggesting that, at least in some cases, SOCS1 mutations may have been selected for their functional activity.

HIV-1 nef protein visits B-cells via macrophage nanotubes: a mechanism for AIDS-related lymphoma pathogenesis?

This letter refers to the recent demonstration that HIV-1 infected macrophages form specialized conduits that connect to B-cells (1). The conduit selectively transports the HIV-1 nef protein, providing nef with numerous means to interfere with cellular processes. Currently, no consideration of the connection between the conduit and the development of AIDS-related lymphoma (ARL) has been offered. ARL is one of the primary causes of death in the HIV-infected population and is related to B-cell proliferation and activation. In this letter we discuss several studies that link HIV-infected macrophages and specific forms of the nef protein to the development of ARL. The conduits discovered by Xu et al. may lead to a better understanding of how HIV infection results in lymphomagenesis.

Whole brain radiation alone produces favourable outcomes for AIDS-related primary central nervous system lymphoma in the HAART era.

Primary central nervous system lymphoma (PCNSL) related to acquired immunodeficiency syndrome (AIDS) is a lethal disorder, but the recent application of highly active antiretroviral therapy (HAART) has significantly improved prognosis. This retrospective cohort study of AIDS-related PCNSL examined the actual clinical outcomes and prognostic variables affecting overall survival (OS) in the HAART era. Twenty-three newly diagnosed AIDS-related PCNSL at 12 regional centre hospitals for HIV/AIDS in Japan between 2002 and 2008 were consecutively enrolled. The estimated 3-yr OS rate of the entire cohort was 64% (95%CI, 41.0-80.3%). Whole brain radiation therapy (WBRT) had an independent positive impact on survival (WBRT >or=30 Gy vs. others, P = 0.02). Nine of 10 patients with a good performance status (PS) (0-2) remained alive with complete response, whereas 10 (77%) of 13 of those with a poor PS (3-4) died mostly after a short period. The estimated 3-yr OS rate of the groups with a good and poor PS was 100% and 38% (95%CI, 14-63%), respectively (P = 0.01). Leukoencephalopathy (grade >or= 2) developed in 21% of those that survived more than 12 months after radiation. The patients receiving a curative intent radiation dose (>or=30 Gy) of WBRT achieved prolonged survival while maintaining a good quality of life in the HAART era, especially among patients with a favourable PS.

Viral hepatitis is associated with reduced bone mineral density in HIV-infected women but not men.

OBJECTIVE: Few studies have examined the impact of viral hepatitis on bone mineral density (BMD), and none have done so among HIV-infected patients. Our objective was to determine whether viral hepatitis was associated with low BMD in HIV. DESIGN: : A cross-sectional study among 1237 HIV-infected patients (625 with viral hepatitis). METHODS: Dual-energy X-ray absorptiometry scans of the lumbar spine and femoral neck were obtained. Clinical data, hepatitis B and C status, and markers of bone metabolism were determined at dual-energy X-ray absorptiometry scanning. Multivariable logistic regression examined the association between hepatitis and low BMD (Z-score < or =-2.0 at the lumbar spine, femoral neck, or both). RESULTS: Mean BMD Z-scores were lower among hepatitis-coinfected women at the lumbar spine {-0.15 versus +0.29; difference = -0.44 [95% confidence Interval (CI) -0.65 to -0.23]; P < 0.001} and femoral neck [-0.64 versus -0.39; difference = -0.25 (95% CI -0.44 to -0.06); P = 0.009] compared with HIV-monoinfected women. No differences in mean BMD Z-scores were observed between coinfected and monoinfected men. After adjustment for age, BMI, duration of HIV, antiretroviral use, physical activity, and smoking, viral hepatitis was associated with low BMD among women (adjusted odds ratio 2.87, 95% CI 1.31-6.29) but not men (adjusted odds ratio 1.19, 95% CI 0.74-1.91). Coinfected women had lower mean parathyroid hormone (60.1 versus 68.1 pg/ml; P = 0.02) but similar mean 25-hydroxyvitamin D (19.1 versus 19.6 ng/ml; P = 0.6) and osteocalcin (3.0 versus 3.2 ng/ml; P = 0.8) concentrations than HIV-monoinfected women. CONCLUSION: Viral hepatitis was associated with a higher risk of low BMD among HIV-infected women but not men.

Plasmablastic lymphoma of the oral cavity: a rapidly progressive lymphoma associated with HIV infection.

Plasmablastic lymphoma of the oral cavity is a form of non-Hodgkin lymphoma (NHL) and was first described in 1997. We describe a case of plasmablastic lymphoma in an HIV-infected patient who presented with an expanding oral lesion and symptoms of a toothache. We review all cases of plasmablastic lymphoma that have been reported in the literature. Plasmablastic lymphoma is strongly associated with immunodeficiency, and most particularly, with HIV infection. The pathophysiological origin of plasmablastic lymphoma has not been fully characterised, but the presence of Epstein-Barr virus (EBV) has often been documented in biopsy specimens, supporting a role for EBV in the pathogenesis of this lymphoma. The differential diagnosis for an expanding oral lesion includes both infectious and malignant processes. Biopsy is essential for making a correct and prompt diagnosis. Treatment usually involves chemotherapy, but antiretroviral therapy may also have an important role. Infectious disease clinicians should be aware of this newly described and increasingly encountered lymphoma, since it is prominently associated with immunosuppression and may be mistaken for other entities.

Improving outcomes for patients with Burkitt lymphoma and HIV.

Burkitt lymphoma (BL) is a highly aggressive B-cell malignancy that occurs with increased frequency among patients infected with HIV. Until recently, the immunocompromised state of patients with HIV and BL was generally deemed to preclude the use of the intensive chemotherapeutic regimens used to treat HIV-negative patients due to toxicity issues. However, the advent of highly active antiretroviral therapy (HAART) and the mounting evidence that less intensive lymphoma regimens are ineffective in BL have led investigators to treat HIV-positive patients with the same chemotherapy now established as the standard of care for immunocompetent patients. Data suggest that these current approaches, along with supportive care, may result in improved patient outcomes. In contrast, the role of adjunctive immunotherapy with rituximab in HIV-BL remains undefined. Further studies, including randomized clinical trials, are needed to better delineate the optimal treatment for patients with this devastating disease.

Highly active antiretroviral therapy as the sole treatment for AIDS-related primary central nervous system lymphoma: a case report with implications for treatment.

A 40-year-old male presented to medical attention with Pneumocystis jiroveci pneumonia and HIV infection. His CD4+ count was 18 cells per microliter and his HIV viral load (VL) was more than 400,000 copies milliliter. After 3 weeks of antibiotic therapy, he continued to have global cognitive deficits. A brain imaging study showed a right temporal mass, which on biopsy proved to be primary central nervous system lymphoma (PCNSL). He began highly active antiretroviral therapy (HAART) but declined palliative whole-brain radiotherapy (WBRT). Four months later, his CD4+ count had improved to 153 cells per microliter and his HIV VL was less than 75 copies per milliliter. At 36 months follow-up, he remained in complete remission (CR). Through a literature review, we identified 4 additional PCNSL patients who achieved prolonged remission after the initiation of HAART. One patient required WBRT and ventriculo-peritoneal shunting for signs and symptoms of obstructive hydrocephalus. The other 3 patients presented with stable neurologic findings and were treated with HAART alone. The median initial CD4+ count for these patients was 50 cells per microliter (range, 2 to 220 cells per microliter). All 5 remained in CR with a median follow-up of 23.5 (range, 13 to 36) months. For patients who present with PCNSL as their initial AIDS-defining event, stable neurologic findings, and effective HAART options, initial treatment with HAART alone may be possible, reserving WBRT and corticosteroids for those who show signs of impending neurologic demise. Chemotherapy and other novel approaches could also be considered for selected patients with lesser degrees of immune suppression and high baseline functional status.

Systematic identification of cellular signals reactivating Kaposi sarcoma-associated herpesvirus.

The herpesvirus life cycle has two distinct phases: latency and lytic replication. The balance between these two phases is critical for viral pathogenesis. It is believed that cellular signals regulate the switch from latency to lytic replication. To systematically evaluate the cellular signals regulating this reactivation process in Kaposi sarcoma-associated herpesvirus, the effects of 26,000 full-length cDNA expression constructs on viral reactivation were individually assessed in primary effusion lymphoma-derived cells that harbor the latent virus. A group of diverse cellular signaling proteins were identified and validated in their effect of inducing viral lytic gene expression from the latent viral genome. The results suggest that multiple cellular signaling pathways can reactivate the virus in a genetically homogeneous cell population. Further analysis revealed that the Raf/MEK/ERK/Ets-1 pathway mediates Ras-induced reactivation. The same pathway also mediates spontaneous reactivation, which sets the first example to our knowledge of a specific cellular pathway being studied in the spontaneous reactivation process. Our study provides a functional genomic approach to systematically identify the cellular signals regulating the herpesvirus life cycle, thus facilitating better understanding of a fundamental issue in virology and identifying novel therapeutic targets.

Fatal secondary pulmonary hypertension due to cardiac involvement in AIDS-associated Burkitt's lymphoma.

Primary cardiac lymphomas are rare lesions in children with acquired immunodeficiency syndrome (AIDS). Most of them are high-grade Burkitt's or Burkitt-like lymphomas. They usually present with congestive cardiac failure, pericardial effusion or tamponade, arrhythmias, with predominant systemic 'B' symptoms and often with widespread extranodal involvement. The clinical profile and operative and pathological findings of a 4-year-old boy with AIDS-associated Burkitt's lymphoma of the heart presenting with acute right heart failure and fatal secondary pulmonary hypertension is reported.

[Physiopathogenic aspects of HIV-associated primary brain lymphomas]. / Les lymphomes cérébraux primitifs associés au SIDA: aspects physiopathogéniques.

HIV-associated Primary brain lymphomas (PBLs) are usually diffuse, large B-cell lymphomas (DLBCLs). In contrast to those occurring in immunocompetent patients, nearly all HIV-associated PBLs are associated with Epstein-Barr virus (EBV). Since viral latency proteins are target antigens for anti-viral cytotoxic T lymphocytes, the double immunodeficiency (HIV infection, central nervous system microenvironment) favors the expression of viral latency proteins (LMP-1, EBNA2). These proteins play a major role in immortalization and transformation of infected B lymphocytes through cell cycle activation and apoptosis inhibition.

Therapy insight: AIDS-related malignancies--the influence of antiviral therapy on pathogenesis and management.

Patients with HIV infection are at an increased risk of a number of malignancies, including Kaposi's sarcoma (KS) and certain B-cell lymphomas. Most of these tumors are caused by oncogenic DNA viruses, including KS-associated herpesvirus and Epstein-Barr virus. HIV contributes to the development of these tumors through several mechanisms, including immunodeficiency, immunodysregulation, and the effects of HIV proteins such as Tat. The development of highly active antiretroviral therapy (HAART) has reduced the incidence of many HIV-associated tumors and has generally improved their responsiveness to therapy. However, the number of people living with AIDS is increasing, and it is possible that the number of AIDS-associated malignancies will rise and the pattern of tumors will change as more people live longer with HIV infection. The goal of KS therapy is long-term tumor control with minimal toxicity. HAART is an important component of this therapy, and some patients do not require other KS-specific therapies. By contrast, the goal of AIDS-related lymphoma therapy in most cases is the attainment of a complete response with curative intent, and the benefits of administering HAART during therapy must be weighed against possible disadvantages. The past decade has seen substantial improvements in the treatment of AIDS-related lymphoma, which is attributed partially to a shift in tumor type and more effective regimens. There is currently an interest in developing new therapies for HIV-associated malignancies, based on viral, vascular or other pathogenesis-based targets.

Recent advances in acquired immunodeficiency syndrome (AIDS)-related lymphoma.

Human immunodeficiency virus-infected patients are at an increased risk for developing both Hodgkin and non-Hodgkin lymphoma when compared with the general population. With the remarkable decrease in the incidence of opportunistic infections since the availability of highly active antiretroviral therapy (HAART), acquired immune deficiency syndrome-related lymphoma (ARL) is now the second most common cancer associated with human immunodeficiency virus after Kaposi sarcoma. Over the last few years, advances in our understanding of the molecular biology of this heterogeneous group of lymphomas have led to the adoption of new classification systems. The prognosis of patients with ARL has improved dramatically with the availability of HAART, and the survival of many of these patients is now comparable to patients in the general population. Apart from the contribution of HAART, this improvement in prognosis can also be attributed to new initiatives in treatment of these patients, such as the use of effective infusional regimens, the feasibility of high-dose therapy with peripheral stem cell rescue for relapsed or refractory disease, and better supportive care. Nonetheless, several controversial issues persist, including the optimal timing of HAART with combination chemotherapy, the role of rituximab when incorporated into treatment regimens, and the optimal therapy for patients with acquired immunodeficiency syndrome-related Burkitt lymphoma. This article reviews the changes in the epidemiology of ARL in the era of HAART, advances in the biology of ARL, new developments in the management of patients with ARL, and several of the controversial issues that oncologists may encounter in the care of these patients.

Acquired immunodeficiency syndrome associated lymphoma.

A prior diagnosis of HIV increases the risk of lymphoma between 150 to 250- fold, depending on the subtype, as compared with the risk observed in the general population. The advent of highly active anti-retroviral therapy (HAART) has seen a dramatic reduction in AIDS morbidity and a modest reduction in the incidence of opportunistic infections along with a corresponding reduction in Kaposi's sarcoma. There has not, however, been a clear reduction in the incidence of lymphoma. As HAART therapy continues to improve in the Western world, the morbidity of HIV infection is beginning to shift from AIDS to other associated illness such as lymphoma. The treatment and etiology of lymphoma is a burgeoning issue in the care of HIV positive populations. This review will provide a basic overview of the association between HIV and lymphoma.

T-cell lymphoma of the rectum in a patient with AIDS and hepatitis C: a case report and discussion.

Primary T-cell non-Hodgkin's lymphoma (NHL) occurring in the context of acquired immune deficiency syndrome (AIDS) is uncommon. Here, we report and discuss such a case presenting in the rectum, and review relevant literature. Although typical in some respects, the case is, in other ways, somewhat unusual for an AIDS-related NHL (ARL); ARL tends to be B cell and advanced stage and our case was T cell and stage IE. In addition, the patient suffered from concomitant cirrhosis related to hepatitis C. Chemotherapeutic options for ARL were limited early in the AIDS epidemic due to poor tolerability. Although this has largely been mitigated by the advent of highly active antiretroviral therapy, our patient eventually suffered complications of chemotherapy, apparently related more to his liver disease than to either his lymphoma or AIDS, that ultimately brought about his demise.