Pegivirus humano: potencial patogénico y riesgo de desarrollo de linfoma no Hodgkin / Human Pegivirus: pathogenic potential and non-Hodgkin lymphoma development risk

Resumen El pegivirus humano (HPgV) es un virus ARN que fue identificado en el año 1995. Actualmente se encuentra clasificado dentro de la familia Flaviviridae, género Pegivirus, relacionado filogenéticamente con el virus de la hepatitis C (VHC). El HPgV es un virus linfotrópico, con replicación en médula ósea, tejidos linfoides, y en células mononucleares de sangre periférica. Este virus se transmite por vía parenteral y sexual. Según estimaciones realizadas, en el mundo existen alrededor de 750 millones de personas infectadas por este agente. Se ha evidenciado que hasta en 25% de los casos se presenta una infección persistente, y aunque se considera que el HPgV es un virus no patogénico, existen evidencias epidemiológicas que sugieren una relación con el desarrollo de desórdenes linfoproliferativos, particularmente linfoma no Hodgkin (LNH). Algunos estudios han reportado una alta prevalencia de HPgV en pacientes con LNH comparado con donantes de sangre y/o pacientes con enfermedades hematológicas no malignas, lo que se asocia a un incremento en el riesgo relativo para el desarrollo de LNH en personas infectadas. De otra parte, existen estudios epidemiológicos que contradicen esta asociación, por lo que el rol de HPgV en la aparición de desórdenes lifoproliferativos es un tema actual de debate. En el presente manuscrito se discute el potencial patogénico derivado de los mecanismos de infección persistente del HPgV, así como las principales evidencias sobre la relación entre el HPgV y el riesgo de desarrollo de LNH.

The human pegivirus (HPgV), classified in the Flaviviridae family - Pegivirus genus, is an RNA virus identified in 1995. HPgV is a lymphotrophic virus, with replication sites in bone marrow and lymphoid tissue, as well as in peripheral blood mononuclear cells (PBMCs). Transmission is through sexual and parenteral routes, and recent estimations suggest nearly 750 million people are infected with HPgV worldwide. Almost 25% of infected individuals can develop persistent infection. Until now, HPgV has been considered a non-pathogenic virus; however, epidemiological studies suggest a potential role in lymphoproliferative diseases, particularly in the development of non-Hodgkin lymphoma (NHL). The evidence of this is controversial and the role of HPgV in lymphomagenesis has not yet been demonstrated. Several studies report a high prevalence of HPgV infection in patients with NHL compared to controls and patients with other hematological diseases. Therefore, analytic studies show that HPgV could be related to an increased risk of NHL development. Conversely, other studies indicate no association between HPgV and NHL, so the role of HPgV in lymphomagenesis is not clear. This review summarizes the main findings related to HPgV's pathogenic potential and association with NHL.

Linfoma no hodgkin asociado a infección por virus de inmunodeficiencia humana estudio de cohorte / Non hodgkin lymphoma associated to human immunodeficiency virus cohort study

Los pacientes con linfoma no Hodgkin asociado a la infección por el virus de inmunodeficiencia humana tienen una mejor sobrevida después de la terapia antirretroviral de alta eficacia. Evaluar el comportamiento de los pacientes con linfoma no Hodgkin asociado a la infección por el virus de inmunodeficiencia humana antes y después de la terapia antirretroviral de alta eficacia. Estudio de cohorte entre 1986 y 2011 de los pacientes con linfoma no Hodgkin asociado a la infección por el virus de inmunodeficiencia humana tratado con ciclofosfamida doxorrubicina vincristina-prednisona. Hubo un 34% de respuestas globales (completa + parcial) en el grupo tratado antes de la terapia antirretroviral de alta eficacia y un 66% después de ella 65% de los pacientes antes de esta terapia murieron de infección por oportunista y 70% después de ella murieron de progresión o recaída del linfoma; hubo mayor toxicidad hematológica y hepática antes de la terapia antirretroviral; la sobrevida fue mayor en los pacientes tratados después de esta. En pacientes con un estado general satisfactorio, buena adherencia a la terapia antirretroviral de alta eficacia, en quienes se mejora la inmunidad celular y se obtiene una carga viral indetectable; podemos lograr que un grupo de ellos tenga una sobrevida larga, con respuestas clínicas completas posterior al tratamiento con el esquema de quimioterapia antes mencionado.

The human immunodeficiency virus infections related to non-Hodgkin´s lymphoma patients have improved their survival since the introduction of highly active antiretroviral therapy of high efficacy. These study behavior of the human immunodeficiency infection related to non Hodgkin lymphoma patients before and after the introduction of highly active and efficacy antiretroviral therapy. Study of cohort between the years 1986 and 2011 of the human immunodeficiency virus infection related to non Hodgkin lymphoma patients treated with these chemotherapy schedule: Cyclophosphamide, doxorubicin, vincristine, and the prednisone. There was 34% of a global (complete + partial) response in the group of patients treated before highly active and efficacy antiretroviral therapy and 66% after these antiretroviral therapy; 65% of patients died due to opportunistic infections before the highly active antiretroviral and efficacy therapy and 70% died due to progression or relapse of lymphoma after the antiretroviral therapy; hematologic and hepatic toxicity were higher before the highly active antiretroviral and efficacy therapy; and the survival was better after the antiretroviral therapy. The patients with good performance status and good adherence to highly active antiretroviral efficacy therapy, and in who improved of the cellular immunity and undetected the viral load were obtained, we can achieve a group of patients with long survival, in complete clinical response after treatment with chemotherapy regimen previous mentioned.

Linfomas asociados con la infección por el virus de la inmunodeficiencia humana: subtipos histológicos y asociación con los virus de Epstein Barr y Herpes-8 / AIDS related lymphomas: Histopathological subtypes and association with Epstein Barr virus and Human Herpes virus type-8

Los linfomas no Hodgkin (LNH) constituyen la segunda neoplasia definitoria de Sida más frecuente. En el presente trabajo se evaluaron 48 casos de linfomas asociados con la enfermedad debida al virus de la inmunodeficiencia humana (HIV) diagnosticados en la División Histopatología del Instituto de Investigaciones Hematológicas de la Academia Nacional de Medicina. Se incluyeron en la investigación 5 mujeres y 43 hombres con una mediana de edad al momento del diagnóstico de la neoplasia de 37 años. La evaluación morfológica se realizó en cortes coloreados con hematoxilina-eosina, estudio inmunohistoquímico para la detección del virus de Epstein Barr (VEB) en 48/48 casos, y mediante sonda oligonucleotídica biotinilada para la detección del ADN del Herpes virus humano tipo-8 (HHV-8) en 14/14 linfomas plasmoblásticos (LP). Todos fueron linfomas de fenotipo B, con un curso clínico agresivo y enfermedad neoplásica avanzada al momento del diagnóstico. Se pudo demostrar la fuerte asociación del VEB con los linfomas asociados al sida, con frecuencias que variaron según el subtipo histológico: 16/21 (76%) para los linfomas difusos de grandes células; 1/3 casos (33%) de linfomas de Burkitt y 3/4 (75%) en los linfomas primarios del sistema nervioso central. Globalmente, el genoma del VEB se detectó en 20/28 (71%) de las muestras de biopsias de LNH de esta serie. La detección del HHV-8 resultó negativa en los 14 LP. Los linfomas de Hodgkin fueron más frecuentes en varones,18/20 (90%), con un curso clínico agresivo y franco predominio de los subtipos histológicos de peor pronóstico (90% de casos). En estas neoplasias también se comprobó una frecuente asociación patogénica con el VEB (90% de casos).

Non-Hodgkin lymphomas (NHL) of the B-cell type are the second most common neoplasm among patients with human immunodeficiency virus (HIV) infection and AIDS. Here, we evaluated 48 cases of AIDS-related lymphomas (ARL) diagnosed at the Histopathological Division of the Instituto de Investigaciones Hematológicas of the National Academy of Medicine. Five were females and 43 were males with a median of age of 37 years at the time of the diagnosis. Micrometer sections were prepared and stained with hematoxilin-eosin; immunohistochemical examination for the presence of Epstein-Barr virus (EBV) was carried out in 48/48 cases. Additionally, biotinilated oligonucleotides were used to determine the presence of DNA of the Human Herpes virus type-8 (HHV-8) in 14/14 biopsy smears corresponding to plasmablastic lymphomas (PL). All were fenotype B cell lymphomas with an aggressive course and advanced neoplasm disease at the time of diagnosis. Virological findings showed the strong association between EBV and AIDS-related NHL. According to the histopathological subtype, the EBV genome was detected in 16/21 (76%) diffuse large B cell lymphomas, 1/3 Burkitt lymphoma and 3/4 (75%) of primary central nervous system lymphomas. Globally, EBV genome was detected in 20/28 NHL of this series. Detection of HHV-8 was negative in all cases of PL. Hodgkin lymphoma were more frequent in males 18/20 (90%), with an aggressive clinical course and a significant predominance of the subtypes associated with worse prognosis (90% of cases). We detected a significant association between EBV and HL (90% of cases). We consider that all cases of AIDS related lymphomas should be assessed for the presence of EBV because its presence may play a role in the prognosis.

Detection of tumor antigens in bovine viral lymphosarcoma by immunoprecipitation method

In this study one lymph node from cow with viral lymphosarcoma and one lymph node from healthy cow were analyzed by three different methods for protein extraction, include simple homogenizing in PBS, sonication and phenol extraction. Tumor antigen detection relies on immunoprecipitation followed by SDS-PAGE. In this experiment Streptococcus pyogenes was used for purification of immune complexes. Eletrophoretic patterns were obtained using reduced and non reduced buffers. In PBS homogenization 3 distinct antigens [39, 32 and 30 kDa] were observed. When sonication or phenol extraction were used, 5 [72, 48, 42, 32 and 30 kDa] and 6 [104, 77, 54, 32, 30 and 26, 5 kDa] distinct antigens were observed, respectively. This study showed that the ability of antigen detection mainly depends on protein extraction procedure and antigen-antibody equilibrium achieved by quantification of precipitins. Immunoprecipitation could be used successfully for study of tumor antigens in bovine leukosis

The investigation of parvovirus B19 infection in patients with haematological disorders by using PCR and ELISA techniques

Parvovirus B19 has a marked tropism for erythroid progenitor cells. This may lead to chronic anemia in predisposed individuals. The purpose of the study was to investigate the frequency of parvovirus B19 infections in patients with diagnosis of haematological disorders. In order to determine the diagnostic use of different markers of parvovirus B19 infection, serum specimens obtained from 79 patients with haematological disorders were tested for specific antibodies and viral DNA through the use of ELISA and PCR techniques. Evidence of parvovirus B19 infection was found in 23/79 (29.1 percent) patients by demonstrating viral DNA and/or specific IgM antibody. B19 infection was established in 3 of 11 patients with chronic myeloid leukemia, in 3 of 11 acute myeloid leukemia, in 2 of 11 patients with multiple myeloma, in 3 of 8 patients with Hodgkin's lymphoma, in 5 of 10 patients with non-Hodgkin's lymphoma, in 1 of 6 patients with myelodysplastic syndrome, in 4 of 11 patients with chronic lymphocytic leukemia, and in 2 of 11 patients with acute lymphocytic leukemia. In 4 of 23 positive patients, only parvovirus B19 DNA could be detected, while 7 patients were tested positive for both parvovirus B19 DNA and specific IgM. Nine patients were tested positive for both B19 DNA and specific IgG. In the remaining 3 positive patients only specific IgM could be detected. Due to the discrepancies between DNA and IgM results, the diagnostic procedures should include a search for specific DNA by PCR methods if specific IgM has been found to be negative.

Hepatitis Cvirus infection in non hodgkin's lymphoma patients: virological evaluation

Viral hepatitis is a common and important problem in immunocompromised cancer patients. The present study was conducted to investigate changes in some virological parameters as a consequence of Hepatitis C Virus [HCV] infection in non Hodgkin's lymphoma patients [NHL]. The Pediatric Service of the National Cancer Institute, Cairo University, Egypt. The study included 40 NHL patients: 20 anti-HCV antibody positive [Gr. I] and 20 anti-HCV antibody negative [Gr. II]. In addition, forty non-cancer controls [NCCs] were included: 20 of them were anti-HCV antibody positive [Gr. Ill] and 20 anti-HCV antibody negative [Gr. IV]. Virological studies included detection of HCV antibody [Ab] of both types [IgG and IgM] by ELISA. In addition. Line Immunoassay for HCV by LIA test as well as RT-PCR to detect HCV viremia were done. Eleven out of the twenty [55%] NHL patients from Gr. I had HCV antibody index value of > 6 in comparison to 8/20 [40%] only in their non-cancer controls. No difference was observed between the positivity of anti-HCV IgM Ab in NHL patients from Gr. I and their non-cancer controls in Gr. Ill; eleven out of 20 [55%] were positive for anti-HCV IgM Ab in both Gr. I and Gr. III. As regards confirmatory HCV-Ab patterns [LIA], nineteen out of 20 [95%] NHL patients of Gr I were LIA positive in comparison to 18 out of 20 [90%] NCCs of Gr. III. Further analysis showed that reactivity to both core and nonstructural regions combined was more frequent in NHL patients [18/19, 95%] than in their non-cancer controls [12/18, 67%]. HCV viremia was displayed by RT-PCR in 18 out of 20 [90%] NHL patients of Gr. I in comparison to 12 out of the 20 [60%] NCCs of Gr. III. From all the above virological findings two main inferences could be drawn: [1] HCV leads a mild course of infection in NCCs as evidenced by normal ALT level in all but 20% [4/20] of subjects, and hence a mild hepatocellular injury, and [2] In the immunocompromised NHL patients the virus leads a potentially more aggressive course as evidenced by higher percentage of positive HCV RNA in blood, higher .HCV-Ab titer and higher incidence of reactivity to both core and NS regions[s]

Epstein-Barr virus in biopsies from patients with Hodgkin and non-Hodgkin lymphoma at the University of Puerto Rico immunohistochemistry laboratory

OBJECTIVES: We aimed to determine the Epstein-Barr Virus (EBV) presence rate in our laboratory's lymphoma tissue biopsies for comparison with that reported in literature. BACKGROUND: The presence of EBV has been established in Hodgkin lymphoma (HL), endemic Burkitt Lymphoma and some non-Hodgkin lymphomas (NHL). It has been linked to geographic, ethnic and socioeconomic factors, with a lower rate in developed countries. METHODS: We used the immunoperoxidase technique to determine the rate of the EBV LMP-1 in eighty-seven biopsies diagnosed as lymphoma. Tissue slides were stained using the Ventana Automated Slide Stainer with the DAKO EBV LMP-1 primary antibody and the results were analyzed with the SYSTAT program. RESULTS: We found an LMP-1 positive rate of 50 per cent for 22 cases of HL and 35 per cent for 63 cases of NHL. Among HL, 5 were children and 16 were adults, with LMP-1 positive rates of 60 per cent and 50 per cent respectively. Among NHL, 3 were children and 59 were adults, with equal LMP-1 positive rates of 33 per cent. The sex LMP-1 positive rates for HL were 42 per cent for 12 males and 60 per cent for 10 females. Among NHL, the sex LMP-1 positive rates were 39 per cent for 38 males and 28 per cent for 27 females. NHL was further subdivided into subtypes and LMP-1 primary antibody positive rates were reported. CONCLUSIONS: We found a similar presence rate of EBV in the HL biopsies to that of developed countries, but a similar presence rate of EBV in NHL biopsies to that of developing countries.

Prevalence of hepatitis c virus infection in patients with B-cell non-Hodgkin's lymphoma

This controlled, cross-sectional study included 30 patients with B-cell non-Hodgkin's lymphoma [B-cell NHL], 30 patients with malignant hematologic neoplesia other than B-cell NHL [control group I] and 30 patients randomly selected from general medical patients and healthy blood donors with non-malignant conditions [control group II]. All study populations were tested for antibodies to HCV by using a second-generation enzyme-linked immunosorbent assay [anti-HCV EIA II]. Positive and indeterminate results were subjected to confirmatory testing using RIBA-hepatitis C virus [recombinant-based immunoblot assay-RIBA II]. Hepatitis C virus RNA was detected by a reverse-transcription polymerase chain reaction [RT-PCR] assay. The results revealed that infection with HCV was detected in nine patients with B-cell non-Hodgkin's lymphoma compared with two of 30 patients in control group I and one of 30 patients in control group II. All the three groups were matched as regarding age, sex and risk factors for hepatitis C virus infection. Patients with B-cell NHL who were HCV positive and HCV negative did not differ significantly with respect to the prevalence of low-grade [22.3% and 28.6%], or intermediate to high-grade lymphoma [77.7% and 71.4%]. In conclusion, the results of this study indicated a higher prevalence of hepatitis C virus infection in patients with B-cell non-Hodgkin's lymphoma than in the control groups. The prevalence of hepatitis C virus infection in the two control groups, in turn, seems to fall within the estimated prevalence in the general population

EBV in situ hybridization study for non-Hodgkin's lymphomas

Epstein-Barr virus(EBV) has been implicated in the pathogenesis of B-lymphoproliferative disorders, T-cell lymphomas and Hodgkin's disease. In this report, we performed an in situ hybridization study on EBV genome in 10 cases of nasal non-Hodgkin's lymphoma(NHL), 20 cases of Waldeyer's ring(WR) NHL, and 20 cases of nodal NHLs to document EBV association with lymphomas in Koreans. For immunophenotyping, monoclonal antibodies for CD 20, MB 2, CD 45Ro & CD 43 were used. For in situ hybridization study, EBV DNA probe for Bam HI 'V' fragment and EBV RNA probe for EBER and BHLF were used. Twenty two cases(44%) of malignant lymphomas were positive for EBV genome. Generally, T-cell lymphomas showed a higher positive rate(61%) than B-cell lymphomas(24%). Among T-cell lymphomas, nasal lymphomas showed a higher positive rate(80%) than WR(50%) or nodal lymphomas(50%). Of 22 EBV genome positive cases, 10 cases were positive for EBER, 10 cases for BHLF, and 2 cases for both EBER and BHLF. The histologic types by Working Formulation(WF) were not correlated with EBV genome positive rate, whereas lymphomas showing the histologic spectrum of polymorphic reticulosis(PR) showed a higher positive rate(65%) than lymphomas without PR-like features(40%). These results indicate that nasal T-cell lymphomas with the histologic spectrum of PR are strongly associated with EBV and that the anatomic site may be an important factor in this association.