Low prevalence of human pegivirus 1 (HPgV-1) in HTLV-1 carriers from Belém, Pará, North Region of Brazil.

INTRODUCTION: Human pegivirus 1 (HPgV-1) is a single-stranded, positive-sense RNA virus belonging to the Flaviviridae family with limited cause-effect evidence of the causation of human diseases. However, studies have shown a potential beneficial impact of HPgV-1 coinfection in HIV disease progression. Human T lymphotropic virus-1 (HTLV-1) is a retrovirus known for causing diseases, especially in muscle and white blood cells, in approximately 5% of patients. Thus, this study aimed to investigate the potential effects of an HPgV-1 infection in patients carrying HTLV-1 in the state of Pará in the North Region of Brazil. METHODS: A group of HTLV-1 carriers was compared to healthy controls. Blood samples were collected, data from medical regards were collected, and a questionnaire was administered. HPgV-1 and HTLV-1 positivity was determined by quantitative polymerase chain reaction (qRT-PCR). The data were analyzed to correlate the effects of HPgV-1 coinfection in HTLV-1 carriers. RESULTS: A total of 158 samples were included in the study: 74 HTLV-1-positive patients (46,8%) and 84 healthy controls (53,2%). The overall HPgV-1 positivity rate was 7.6% (12/158), resulting in a prevalence of 5.4% (4/74) and 9.5% (8/84) in HTLV-1 carriers and healthy controls, respectively. No significant differences were found when comparing any clinical or demographic data between groups. CONCLUSION: This study indicated that the prevalence of HPgV-1 infection is low in HTLV-1 carriers in Belém, Pará, and probably does not alter the clinical course of HTLV-1 infection, however, further studies are still needed.

[Human Pegivirus: Pathogenic potential and non-Hodgkin lymphoma development risk]. / Pegivirus humano: Potencial patogénico y riesgo de desarrollo de linfoma no Hodgkin.

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.

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.

GBV-C/HIV-1 coinfection is associated with low HIV-1 viral load and high CD4+ T lymphocyte count.

GB virus C (GBV-C) is a lymphotropic virus with a low level or non-existent replication in the liver. The interaction between HIV-1 and GBV-C apparently reduces the progression of HIV-1 infection to AIDS and improves the quality of life of HIV-1 infected individuals. A cross-sectional study was established to determine the possible effect of HIV-1/GBV-C coinfection on HIV-1 viral load and CD4+ T lymphocyte counts. Samples from 313 HIV-1 infected persons from the Virus Laboratory of the Federal University of Pará as well as demographic and clinical information were obtained from medical records. This study used a nested PCR method to determine GBV-C viremia. The prevalence of HIV-1/GBV-C coinfection was 17%. There were no significant differences in the distribution according to age, sex or ethnicity between the groups. The differences in HIV-1 viral load and CD4+ T lymphocyte count between the HIV-1 and HIV-1/GBV-C groups were highly significant, indicating that coinfection results in lower viral loads and higher CD4+ T lymphocyte counts compared to HIV-1 mono-infection. The results indicate a protective effect among coinfected individuals.

Prevalence and vertical transmission of human pegivirus among pregnant women infected with HIV.

OBJECTIVE: To determine the prevalence of human pegivirus (HPgV) and factors associated with vertical transmission among pregnant women infected with HIV. METHOD: A retrospective cross-sectional study was conducted among pregnant women treated at an HIV reference service in Rio Grande, Brazil, between January 1, 2010, and January 1, 2015. The polymerase chain reaction was used to diagnose HPgV infection among the women and their neonates. Clinical, obstetric, and neonatal data were obtained from medical records. RESULTS: Infection with HPgV was detected among 16 (25%) of 63 women and 5 (8%) of 63 newborns, corresponding to a vertical transmission rate of 31%. Multivariate analysis demonstrated that the absence of prenatal care was the only risk factor for vertical transmission of HPgV (prevalence ratio 19.61, 95% confidence interval 1.29-297.48; P=0.032). CONCLUSION: Prenatal care could protect against vertical transmission of HPgV among women infected with HIV; however, studies among HIV-negative individuals are still required to verify this correlation.

Prevalence of human pegivirus (HPgV) infection in patients carrying HIV-1C or non-C in southern Brazil.

Previous studies have demonstrated that coinfection with HPgV is a protective factor for human immunodeficiency virus (HIV)-infected patients, leading to slower disease progression, and longer survival after established disease. The present study sought to estimate the prevalence of HPgV infection and associated risk factors in patients harboring C or non-C HIV-1 subtypes followed-up at HU-FURG, southern Brazil. Samples from 347 HIV-1-infected subjects were subjected to plasma RNA extraction, cDNA synthesis, HPgV RNA detection, and HIV-1 genotyping. The overall prevalence of HPgV RNA was 34%. Individuals aged 18-30 years had higher chances of infection compared with those 50 years or older (95%CI 1.18-52.36, P = 0.03). The number of sexual partner between one and three was a risk factor for HPgV infection (95%CI 1.54-10.23; P < 0.01), as well as the time since diagnosis of HIV-1 ≥ 11 years (95%CI 1.01-2.89; P = 0.04). Patients infected with HIV non-C subtypes had six times more chance of being HPgV-infected when compared to subtype C-infected subjects (95%CI 2.28-14.78; P < 0.01). This was the first study conducted in southern Brazil to find the circulation of HPgV. HIV/HPgV coinfection was associated with a longer survival among HIV+ patients. Of novelty, individuals infected by HIV non-C subtypes were more susceptible to HPgV infection. However, additional studies are needed to correlate the HIV-1 subtypes with HPgV infection and to clarify cellular and molecular pathways through which such associations are ruled. J. Med. Virol 88:2106-2114, 2016. © 2016 Wiley Periodicals, Inc.

[Interaction between HIV-1 and GB virus type-C during coinfection status]. / Interacción entre el virus de la inmunodeficiencia humana y el virus GB tipo-C durante el estado de co-infección.

The human immunodeficiency virus (HIV) infection is one of the most important problems in public health. It is estimated that 3 3 million people are infected around the world. HIV and GBV-C share the same transmission route, being frequent the co-infection. Since both viruses replicate in CD4+ lymphocytes, recent studies have described an interaction. Decreasing of HIV viral load and higher CD4 counts have been observed in co-infected patients, leading a better clinical outcome. Nevertheless, some epidemiological studies have shown contradictory results. Additionally, in vitro models report inhibition of HIV by E1, E2, NS3 and NS5A GBV-C proteins, resulting in a decreasing of p24 antigen. This review summarizes the principal findings about co-infection and mechanisms that have been proposed for HIV-1 inhibition.

Interacción entre el virus de la inmunodeficiencia humana y el virus GB tipo-C durante el estado de co-infección / Interaction between HIV-1 and GB virus type-C during coinfection status

The human immunodeficiency virus (HIV) infection is one of the most important problems in public health. It is estimated that 3 3 million people are infected around the world. HIV and GBV-C share the same transmission route, being frequent the co-infection. Since both viruses replicate in CD4+ lymphocytes, recent studies have described an interaction. Decreasing of HIV viral load and higher CD4 counts have been observed in co-infected patients, leading a better clinical outcome. Nevertheless, some epidemiological studies have shown contradictory results. Additionally, in vitro models report inhibition of HIV by E1, E2, NS3 and NS5A GBV-C proteins, resulting in a decreasing of p24 antigen. This review summarizes the principal findings about co-infection and mechanisms that have been proposed for HIV-1 inhibition.

La infección por el virus de la inmunodeficiencia humana (VIH) continúa siendo uno de los principales problemas en salud pública; se estima que existen actualmente más de 33 millones de personas infectadas en el mundo. El VIH y el virus GB tipo C (GBV-C) comparten la misma vía de transmisión, por lo que es frecuente encontrar individuos co-infectados. Estudios recientes han descrito un efecto inhibitorio asociado a disminución en la carga viral de VIH, altos recuentos de CD4 y mayor tiempo de sobrevida en pacientes co-infectados, resultando en un mejor pronóstico y menor progreso a SIDA; adicionalmente, estudios in vitro indican que las proteínas virales E1, E2, NS3 y NS5A del GBV-C estarían implicadas en la inhibición del VIH-1. En el presente artículo se revisan los principales aspectos de la co-infección, y se describen los mecanismos propuestos para la inhibición de la replicación del VIH-1 mediada por las proteínas virales del GBV-C.

Influence of hepatitis G virus (GB virus C) on the prognosis of HIV-infected women.

This study was undertaken to evaluate the prevalence of GB virus C (GBV-C) viraemia and anti-E2 antibody, and to assess the effect of co-infection with GBV-C and HIV during a 10-year follow-up of a cohort of 248 HIV-infected women. Laboratory variables (mean and median CD4 counts, and HIV and GBV-C viral loads) and clinical parameters were investigated. At baseline, 115 women had past exposure to GBV-C: 57 (23%) were GBV-C RNA positive and 58 (23%) were anti-E2 positive. There was no statistical difference between the groups (GBV-C RNA + /anti-E2 - , GBV-C RNA - /anti-E2 + and GBV-C RNA - /anti-E2 - ) regarding baseline CD4 counts or HIV viral loads (P = 0.360 and 0.713, respectively). Relative risk of death for the GBV-C RNA + /anti-E2 - group was 63% lower than that for the GBV-C RNA - /anti-E2 - group. Multivariate analysis demonstrated that only HIV loads ≥ 100,000 copies/mL and AIDS-defining illness during follow-up were associated with shorter survival after AIDS development. It is likely that antiretroviral therapy (ART) use in our cohort blurred a putative protective effect related to the presence of GBV-C RNA.

Analysis of GB virus C infection among HIV-HCV coinfected patients.

The aim of this study was to evaluate the effect of GB virus C on laboratory markers and histological parameters among HIV-seropositive patients coinfected with HCV. Lower degrees of hepatic lesions were observed in the triple-infected patients, in comparison with HIV-HCV coinfected patients who were negative for GBV-C RNA.

Analysis of GB virus C infection among HIV-HCV coinfected patients / Análise da infecção pelo vírus GB-C em pacientes com coinfecção VIH-VHC

The aim of this study was to evaluate the effect of GB virus C on laboratory markers and histological parameters among HIV-seropositive patients coinfected with HCV. Lower degrees of hepatic lesions were observed in the triple-infected patients, in comparison with HIV-HCV coinfected patients who were negative for GBV-C RNA.

O objetivo do estudo foi avaliar o efeito da infecção pelo vírus GB-C em marcadores laboratoriais e parâmetros histológicos em pacientes HIV soropositivos coinfectados com VHC. Menor grau de lesão hepática foi observado nos pacientes com tripla infecção em comparação aos pacientes coinfectados com VIH-VHC negativos para GBV-C RNA.

GB virus type C infection modulates T-cell activation independently of HIV-1 viral load.

BACKGROUND: Many clinical studies have suggested a beneficial effect of GB virus type C (GBV-C) on the course of HIV-1 infection, but the mechanisms involved in such amelioration are not clear. As recent evidence has implicated cellular activation in HIV-1 pathogenesis, we investigated the effect of GBV-C viremia on T-cell activation in early HIV-1 infection. METHODS: Forty-eight recently infected HIV-1 patients (23 GBV-C viremic) were evaluated for T-cell counts, expanded immunophenotyping GBV-C RNA detection, and HIV-1 viral load. Nonparametric univariate and multivariate analyses were carried out to identify variables associated with cellular activation, including GBV-C status, HIV-1 viral load, T lymphocyte counts, and CD38 and chemokine (C-C motif) receptor 5 (CCR5) surface expression. FINDING: We not only confirmed the positive correlation between HIV-1 viral load and the percentage of T cells positive for CD38(+)CD8(+) but also observed that GBV-C viremic patients had a lower percentage of T cells positive for CD38(+)CD4(+), CD38(+)CD8(+), CCR5(+)CD4(+), and CCR5(+)CD8(+) compared with HIV-1-infected patients who were not GBV-C viremic. In regression models, GBV-C RNA(+) status was associated with a reduction in the CD38 on CD4(+) or CD8(+) T cells and CCR5(+) on CD8(+) T cells, independent of the HIV-1 viral load or CD4(+) and CD8(+) T-cell counts. These results were also supported by the lower expression of CD69 and CD25 in GBV-C viremic patients. INTERPRETATION: The association between GBV-C replication and lower T-cell activation may be a key mechanism involved in the protection conferred by this virus against HIV-1 disease progression to immunodeficiency in HIV-1-infected patients.

HIV-GB virus C co-infection: an overview.

GB virus C (GBV-C) and hepatitis G virus (HGV) are two isolates of the same virus, independently identified in humans in the 1990s by two research laboratories, and were initially considered a potential cause of liver disease. Studies failed to associate the virus with hepatitis or any known human disease. GBV-C reappeared in the scientific scene when some research groups, in an attempt to find the interference of the virus among HIV seropositive patients, reported a lower mortality rate and slower disease progression among co-infected patients. From then on, several mechanisms have been proposed to clarify this putative benefit; however, the question whether GBV-C exerts a protective effect in HIV-infected patients remains to be resolved.

Effect of GB virus C on response to antiretroviral therapy in HIV-infected Brazilians.

OBJECTIVES: GB virus C (GBV-C) infection is associated with delayed mortality in HIV-infected people in most, but not all, studies. Previous investigations of the effect of GBV-C viraemia on response to antiretroviral therapy (ART) were inconclusive. To determine the effect of GBV-C on ART, we retrospectively analysed plasma samples taken from patients in a prospective randomized clinical trial of ART in HIV-positive Brazilians. METHODS: GBV-C viraemia was characterized by testing stored serum samples from 175 participants by reverse transcriptase-polymerase chain reaction (RT-PCR). Subjects were randomized to receive indinavir (n=59), zidovudine and lamivudine (n=58), or zidovudine, lamivudine and indinavir (n=58). The effect of GBV-C viraemia on the average change in HIV viral load and CD4 count following initiation of therapy was evaluated in a multiple regression analysis. RESULTS: The prevalence of GBV-C viraemia was similar to that observed in previous studies (24%). HIV viral load decreased following ART to a significantly greater extent in patients with GBV-C viraemia (by 0.48 log(10) HIV-1 RNA copies/mL, P=0.009, adjusting for age, ART group, and baseline CD4 count). Although there was no significant difference in change in CD4 count between individuals with and without GBV-C viraemia overall, CD4 counts were higher following 48 weeks of therapy in GBV-C viraemic individuals receiving the least potent ART regimen (zidovudine and lamivudine) compared with those without GBV-C infection. CONCLUSIONS: GBV-C viraemia is associated with an enhanced reduction of HIV viral load in response to ART. In this study of treatment-naive individuals during 48 weeks of follow up, patients with GBV-C viraemia had reductions in HIV viral load that were approximately 0.5 log copies/mL greater than those found in patients without GBV-C viraemia. This is similar to reductions observed with nucleoside reverse transcriptase inhibitors.

GBV-C/HGV and HIV-1 coinfection.

An interesting interaction pattern has been found between HIV-1 and GBV-C/HGV, resulting in protection against progression to AIDS. The mechanisms involved in this interaction remain to be clarified. We examined the current knowledge concerning this coinfection and developed hypotheses to explain its effects. A better understanding of this interaction could result in new concepts, which may lead to new strategies to control HIV-1 replication and progression to AIDS.

GBV-C/HGV and HIV-1 coinfection

An interesting interaction pattern has been found between HIV-1 and GBV-C/HGV, resulting in protection against progression to AIDS. The mechanisms involved in this interaction remain to be clarified. We examined the current knowledge concerning this coinfection and developed hypotheses to explain its effects. A better understanding of this interaction could result in new concepts, which may lead to new strategies to control HIV-1 replication and progression to AIDS.

Liver histology in co-infection of hepatitis C virus (HCV) and hepatitis G virus (HGV).

As little is known about liver histology in the co-infection of hepatitis C virus (HCV) and hepatitis G virus (HGV), HGV RNA was investigated in 46 blood donors with hepatitis C, 22 of them with liver biopsy: co-infection HCV / HGV (n = 6) and HCV isolated infection (n = 16). Besides staging and grading of inflammation at portal, peri-portal and lobular areas (Brazilian Consensus), the fibrosis progression index was also calculated. All patients had no symptoms or signs of liver disease and prevalence of HGV / HCV co-infection was 15.2%. Most patients had mild liver disease and fibrosis progression index, calculated only in patients with known duration of infection, was 0.110 for co-infection and 0.130 for isolated HCV infection, characterizing these patients as "slow fibrosers". No statistical differences could be found between the groups, although a lesser degree of inflammation was always present in co-infection. In conclusion co-infection HCV / HGV does not induce a more aggressive liver disease, supporting the hypothesis that HGV is not pathogenic.

[Prevalence of hepatitis G virus infection in a cohort of hemophilic HIV positive patients]. / Prevalencia de infección por virus de hepatitis G en una cohorte de pacientes hemofílicos HIV+.

We analysed the prevalence of hepatitis G virus (HGV) infection in HCV+/HIV+ hemophilic patients determining HGV viremia in plasma by polymerase chain reaction (PCR). The overall prevalence of HGV infection was 13.51%. Viremia by HGV was more frequent in younger patients. Two subgroups of patients were considered taking into account prognosis of HIV disease progression. The prevalence of HGV infection was significantly higher in those with better prognosis and low risk of evolution to AIDS. The results suggest that HGV infection may slow disease progression, directly or indirectly.

Chronic hepatitis C infection: influence of the viral load, genotypes, and GBV-C/HGV coinfection on the severity of the disease in a Brazilian population.

The distributions of the different genotypes of the hepatitis C virus (HCV) and GBV-C virus (GBV-C/HGV) vary geographically and information worldwide is still incomplete. In particular, there are few data on the distribution of genotypes (and their relationship to the severity of liver disease) in South America. Findings are described in 114 consecutive patients from Northeast Brazil (median age 52 years, range 18-72 years) who had abnormal levels of serum aminotransferases and seropositivity for HCV RNA. The patients were recruited from an outpatient clinic between November 1997 and April 1998. Quantitative HCV RNA and GBV-C/HGV RNA estimations were carried out by double-nested polymerase chain reaction (PCR) using primers from the 5'-untranslated regions (UTRs) of the genomes. HCV genotypes were determined by restriction fragment length polymorphism (RFLP) analysis with 5'-UTR primers and by PCR with type-specific 5'-UTR primers. GBV-C/HGV-RNA genotypes were determined by RFLP with specific 5'-UTR primers and phylogenetic trees were constructed using the Neighbour-Joining and Drawtree programs. Histological features were graded and staged according to international criteria. Of the 114 patients, 35 (30.7%) patients had cirrhosis and 22 (27.8%) had mild, 51 (64.6%) had moderate, and 6 (7.6%) had severe chronic hepatitis. Median HCV viral load was 10(6) genome equivalents per millilitre (range 10(4)-10(9)/ml). Frequencies of genotypes were 5.3% type 1a, 44.7% type 1b, 3.5% type 2, 41.2% type 3, and 5.3% mixed types. GBV-C/HGV-RNA was detected in the sera of 12 (10.5%) patients and was distributed among three phylogenetic groups. There were no significant differences between patients with the predominant HCV genotypes (1b and 3) with respect to gender, age group, viral load, severity of liver disease, or coinfection with GBV-C/HGV.