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. 2024 Oct 11;350:199479. doi: 10.1016/j.virusres.2024.199479

Human pegivirus -1 (HPgV-1) RNA frequency and genotype distribution in pediatric oncology patients with febrile neutropenia

Anielly Sarana da Silva a, Gabriel Montenegro de Campos a, Gabriela Marengone Altizani b, Alice Chagas Barros c, Dennis Maletich Junqueira d, Simone Kashima a, Sandra Coccuzzo Sampaio e, Maria Carolina Elias e, Marta Giovanetti f,g,h, Carlos Alberto Scrideli b, Svetoslav Nanev Slavov e,⁎
PMCID: PMC11736395  PMID: 39374843

Highlights

  • •

    The frequency and impact of HPgV-1 in oncologic pediatric patients with febrile neutropenia (FN) have not yet been explored.

  • •

    This study evaluated the prevalence of HPgV-1 RNA in pediatric patients with FN.

  • •

    HPgV-1 RNA was detected in 23.3 % of the samples, with 26.7 % among FN patients and 20.0 % among those in treatment or remission.

  • •

    Phylogenetic analysis revealed a predominance of HPgV-1 genotype 2.

  • •

    Further investigation is necessary to understand the HPgV-1 impact in patients with neutropenia.

Keywords: Febrile neutropenia, Human pegivirus-1, Pediatric patients, Oncology

Abstract

Human Pegivirus-1, typically regarded as a commensal virus, exhibits high prevalence in humans. Its frequency and impact on oncologic pediatric patients with febrile neutropenia (FN), a frequent chemotherapy complication, remains unexplored. In this study, we assessed HPgV-1 RNA prevalence in pediatric patients experiencing FN. Blood samples were collected from 30 children, 15 presenting FN and 15 comprising a control group of either undergoing treatment or in remission. Overall, HPgV-1 RNA was detected in 23.3 % of samples (26.7 % among FN patients and 20.0 % among those under treatment or in remission). Phylogenetic analysis unveiled HPgV-1 genotype 2 predominance among these samples, the most prevalent strain circulating in Brazil. Our findings prompt crucial inquiries into the role of HPgV-1 RNA in FN: is it an incidental finding and if it can influences this clinical entity? Further investigation is imperative to elucidate HPgV-1 implications in vulnerable patients cohorts, potentially informing new approaches and understanding viral dynamics in immunocompromised populations.

Human Pegivirus-1 (HPgV-1), formerly known as GB virus C (GBV-C), is a flavivirus with a positive strand RNA genome with similar organization to that of HCV (Leary et al., al.,1996). Seven HPgV-1 genotypes have been identified showing specific geographic distribution being genotypes 1 and 5 predominantly found in Africa (Xiang et al., 2005; N'Guessan et al., 2018), genotype 2 in Europe, North and South America (Jõgeda et al., 2017; Slavov et al., 2019), genotype 3 in Asia and in Amerindian populations (Lu et al., 2001) and genotypes 4,6 and 7 primarily observed in Asiatic countries such as the Philippines, China, Japan, and Qatar (AbuOdeh et al., 2015; Miao et al., 2017). Although HPgV-1 was initially identified in the serum of a febrile patient with jaundice (Simons et al., 1995), subsequent research confirmed its widespread occurrence and its commensal nature (Alhetheel et al., 2014; Slavov et al., 2019). No clinical picture has been attributed to HPgV-1 but studies suggest that HPgV-1 may confer beneficial effects in patients with HIV slowing the progression to AIDS and extending their survival rates (Bhattarai et al., 2012). In patients with HIV/HPgV-1 co-infection, the HIV proviral load was lower compared to HIV patients who were negative for HPgV-1 RNA. This was also associated with lower clinical markers of hepatic injury, higher levels of IL-7, and increased CD4+ counts (Vimali et al., 2023, 2024). Additionally, an association between the presence of HPgV-1 RNA and non-Hodgkin lymphoma has been observed (Krajden et al., 2010).

Febrile neutropenia (FN) is defined as an acute onset of fever, often coupled with a concomitant decline in the absolute neutrophil count (ANC) (Davis and Wilson, 2020). This condition frequently emerges as a complication of chemotherapy treatments, particularly subsequent to bone marrow transplantation (Lyman et al., 2014). Although bacterial infections are primarily implicated in instances of FN, there is also evidence to suggest that viruses and fungi may play a contributory role in the pathogenesis of this condition (Punnapuzha et al., 2023).

In individuals experiencing immune suppression, such as that induced by oncological disorders, the dynamics of commensal viruses, including that of HPgV-1, may exhibit distinct pattern. The relevance of HPgV-1 in the context of FN has not been thoroughly explored, particularly in pediatric oncology settings. In this study, which involved samples collected as part of a metagenomic investigation into the causes of FN in pediatric patients with no bacterial growth, we observed notably high numbers of sequence reads corresponding to HPgV-1. This observation prompted a more detailed investigation into the presence of this virus in the respective patients, including the detection of infection through molecular methods and subsequent HPgV-1 genotyping.

Between April-September 2023, blood samples were collected from 30 children comprising two distinct groups: 15 hospitalized children with febrile neutropenia (FN), and 15 children with oncological diseases who were either currently receiving treatment or were in remission (febrile neutropenia control group, FNC). In our study, the control group consisted of oncologic patients without febrile neutropenia. We selected this strategy, to enable more meaningful comparison, as it is uncommon for healthy individuals to develop neutropenia. Furthermore, comparing febrile neutropenic patients with healthy individuals would likely reflect more on oncological diagnosis, rather than the neutropenia itself. This research adhered to stringent ethical protocols as mandated by the Institutional Ethics Committee Board of the University Hospital of the Faculty of Medicine of Ribeirão Preto, University of São Paulo. Ethical approval for this study was granted under the reference number CAAE 66508422.0.0000.5440 and written informed consent was secured from the legal guardians of all participating minors.

Extraction was performed using 140 μL of plasma with the QIAamp Viral RNA MiniKit (QIAGEN, São Paulo, Brazil), following manufacturer's instructions. Reverse transcription was carried out using the High-Capacity cDNA Reverse Transcription Kit (ThermoFisher Scientific, Waltham, MA, USA) following manufacturer's instructions. Viral RNA was detected using real-time PCR with primers and probes available in the literature targeting the 5´-UTR genomic portion (Chang et al., 2014). The amplification was performed using GoTaq Probe 1-Step RT-qPCR System (Promega, Madison, WI, USA), 400 nM of each primer and 200 nM of the probe in a 20 μL final reaction volume. Cycle protocol contained 40 min at 40 °C for reverse transcription, 2 min at 95 °C for denaturation, and 40 cycles consisting of 95 °C for 15 s and 60 °C for 1 min (denaturation and annealing). All steps pre- and post-amplification were carried out in different laboratory rooms to avoid contamination.

Genotyping of HPgV-1 RNA was conducted using nested PCR to amplify a 379 bp fragment of the 5′-UTR region, employing previously established primer pairs (Miao et al., 2017). The 5′-UTR of HPgV-1 may play a role in regulating viral replication and translation (Grace K et al., 1999). In brief, the following primer sequences were applied (i) first reaction: forward primer GUTRF-1 (5′-GGTTGGTAGGTCGTAAATCCCG-3´) and reverse primer GUTRR-1 (5′-GGTTGGTAGGTCGTAAATCCCG-3′) and (ii) second reaction: forward primer GUTRF-2 (5′-GTAGGTCGTAAATCCCGGTCA-3′) and reverse primer GUTRR-2 (5′-CGAAGGATTCTTGGGCTACC-3′) in a final volume of 50 μL. The amplification was performed in a SimpliAmp Thermal Cycler (ThermoFisher Scientific) under the following conditions: initial denaturation at 95 °C for 5 min, and then 40 and 35 cycles (first and second reaction, respectively) composed of 95 °C for 30 s, 55 °C for 30 s, and 72 °C for 1 min, terminating with a final elongation for 10 min. The amplicons were visualized in 2 % agarose gel using a ChemiDocTM XRS Optical System (Bio-Rad, Hercules, CA, USA). Positive samples were sequenced in an ABI 3500 XL DNA sequencer using the BigDye™ Terminator v.3.1 Cycle Sequencing Kit (ThermoFisher Scientific) with 1000 nM of the primer GUTRF-2, 2 µl of sequencing buffer and 2 µl of reaction mix for a final volume of 10 µl. Cycling was composed of initial denaturation at 95 °C for 1 min, 25 cycles of 96 °C for 10 s, 50 °C for 5 s, and 60 °C for 4 min.

Alignment of the obtained HPgV-1 5′-UTR sequences with a reference dataset composed of 70 HPgV-1 sequences obtained from the Genbank was performed using MAFFT v.7 (Katoh and Standley, 2013). The manual curation of the alignment was performed using Aliview v. 1.17.1 (Larsson, 2014). A maximum likelihood phylogenetic tree was reconstructed in IQ-TREE2 v.2.3.4 (Minh et al., 2020) using a bootstrap support of 1000 replicates. ModelFinder Plus (Kalyaanamoorthy et al., 2017) was employed to determine the most suitable nucleotide substitution model prior to the phylogenetic reconstruction. The final phylogenetic tree was visualized in ggtree v. 3.10.0 (Yu, 2022) using R v.4.2.2 (R Core Team, 2018).

Evaluation of the relationship between HPgV-1 RNA presence and neutrophil count was conducted by applying Exact two-sample Kolmogorov-Smirnov test, comparing ACN on patients positive or negative for HPgV-1 within groups. Results were considered significant when p-value was <0.05. The statistical analyses were performed using R v.4.2.2 (R Core Team, 2018).

Thirty oncologic pediatric patients were included in this study. In total, the FN group consisted of 12 male (n = 12/15; 80 %) and 3 female children (n = 3/15; 20 %) with a mean age 5.6 ± 3.8 years of age. The FNC group was composed of 66.7 % male (n = 10/15) and 33.3 % female patients (n = 5/15) with a mean age of 8.1 ± 4.9 years of age. Main diagnosis in the FN group was acute lymphoblastic leukemia (ALL), present in 46.7 % of patients (n = 7/15). In the remainder, the diagnoses were very heterogeneous (lymphoma, infant leukemias, retinoblastoma, Wilms' tumor, Ewing sarcoma). The main diagnosis of the HPgV-1 positive patients is shown on Table 1.

Table 1.

Clinical and virological data of the positive for HPgV-1 RNA patients.

Sample ID Main diagnosis Complications Nested-PCR Cycle threshold Genotype
FN*6 ALL⁎⁎⁎, central nervous system relapse Concomitant convergent strabismus + 20.02 2A
FN9 Adrenal carcinoma NA + NA 2B
FN13 Infant leukemia Epistaxis, toxic liver disease with fibrosis, unspecified thrombocytopenia + 26.85 2A
FN16 ALL NA + NA 2A
FNC⁎⁎7 ALL 28.17 NA
FNC14 Retinoblastoma NA + NA 2A
FNC15 Ewing's sarcoma NA + 25.97 2B
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⁎

FN: febrile neutropenia.

⁎⁎

FNC: control group (patients with oncologic diseases who do not present febrile neutropenia).

⁎⁎⁎

ALL: Acute lymphoblastic leukemia; NA: non-applicable.

Seven out of 30 patients (n = 7/30, 23.3 %) were positive for HPgV-1 RNA. Among those patients diagnosed with febrile neutropenia, the estimated prevalence reached 26.7 % (n = 4/15), while in the control group 20.0 % (n = 3/15) of the patients were positive. The characteristics of the HPgV-1 RNA positive patients are shown in Table 1. Real-time amplification showed positive results in 4 patients (2 from the patients with FN and 2 from FNC group) with a mean cycle threshold 25.25. All samples that tested positive for HPgV-1 RNA by real-time PCR also tested positive by nested-PCR. The higher detection rates with nested-PCR were anticipated, as this method is more sensitive and capable of amplifying very low quantities of viral genetic material, at which HPgV-1 may be present.

As expected, patients with febrile neutropenia demonstrated a lower mean ANC of 1100 ± 4459.93 cells/µl compared to 1850 ± 10,371.19 cells/µl in the control group. The range of ANC in HPgV-1 positive patients varied from 100 to 11,800 cells/µl, while the control group presented a range between 0 and 26,900 cells/µl. Notably, the presence or absence of HPgV-1 did not appear to significantly impact ANC in either group (p-value = 0.4799 for FN group, p-value = 0.8799 for FNC group) (Table 2).

Table 2.

Absolute neutrophil counts among the HPgV-1 positive and negative patients.

Febrile Neutropenia
 Control Group
HPgV-1 positive
 HPgV-1 negative
 HPgV-1 positive
 HPgV-1 negative
ID* ANC⁎⁎ ID ANC ID ANC ID ANC
FN6 11,800 FN1 200 FNC7 1300 FNC1 10,200
FN9 2500 FN2 500 FNC14 1500 FNC4 100
FN13 1300 FN3 100 NFC15 1500 FNC5 1800
FN16 100 FN4 900 FNC8 8600
FN5 100 FNC9 1500
FN7 200 FNC10 2200
FN8 0 FNC11 0
FN10 100 FNC12 1700
FN11 400 FNC13 5700
FN12 8300 FNC17 2600
FN14 200 FNC19 9900
FNC21 26,900
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⁎

ID: sample identitiy.

⁎⁎

ANC: Absolute Neutrophil Count.

Sequencing of the 5′-UTR was conducted for all HPgV-1 RNA positive samples. One reaction yielded low-quality results presenting partial fragments with an excess of ambiguous bases and was excluded from further phylogenetic analysis. The best nucleotide substitution model was TVM+F + I + G4. All HPgV-1 sequences obtained in this study were classified as genotype 2 (Fig. 1). At the subgenotype level, NF9 and NFC5 were classified as subgenotype 2B, while the remaining samples were categorized as subgenotype 2A.

Fig. 1.

Fig 1

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Maximum likelihood tree encompassing 70 reference sequences of HPgV-1 and 6 HPgV-1 strains obtained in this study. All of the sequences belonged to genotype 2 (NF6, 13,16 and NFC14 belonged to subgenotype 2A and NF9 and NFC15 to subgenotype 2B). Obtained sequences were deposited in GenBank under accession numbers: PP780641–PP780643 and PQ434417–PQ434419.

In this study, we assessed the prevalence and genotypic distribution of HPgV-1 among pediatric oncologic patients experiencing febrile neutropenia, as well as those in remission or undergoing treatment for oncologic diseases. Our understanding of commensal viruses is evolving; accumulating evidence suggests that their behavior may differ in patients with immune suppression.

The overall prevalence of HPgV-2 RNA among the tested patients was 23.3 %. Current literature offers limited insights regarding the prevalence of this virus among pediatric populations. Our results align with findings from studies conducted on pediatric patients with thalassemia in Italy (Kondili et al., 2001) and Thailand (Poovorawan et al., 1998), as well as Japanese children with chronic hepatitis C (Komatsu et al., 1999), and pediatric patients in the US post-liver transplantation (Elkayam et al., 1999). However, our prevalence rates were slightly higher than those observed among pediatric patients with hematopoietic transplantation in Thailand (Ludowyke et al., 2022) and were significantly elevated compared to pediatric oncology patients in Turkey (Kocabaş et al., 1999). Various factors, such as the nature of the clinical disease or the sensitivity of the diagnostic tests, may influence the HPgV-1 prevalence. Furthermore, in Brazil, there is a lack of data on the prevalence of HPgV-1 among patients with neutropenia, and worldwide information remains also scarce.

A comparative analysis of clinical parameters between HPgV-1 positive and negative groups suggest that HPgV-1 was not correlated with the levels of absolute neutrophil count. To date, no clinical disease has been definitively linked to HPgV-1, which is often considered a commensal bystander virus. However, evidence suggests that commensal viruses can exert varying impacts on patients presenting immune suppression, potentially serving as a biological marker of immune status (Freer et al., 2018).

Given these findings, further research is necessary to explore the role of HPgV-1 in conditions of immune suppression, particularly to ascertain whether it exerts any significant effects or merely acts as a bystander. This exploration is critical for understanding the potential utility of HPgV-1 as a marker or modulator in immunocompromised states.

In our study, all sequenced samples were classified as belonging to genotype 2, encompassing both subgenotypes. This genotype is predominant in various regions including Europe, the USA, and Brazil, as reported in multiple studies (Nishiya et al., 2003; Slavov et al., 2019; da Silva et al., 2023). The analyzed sequences were interspersed among isolates from various countries and notably did not form a monophyletic cluster. This observation could be attributed to either the limited number of samples analyzed or to a diversification of HPgV-1 genotypes circulating in this part of the state of São Paulo. To date, no definitive correlation has been established between HPgV-1 genotype and the clinical outcomes of the associated diseases (Giret et al., 2011), a finding that was also consistent with our study's observations.

Our study has several limitations, most notably the relatively small number of collected samples. However, during the study period, we obtained samples from all patients presenting with febrile neutropenia, a potentially life-threatening condition in those receiving oncologic treatment. Additionally, this condition is not particularly common and therefore, the limited sample size does not diminish the importance of our study, which is a pioneering investigation highlighting the prevalence of HPgV-1 in this patient population.

In summary, this study offers valuable insights into the prevalence and distribution of HPgV-1 genotypes within a pediatric oncology population experiencing neutropenia. While our findings do not establish a direct causal relationship between the presence of HPgV-1 RNA and clinical parameters, the significance of HPgV-1 RNA in patients with immune suppression remains unclear. It is uncertain whether its presence is merely incidental or if it has potential clinical implications for influencing the progression of the underlying disease. Further research is essential to elucidate the role of HPgV-1 in this vulnerable patient cohort, which may enhance our understanding of viral behavior in immunocompromised states.

CRediT authorship contribution statement

Anielly Sarana da Silva: Writing – original draft, Methodology, Investigation, Formal analysis, Data curation. Gabriel Montenegro de Campos: Writing – original draft, Software, Methodology, Investigation, Formal analysis, Data curation. Gabriela Marengone Altizani: Methodology, Investigation, Formal analysis, Data curation. Alice Chagas Barros: Methodology, Investigation. Dennis Maletich Junqueira: Software, Methodology, Investigation, Formal analysis. Simone Kashima: Methodology, Investigation, Formal analysis. Sandra Coccuzzo Sampaio: Writing – original draft, Software, Resources, Formal analysis. Maria Carolina Elias: Resources, Formal analysis, Data curation. Marta Giovanetti: Software, Methodology, Investigation, Formal analysis, Conceptualization. Carlos Alberto Scrideli: Writing – original draft, Supervision, Investigation, Formal analysis, Data curation, Conceptualization. Svetoslav Nanev Slavov: Writing – original draft, Supervision, Project administration, Investigation, Funding acquisition, Formal analysis, Conceptualization.

Declaration of competing interest

The authors declare no competing interests.

Acknowledgements

This project was financially supported by the São Paulo Research Foundation (FAPESP) project numbers 22/14958–0, 22/00910–6, 17/23205–8 (Young Researcher Project), 21/11944–6 (CeVIVAs) and the Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq), Brazil (project number 403075/2023). Svetoslav Slavov receives scientific productivity scholarship (CNPq) 305111/2022–1. We are also grateful to Sandra Navarro Bresciani for the figures.

Data availability

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