Maurício Cristiano Rocha–Junior

Universidade de São Paulo

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Dimas Tadeu Covas

Instituto Butantan

Simone Kashima

Universidade de São Paulo

Rodrigo Haddad

Universidade de Brasília

Eduardo Antônio Donadi

Universidade de São Paulo

Evandra Strazza Rodrigues

Clinics Hospital of Ribeirão Preto

Svetoslav Nanev Slavov

Instituto Butantan

Osvaldo Massaiti Takayanagui

Universidade de São Paulo

O. M. Takayanagui

Universidade de São Paulo

Ana Cristina Silva‐Pinto

Universidade de São Paulo

Daiani Cristina Cilião‐Alves

Centro Universitário Euroamericano

Cooperative Institutions

Universidade de São Paulo

Clinics Hospital of Ribeirão Preto

Universidade de Ribeirão Preto

Fundação Hemopa

Universidade Brasil

Hospital das Clínicas da Faculdade de Medicina da Universidade de São Paulo

Universidade de Brasília

Fundação Oswaldo Cruz

Universidade Federal do Rio de Janeiro

Instituto de Medicina Tropical

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HLA-G 3′-untranslated region polymorphisms are associated with HTLV-1 infection, proviral load and HTLV-associated myelopathy/tropical spastic paraparesis development

Journal of General Virology (2016)

Daiani Cristina Cilião Alves Rodrigo Haddad Maurício Cristiano Rocha–Junior Virgínia Mara de Deus Wagatsuma Gustavo Martelli‐Palomino

Most human T-lymphotropic virus type 1 (HTLV-1)-infected patients remain asymptomatic throughout life. The factors associated with HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP) development have not been fully elucidated; immunological and genetic factors may be involved. The association of 14 bp INS/DEL HLA-G polymorphism with HTLV-1 infection susceptibility has been reported previously. Here, other polymorphic sites at the HLA-G 3′-UTR (14-bp D/I, +3003C/T, +3010C/G, +3027A/C, +3035C/T, +3142C/G, +3187A/G and +3196C/G) were evaluated in 37 HTLV-1-infected individuals exhibiting HAM/TSP, 45 HTLV-1 asymptomatic carriers (HAC) and 153 uninfected individuals, followed up at University Hospital of the Faculty of Medicine of Ribeirão Preto, University of São Paulo, Brazil. It was observed that: (i) 14bpDI genotype is a risk factor for HTLV-1 infection, while the 14bpDD and +3142CC genotypes were associated with protection against infection; (ii) the +3142C allele and the +3003CT and +3142CC genotypes were associated with susceptibility, while 14bpII and +3003TT genotypes were associated with protection against HAM/TSP development; and (iii) the 14bpII, +3010CC, +3142GG and +3187AA genotypes were associated with lower HTLV-1 proviral load compared to respective counterpart genotypes. Findings that HLA-G has a well-recognized immunomodulatory role and that the genetic variability at HLA-G 3′-UTR may post-transcriptionally modify HLA-G production indicate a differential genetic susceptibility to: (i) the development of HTLV-1 infection, (ii) the magnitude of HTLV-1 proviral load and (iii) HAM/TSP development.

Tropical spastic paraparesis

Human T-lymphotropic virus

Asymptomatic carrier

HLA-G

10.1099/jgv.0.000559

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Citations (8)

No evidence of xenotropic murine leukemia virus-related virus infection in Brazilian multiply transfused patients with sickle cell disease and beta-thalassemia major.

PubMed (2014)

Svetoslav Nanev Slavov Kátia Kaori Otaguiri Mayra Dorigan de Macedo Maurício Cristiano Rocha–Junior Ana Cristina Silva‐Pinto

Although xenotropic murine leukemia virus-related virus (XMRV) has been regarded as a laboratory contaminant, it remains one of the most controversial viruses. The objective of the study was to determine if XMRV is present in 44 patients with beta-thalassemia major, 48 with sickle cell disease, and 89 volunteer blood donors. After RNA/ DNA extraction from plasma/buffy coat the samples were screened for XMRV sequences by conserved nested GAG primers. None of the RNA samples showed a positive result. Surprisingly, four DNA samples obtained from blood donors were positive for XMRV provirus. The subsequent phylogenetic analysis revealed that these sequences are identical to the positive control (murine leukemia retrovirus) and are probably consistent with laboratory contamination. XMRV infection (provirus and viral RNA) was absent in multiply transfused patients and volunteer blood donors. The positive result obtained from some blood donors probably reflects laboratory contamination. We believe that XMRV does not pose risk to blood transfusion.

Provirus

Buffy coat

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Interleukin‐18 and interferon‐gamma polymorphisms are implicated on proviral load and susceptibility to human T‐lymphotropic virus type 1 infection

Tissue Antigens (2012)

Maurício Cristiano Rocha–Junior Rodrigo Haddad Daiani Cristina Cilião Alves Virgínia Mara de Deus Wagatsuma Celso Teixeira Mendes‐Junior

Interleukin‐18 (IL‐18) and interferon‐gamma (IFN‐γ) exert important functions in both innate and adaptive immune responses against intracellular pathogens and viruses. Previous studies suggested that host genetic factors, including cytokines gene polymorphisms, could be involved in the pathogenesis of human T‐cell leukemia virus type 1 (HTLV‐1)‐associated myelopathy/tropical spastic paraparesis (HAM/TSP). Thus, we analyzed −137C/G and −607A/C of the IL‐18 promoter and +874T/A of the IFN‐γ in DNA samples from 98 HTLV‐1‐infected individuals exhibiting or not clinical symptoms and 150 healthy control individuals. The IL‐18 promoter −607CC genotype was significantly lower in HTLV‐1 asymptomatic carriers (HAC) and HTLV‐1‐infected individuals (HAC + HAM/TSP) than healthy control group. In contrast, the −607AC genotype was significantly higher in HAC and HTLV‐1‐infected individuals group compared to the healthy control group. The −137G/−607A IL‐18 haplotype was higher in infected group than healthy control group, and the −137C/−607C IL‐18 haplotype was increased in the healthy control group compared to the others. Finally, the IFN‐γ polymorphism analysis showed that the HTLV‐1‐infected individuals with +874AT genotype presented higher proviral load than +874AA genotype. These data indicate that the IL‐18 −607AC genotype and −137G/−607A haplotype could be a risk factor for HTLV‐1 infection, whereas the protective effect could be conferred by −607CC genotype and −137C/−607C haplotype. Also, the IFN‐γ could be implicated on the proviral load levels.

Tropical spastic paraparesis

Pathogenesis

10.1111/j.1399-0039.2012.01887.x

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Citations (19)

HLA-G 14-bp Insertion/Deletion Polymorphism Is a Risk Factor for HTLV-1 Infection

AIDS Research and Human Retroviruses (2010)

Rodrigo Haddad Daiani Cristina Cilião Alves Maurício Cristiano Rocha–Junior Rochele Azevedo Maria do Socorro Pombo–de–Oliveira

About 95% of HTLV-1 infected patients remain asymptomatic throughout life, and the risk factors associated with the development of related diseases, such as HAM/TSP and ATL, are not fully understood. The human leukocyte antigen-G molecule (HLA-G), a nonclassical HLA class I molecule encoded by MHC, is expressed in several pathological conditions, including viral infection, and is related to immunosuppressive effects that allow the virus-infected cells to escape the antiviral defense of the host. The 14-bp insertion/deletion polymorphism of exon 8 HLA-G gene influences the stability of the transcripts and could be related to HTLV-1-infected cell protection and to the increase of proviral load. The present study analyzed by conventional PCR the 14-bp insertion/deletion polymorphism of exon 8 HLA-G gene in 150 unrelated healthy subjects, 82 HTLV-1 infected patients with symptoms (33 ATL and 49 HAM), and 56 asymptomatic HTLV-1 infected patients (HAC). In addition, the proviral load was determined by quantitative real-time PCR in all infected groups and correlated with 14-bp insertion/deletion genotypes. The heterozygote genotype frequencies were significantly higher in HAM, in the symptomatic group, and in infected patients compared to control (p < 0.05). The proviral load was higher in the symptomatic group than the HAC group (p < 0.0005). The comparison of proviral load and genotypes showed that −14-bp/−14-bp genotype had a higher proviral load than +14-bp/−14-bp and +14-bp/+14-bp genotypes. Although HLA-G 14-bp polymorphism does not appear to be associated with HTLV-1 related disease development, it could be a genetic risk factor for susceptibility to infection.

Heterozygote advantage

10.1089/aid.2010.0165

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Citations (28)

Rapid blood group genotyping by allelic discriminative real‐time PCR in multiply‐transfused patients

Transfusion Medicine (2015)

Evandra Strazza Rodrigues Mayra Dorigan de Macedo Fernanda Ursoli de Melo Maurício Cristiano Rocha–Junior Virgínia Mara de Deus Wagatsuma

Center (category theory)

10.1111/tme.12186

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Citations (5)

Rapid and Sensitive Qualitative Duoplex Real-Time PCR Method for Discriminatory and Confirmatory Diagnosis of HTLV-1 and HTLV-2 Infections: Brazilian Multicentric Study

Frontiers in Medicine (2022)

Maurício Cristiano Rocha–Junior Evandra Strazza Rodrigues Svetoslav Nanev Slavov Tatiane Assone Maíra Pedreschi

Human T cell lymphotropic virus (HTLV) is the caustive agent of two main conditions i. e., the HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP) and the adult T-cell leukemia/lymphoma (ATLL). HTLV diagnosis is based on serological and molecular approaches; however, an accurate and validated method is still needed. The objective of this study was to establish a rapid and sensitive molecular test to confirm and discriminate HTLV 1/2 types. The test validation was performed as a multicentric study involving HTLV confirmation centers throughout Brazil. Proviral DNA was extracted from whole blood and the amplification was performed using in-house designed primer and probe sets targeting the pol genomic region. An internal control to validate the extraction and amplification was also included. The limit of detection (LoD) of the assay was four copies/reaction for HTLV-1 and 10.9 copies/reaction for HTLV-2. The diagnostic sensitivity of the platform was 94.6% for HTLV-1, 78.6% for HTLV-2, and the specificity was 100% for both viruses. Cross-reactions of the test with human viruses including HAV, HBV, HCV, HIV-1/2, and parvovirus B19 were not observed. During the multicentric validation, the test was used to screen a total of 692 blood samples obtained from previously confirmed HTLV-positive individuals. From these, 91.1% tested positive being concordant with the previously obtained results. In conclusion, our duoplex-RT-PCR-HTLV1 /2 presented adequate efficiency for HTLV-1/2 differentiation showing high sensitivity and specificity. Therefore, it can be a suitable tool for confirmation of suspected and inconclusive HTLV cases, prenatal and pre-transplant diagnosis, in Brazil and in other countries HTLV-endemic countries.

Tropical spastic paraparesis

Primer (cosmetics)

10.3389/fmed.2022.881630

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Citations (3)

Development of a molecular platform for HTLV confirmatory diagnosis: importance of the internal amplification control

Retrovirology (2011)

Maurício Cristiano Rocha–Junior Rodrigo Haddad Evandra Strazza Rodrigues Osvaldo Massaiti Takayanagui Dimas Tadeu Covas

Background Brazil may harbor the largest absolute number of HTLV-1-infected individuals worldwide. The current HTLV diagnosis is based mainly on antibodies detection. However, these tests exhibit high proportion of indeterminate results. Several real-time PCR techniques have been developed for the detection of HTLV-1/2. However, up to day the major drawbacks of HTLV-1/2 molecular diagnosis are the lack of standard molecular tests and the absence of suitable internal amplification control (IAC). The aim of this study was to develop a multiplex qualitative real-time PCR for the simultaneous detection and discrimination of HTLV-1/2 and to design an IAC for reaction monitoring. Methods After multiple sequence alignments of the full genomes of HTLV-1/2 subtypes, a conserved tax region was chosen for the design of specific primers and probes. The IAC was generated after the annealing of synthetic nucleotide sequences and cloned into TOPO TA ® vector. MT-2 and Gu cell lines were used as positive controls for HTLV-1 and HTLV-2, respectively. Results The developed multiplex real-time reaction detected both HTLV-1 and HTLV-2 (105 to 101 copies/reaction) at the presence of IAC in the same reaction. Analytical sensitivity was 1.2 copies/reaction for HTLV-1 and 19.1 copies/reaction for HTLV-2. The analytical sensitivity analysis was performed in singleplex format. Conclusion The detection of HTLV-1/2 and IAC by multiplex realtime PCR was efficient. The developed IAC is suitable for the molecular diagnosis and its presence ensures that the negative results are not due to failure in prePCR procedures.

Multiplex

10.1186/1742-4690-8-s1-a251

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Citations (0)

Frequent human parvovirus B19DNA occurrence and high seroprevalence in haemophilic patients from a non‐metropolitan blood centre, Brazil

Transfusion Medicine (2014)

Svetoslav Nanev Slavov Simone Kashima Maurício Cristiano Rocha–Junior Léa Campos de Oliveira Ana Cristina Silva‐Pinto

Transfusion medicine

10.1111/tme.12113

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Citations (9)

HLA-G 3142C/G polymorphism is related to development of symptoms in HTLV-1 infected individuals

Retrovirology (2014)

Daiani Cristina Cilião‐Alves Maurício Cristiano Rocha–Junior Rodrigo Haddad Virgínia M D Wagatsuma Osvaldo Massaiti Takayanagui

The majority of HTLV-1 infected individuals remain asymptomatic (HAC) throughout life, and the risk factors associated to the development of related diseases, such as HAM/TSP and ATL, are not fully understood. The human leukocyte antigen-G (HLA-G) is expressed in several pathological conditions and it has been associated to immunosuppressive effects allowing the virusinfected cells to escape of the host antiviral defense. Here, we evaluated the correlation between HLA-G polymorphisms in symptomatic and asymptomatic HTLV-1 infected individuals. Four polymorphisms of the exon 8 of the HLA-G gene were analysed by gene sequencing in HAC (n=48) and HAM/TSP patients (n=43). No difference was found between the groups for 3035C/T, 3187A/G and 3196C/G polymorphisms. On the other hand, despite of the absence of statistical significance, HAC group showed higher frequency of the 3142GG genotype (responsible for decreased transcription of theHLA-G) compared to HAM/TSP group (p=0,0607). Still, HAC group showed lower frequency of the 3142CC genotype (responsible for increased transcription of the HLA-G) compared to HAM/TSP group (p=0,0762). Furthermore, HAC group showed statistically higher frequency of the 3142G allele and lower frequency of the 3142C allele compared to HAM/TSP group (p=0,0244). In conclusion, HTLV-1-related symptoms in HAM/TSP group could be partially determined by higher expression of HLA-G (caused by higher frequency of the 3142C allele). We hypothesise that the higher expression of HLA-G protects the HTLV-1 infected cell against immune system attack the increasing proviral load and trigger the HAM/TSP symptoms. Financial support FUNDHERP, FAPESP and CNPq.

HLA-G

10.1186/1742-4690-11-s1-p74

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Citations (1)

Association of interleukin - 18 gene polymorphism with susceptibility or protective effect to HTLV-1 infection

Retrovirology (2011)

Virgínia M D Wagatsuma Daiani Cristina Cilião‐Alves Maurício Cristiano Rocha–Junior Rodrigo Haddad O. M. Takayanagui

Methods The promoter region polymorphic sites (-137C/G and -607A/C) were evaluated by polymerase chain reaction sequence specific primers (PCR-SSP) analysis using peripheral blood DNA obtained from HAC (54), HAM (44) and healthy control (150) individuals. Proviral load of infected patients (HAC and HAM) was determined by real-time PCR. Results The -607CC genotype was less frequent for HAC group (p=0.0501; OR=0.4890; CI=0.2480 to 0.9643), and infected patients (p=0.0232; OR=0.5207; CI=0.3033 to 0.8937) compared to healthy controls. The -607AC genotype was more frequent for HAC group (p=0.0387; OR=1.991; CI=1.043 to 3.801), and infected patients (p=0.0376; OR=1.757; CI=1.047 to 2.948) compared to healthy controls. No significant difference was observed for allelic and genotypic frequencies of the -137C/G among deferments groups. No significant difference was observed for allelic and genotypic frequencies of the -137C/G and -607A/C polymorphisms when correlated with proviral load. Conclusion The -607CC (high producer of IL-18) genotype exhibited protective effect against the infection, whereas the -607AC genotype conferred susceptibility to HTLV-1 infection.

10.1186/1742-4690-8-s1-a118

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Citations (2)