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Difficulties in the diagnosis of HTLV-2 infection in HIV/AIDS patients from Brazil: comparative performances of serologic and molecular assays, and detection of HTLV-2b subtype

Dificuldades no diagnóstico de infecção por HTLV-2 em pacientes com HIV/Aids do Brasil: análise comparativa de ensaios sorológicos e moleculares e detecção de subtipo HTLV-2b

Abstracts

The current diagnosis of human T-lymphotropic virus type-2 (HTLV-2) infection is based on the search of specific antibodies; nevertheless, several studies conducted in Brazil pointed deficiencies of the commercially available kits in detecting HTLV-2, mostly in HIV/AIDS patients. This study searched for the presence of HTLV-1 and -2 in 758 HIV/AIDS patients from Londrina, Paraná, Brazil. Serum samples were screened for HTLV-1/2 antibodies using two EIA kits (Vironostika and Murex), and confirmed by WB (HTLV Blot 2.4, Genelabs). The results obtained by EIA disclosed 49 (6.5%) reactive sera: 43 positive by both EIA kits, and six with discordant results. WB confirmed HTLV-1 infection in seven samples (0.9%) and HTLV-2 in 21 sera (2.8%). Negative and indeterminate results were detected in four (0.5%) and 16 (2.1%) sera, respectively. Blood from 47 out of 49 HTLV seroreactive patients were collected and analyzed for the presence of env, LTR and tax genomic segments of HTLVs by PCR. PCR confirmed six cases of HTLV-1 and 37 cases of HTLV-2 infection (14 out of 16 that were found to be WB indeterminate). Restriction analysis of the env PCR products of HTLV-2 disclosed 36 isolates of HTLV-2a/c subtype, and one of HTLV-2b subtype. These results emphasize the need of improving serologic tests for detecting truly HTLV-2 infected patients from Brazil, and confirm the presence of HTLV-2b subtype in the South of this country.

Human T-lymphotropic virus type 2 (HTLV-2); HIV/HTLV-2 coinfection; Diagnosis; Serology; PCR; HTLV-2 subtype


O diagnóstico de infecção por HTLV-2 se baseia na pesquisa de anticorpos específicos, entretanto, vários estudos conduzidos no Brasil têm apontado falhas nos kits sorológicos disponíveis no mercado em detectar HTLV-2, principalmente nos pacientes com HIV/aids. Este trabalho avaliou a presença de infecção por HTLV-1 e -2 em 758 pacientes HIV/aids de Londrina, Paraná, Brasil. Amostras de soro foram analisadas quanto à presença de anticorpos anti-HTLV-1/2 por dois kits de EIA (Vironostika e Murex) e confirmados por WB (HTLV Blot 2.4, Genelabs). Os resultados obtidos pelos testes sorológicos mostraram 49 (6,5%) soros reagentes: 43 positivos para ambos os kits e seis com resultados discordantes. O WB confirmou infecção por HTLV-1 em sete soros (0,9%) e HTLV-2 em 21 soros (2,8%). Resultados negativos e indeterminados foram detectados, respectivamente, em quatro (0,5%) e 16 (2,1%) soros. Amostras de sangue de 47 dos 49 pacientes com sorologia reagente foram avaliadas quanto à presença de segmentos do genoma dos HTLVs (env, LTR e tax), usando a técnica de PCR. As PCRs confirmaram seis casos de infecção por HTLV-1 e 37 casos por HTLV-2 (14 dos 16 cuja sorologia resultou WB indeterminada). A subtipagem de HTLV-2 por análise de restrição enzimática de produtos da PCR env mostrou 36 isolados de subtipo HTLV-2a/c e um HTLV-2b. Esses resultados reforçam a necessidade de melhorar o diagnóstico de infecção por HTLV-2 no Brasil e confirmam a presença do subtipo HTLV-2b na região sul do país.


HIV

Difficulties in the diagnosis of HTLV-2 infection in HIV/AIDS patients from Brazil: comparative performances of serologic and molecular assays, and detection of HTLV-2b subtype

Dificuldades no diagnóstico de infecção por HTLV-2 em pacientes com HIV/Aids do Brasil: análise comparativa de ensaios sorológicos e moleculares e detecção de subtipo HTLV-2b

Helena Kaminami MorimotoI; Arilson Akira MorimotoII; Edna Maria Vissoci ReicheI; Luiz Toshio UedaIII; Tiemi MatsuoIV; Fernando Vissoci ReicheV; Adele Caterino-de-AraujoVI

IDepartamento de Patologia, Análises Clínicas e Toxicológicas, Centro de Ciências da Saúde, Universidade Estadual de Londrina, Paraná, Brasil

IIDivisão de Doenças Infecciosas, Departamento de Medicina Clínica, Centro de Ciências da Saúde, Universidade Estadual de Londrina, Paraná, Brasil

IIICentro Integrado de Doenças Infecciosas de Londrina, Londrina, Paraná, Brasil

IVCentro de Ciências Exatas e Bioestatística, Universidade Estadual de Londrina, Paraná, Brasil

VEscola de Medicina, Centro de Ciências da Saúde, Universidade Estadual de Londrina, Paraná, Brasil

VISeção de Imunologia, Instituto Adolfo Lutz, São Paulo, SP, Brasil

Correspondence to Correspondence to: Dra. Adele Caterino-de-Araujo Instituto Adolfo Lutz, Seção de Imunologia Av. Dr. Arnaldo 355, 11º andar 01246-902 São Paulo, SP, Brasil Phone/Fax: 55-11-30682898 E-mail: caterino@ial.sp.gov.br

SUMMARY

The current diagnosis of human T-lymphotropic virus type-2 (HTLV-2) infection is based on the search of specific antibodies; nevertheless, several studies conducted in Brazil pointed deficiencies of the commercially available kits in detecting HTLV-2, mostly in HIV/AIDS patients. This study searched for the presence of HTLV-1 and -2 in 758 HIV/AIDS patients from Londrina, Paraná, Brazil. Serum samples were screened for HTLV-1/2 antibodies using two EIA kits (Vironostika and Murex), and confirmed by WB (HTLV Blot 2.4, Genelabs). The results obtained by EIA disclosed 49 (6.5%) reactive sera: 43 positive by both EIA kits, and six with discordant results. WB confirmed HTLV-1 infection in seven samples (0.9%) and HTLV-2 in 21 sera (2.8%). Negative and indeterminate results were detected in four (0.5%) and 16 (2.1%) sera, respectively. Blood from 47 out of 49 HTLV seroreactive patients were collected and analyzed for the presence of env, LTR and tax genomic segments of HTLVs by PCR. PCR confirmed six cases of HTLV-1 and 37 cases of HTLV-2 infection (14 out of 16 that were found to be WB indeterminate). Restriction analysis of the env PCR products of HTLV-2 disclosed 36 isolates of HTLV-2a/c subtype, and one of HTLV-2b subtype. These results emphasize the need of improving serologic tests for detecting truly HTLV-2 infected patients from Brazil, and confirm the presence of HTLV-2b subtype in the South of this country.

Keywords: Human T-lymphotropic virus type 2 (HTLV-2); HIV/HTLV-2 coinfection; Diagnosis; Serology; PCR; HTLV-2 subtype.

RESUMO

O diagnóstico de infecção por HTLV-2 se baseia na pesquisa de anticorpos específicos, entretanto, vários estudos conduzidos no Brasil têm apontado falhas nos kits sorológicos disponíveis no mercado em detectar HTLV-2, principalmente nos pacientes com HIV/aids. Este trabalho avaliou a presença de infecção por HTLV-1 e -2 em 758 pacientes HIV/aids de Londrina, Paraná, Brasil. Amostras de soro foram analisadas quanto à presença de anticorpos anti-HTLV-1/2 por dois kits de EIA (Vironostika e Murex) e confirmados por WB (HTLV Blot 2.4, Genelabs). Os resultados obtidos pelos testes sorológicos mostraram 49 (6,5%) soros reagentes: 43 positivos para ambos os kits e seis com resultados discordantes. O WB confirmou infecção por HTLV-1 em sete soros (0,9%) e HTLV-2 em 21 soros (2,8%). Resultados negativos e indeterminados foram detectados, respectivamente, em quatro (0,5%) e 16 (2,1%) soros. Amostras de sangue de 47 dos 49 pacientes com sorologia reagente foram avaliadas quanto à presença de segmentos do genoma dos HTLVs (env, LTR e tax), usando a técnica de PCR. As PCRs confirmaram seis casos de infecção por HTLV-1 e 37 casos por HTLV-2 (14 dos 16 cuja sorologia resultou WB indeterminada). A subtipagem de HTLV-2 por análise de restrição enzimática de produtos da PCR env mostrou 36 isolados de subtipo HTLV-2a/c e um HTLV-2b. Esses resultados reforçam a necessidade de melhorar o diagnóstico de infecção por HTLV-2 no Brasil e confirmam a presença do subtipo HTLV-2b na região sul do país.

INTRODUCTION

Human T-lymphotropic virus type 2 (HTLV-2) is a human retrovirus which is endemic in Amerindians from the Amazon region of Brazil, as well is epidemic among HIV/AIDS patients living in urban areas of this country28.

A recent molecular subtype of HTLV-2, named HTLV-2c, was recognized among endemic and epidemic populations from Brazil13,15,16,18. The HTLV-2c is phylogenetically related to HTLV-2a, but possess an extended Tax protein, similar to HTLV-2b8,15,17. This diversity could account for the designation of HTLV-2c, which by some authors was previously considered as a molecular variant of HTLV-2a1,12,19,30,32.

In spite of the proximity of Brazil to other Latin America countries where HTLV-2b is endemic28, only recently this subtype was reported among urban population in Porto Alegre, South of Brazil27.

The routes of HTLV-2 transmission/acquisition differ from endemic and epidemic populations: breastfeeding and sexual contact has been reported as the major routes of transmission in endemic populations, while parenteral transmission by intravenous drug use (IDU) or sexual contact with IDU, are responsible for epidemic transmission of HTLV-229.

Unfortunately, for Brazilian population, commercially available serologic kits lack in confirming HTLV-2 infection, especially in HIV/AIDS coinfected patients6,9. Indeed, although the controversial role of HTLV-2 in the pathogenesis of several diseases, an association of neurological syndromes, pneumonia, bronchitis and arthritis, have been documented in HTLV-2-infected patients, as well as cutaneous lymphoma in few cases of HIV/HTLV-2 co-infected patients3-4,21,28. Paradoxically, antiretroviral therapy increases HTLV-2 proviral load, and may alter the course of HIV disease22,25. Thus, it is important to know the real status of HTLV-2 in HIV/AIDS patients in order to properly attend these individuals.

The aim of the present study was to detect the real prevalence of HTLV-2 infection in HIV/AIDS patients from the South of Brazil using serologic and molecular assays, and by restriction analysis of one segment of the env gene of HTLV-2, confirm HTLV-2b subtype in this geographic area.

MATERIAL AND METHODS

Ethical aspects: The study was approved by the Ethics Committees of Universidade Estadual de Londrina and of Universidade de São Paulo. Patients were enrolled either at admission to the health care units or during regular medical visits and were included after signing an informed consent form.

Study population: A cross-sectional study was conducted as an epidemiological investigation with descriptive and analytical components. Serial blood samples were obtained by time, place and conveniences. The population consisted of HIV-1-infected patients seen at different Regional Health Units of the AIDS Reference Centers (located in the cities of Londrina, Cornélio Procópio, Jacarezinho and Ivaiporã, in Paraná State, South Brazil).

Serologic screening tests for HTLV-1/2: Blood samples were collected from September 2001 to December 2002 and were tested for anti-HTLV-1/2 antibodies using two EIA kits with different antigens: one consisting of purified viral lysates of HTLV-1 and HTLV-2, associated with recombinant antigen p21E of HTLV-1 (VironostikaTM HTLV-I/II, BioMeriéux, Bostel, The Netherlands), and the other consisting of a synthetic peptide from the envelope protein of HTLV-1 and HTLV-2 associated with a recombinant transmembrane protein of HTLV-2 (MurexTM HTLV-I+II, Abbott, Dartford Kent England, UK). Reactive and discordant EIA samples were submitted to a confirmatory WB (HTLV BLOT 2.4TM, Abbott Murex, Singapore System, Abbott, Delkenhein, Germany). All assays were conducted and analyzed according to manufacturer instructions.

Molecular biology approaches to confirm HTLV-1 and -2 infections: Patients who presented reactive or indetermined results on WB assay were recalled for a new blood sampling. Peripheral mononuclear blood cells (PBMC) were obtained by density gradient centrifugation (HistopaqueTM - 1077, Sigma, St. Louis, USA) and stored dry at -20 ºC for DNA extraction and polymerase chain reaction (PCR). Several genomic segments of HTLV-1 and HTLV-2 were amplified to confirm HTLV-1 and HTLV-2 infection and to discard false-negative or indeterminate results obtained by WB. Primers of the LTR, env and tax regions of the genome were used as previously described, and summarized in Table 17. In addition, to confirm the HTLV-2b subtype, restriction fragment length polymorphism (RFLP) analyses were performed using the PCR env products and the restriction enzyme XhoI, of which the restriction site is present in HTLV-2a and 2c env sequences7-8, and absent in HTLV-2b5.

RESULTS

From September 2001 to December 2002, 784 HIV-1-infected patients were attended at the AIDS Reference Centers in Londrina and region where their blood samples were collected. Twenty-six (3.3%) of 784 patients did not allow blood collection and were excluded from the study. Among 758 serum samples analyzed for the presence of HTLV-1/2 antibodies by the EIA viral lysate kit and EIA recombinant kit, 709 (93.5%) resulted non-reactive and 49 (6.5%) were reactive in at least one of the kits.

Forty-three sera (87.8%) presented concordant results with EIA tests; out of these, two (4.7%) were WB negative, seven (16.3%) confirmed infection by HTLV-1, 21 (48.8%) by HTLV-2, one (2.3%) by HTLV. It was not possible to confirm infection by HTLV in 12 cases (27.9%), evidencing an indeterminate WB pattern (Table 2).

Six serum samples (12.2%) resulted discordant in the screening EIA tests, and when analyzed by WB, two (33.3%) were considered negative and four (66.7%) HTLV indeterminate (Table 2).

For the 49 reactive or discordant samples in the serologic screening, it was possible to perform PCR in 47 cases (95.9%), of which four (8.5%) resulted negative and 43 (91.5%) confirmed the presence of DNA/HTLV in the PBMC for the three different regions of the genome. Of these, 37 (86%) were HTLV-2 positive and six (14%) were HTLV-1 positive. One sample (pt. 44) showed discordant results: HTLV-1 seroreactivity and HTLV-2 truly infection by PCR analysis. This patient was then referred to a new blood collection and the results confirmed previous information (Table 2).

Using WB as the "gold standard" to define HTLV-1 and -2 infections, the results demonstrated that both EIA kits were highly sensitive in detecting HTLV-1 and HTLV-2 antibodies (Table 3). On the other hand, in using PCR as the "gold standard", the ELISA recombinant test was more sensitive than the viral lysate EIA for detecting HTLV-2-specific antibodies (100.0% vs 89% sensitivity, respectively) (Table 4). When a 20.0% reduced cut-off value was used for the viral lysate assay, the sensitivity of HTLV-2 antibody detection was increased; however, one case that was classified as HTLV-2 positive by PCR remained negative with the reduced cut-off (pt. 6, Table 2).

The 37 PCR positive samples for HTLV-2 had their env PCR products tested by the RFLP technique in order to rapidly search for HTLV-2b subtype. One out of 37 amplicons did not present the restriction site for enzyme XhoI and was subtyped as HTLV-2b, while 36 (97.3%) presented this site and were subtyped as HTLV-2a/c.

DISCUSSION

The municipality of Londrina ranks second in the number of AIDS cases in the Paraná State, Brazil, and almost the totality of HIV/AIDS patients attended at the AIDS Reference Centers in Londrina and region during the years of 2001-2002 had their blood collected and analyzed previously for the seroprevalence and risk factors for HTLV-1 and -2, as well as hepatitis B virus (HBV), hepatitis C virus (HCV) and syphilis. The results obtained disclosed an overall seroprevalence of 6.4% for HTLV-1/2; 0.8% for HTLV-1 and 4.9% for HTLV-2, and a strong association with IDU24. On the other hand, Brazil is a country which possess HTLV-2 endemic and epidemic populations, but the majority of epidemiological and molecular studies referred data on the North and Southeast regions of Brazil28. Only very recently, a study conducted in Porto Alegre, South of Brazil, disclosed the presence of both, HTLV-2a and HTLV-2b among urban individuals from this geographic area. Thus, in order to add some information concerning HTLV-1 and -2 infections in the South of Brazil, we conducted the present study.

The same cohort of HIV/AIDS patients from Londrina and region early evaluated for HTLV-1/2 seroprevalence24, were now confirmed HTLV-1 and -2 infected by molecular approaches, and careful analysis of serologic screening tests was performed in order to establish the ideal testing algorithm useful in Brazil.

The serological analysis disclosed both EIAs as 100% sensitive in detecting HTLV-1 infection, the same sensitivity previously described for HTLV-1 infection in Japan14. In contrast, for HTLV-2 truly infection, the viral lysate EIA kit detected only 89% of cases, while the recombinant EIA, 100% of cases. These results are in accordance with the results obtained by others2,26.

The strategy of using two, instead of one, EIA screening test for HTLV-2 serology, increased the sensitivity in detecting HTLV-2 from 89.9% to 97.5%31. Indeed, the EIAs which have recombinant proteins and/or synthetic peptides of HTLV-1 and of HTLV-2 and that use the "sandwich" principle, are highly sensitive and specific in detecting HTLV antibodies when compared with indirect assays that use only viral lysates2,33. Here, the recombinant test ("sandwich") showed the best performance in detecting HTLV-2-infected patients, including patients whose sera resulted indeterminate on WB.

Of note, the indeterminate WB profile observed in the present study differs from the HTLV-1 gag indeterminate profile (HGIP) described in Africa, associated with P. falciparum infection23. Here, the majority of sera presented reactivity to GD21 and/or gp46-II, p24, and could reflect HTLV-2 seroconversion. Delayed HTLV-1 seroconversion in sero-indeterminate blood donors from endemic regions were early detected11.

Previous studies showed that WB has a sensitivity ranging from 70% to 84% in detecting HTLV-2 infection26,31, and the PCR's sensitivity of 85.1%20. Thus, both tests lack in detecting all HTLV-2-infected cases, requiring an association of the WB and PCR assays26.

The Centers for Disease Control (CDC) using a questionnaire sent to several laboratories in the United States showed that only 18.5% of the laboratories performed the WB test, and 8.8% used other methods including PCR, antigen detection, radioimmunoprecipitation assay (RIPA), and viral culture10. At Brazilian blood centers, the serologic screening of HTLV-1/2 infection with two EIAs of different principles seems to be enough to discard donation bags. On the other hand, whether the purpose is to diagnose HTLV-2 infection in high-risk population, the recombinant EIA and PCR assays seems to be the best choice.

An interesting event detected in the present study was the discordant results obtained by WB and PCR in one patient; he was considered HTLV-1-infected by the WB test, and HTLV-2-infected by the PCR of the env, LTR and tax regions of the virus genome. A second blood collection and analyses of this patient supported the results previously obtained. Thus, we could hyphotesize that antibodies against gp46 of the HTLV-2 strain that infect this patient cross-react with the rgp46-I present on the WB strip. Similar discordant results were described in other infected patients from Brazil6,9.

The sole HTLV-2b case detected in the present study contrast with the large number of cases detected in Porto Alegre27. Nevertheless, we have to consider the risk factors and HIV status of the populations analyzed, which could influence on the results obtained. Interestingly, the HTLV-2b-infected patient from Londrina was of a Paraguayan origin.

In conclusion, the data presented in this study suggest the use of recombinant EIA as screening, and PCR as confirmatory tests in HTLV-2 diagnosis of high-risk population of Brazil, and confirm the presence of HTLV-2b in the South of this country.

Received: 25 July 2006

Accepted: 28 November 2006

Support: CAPES, Instituto Adolfo Lutz.

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  • Correspondence to:
    Dra. Adele Caterino-de-Araujo
    Instituto Adolfo Lutz, Seção de Imunologia
    Av. Dr. Arnaldo 355, 11º andar
    01246-902 São Paulo, SP, Brasil
    Phone/Fax: 55-11-30682898
    E-mail:
  • Publication Dates

    • Publication in this collection
      30 Aug 2007
    • Date of issue
      Aug 2007

    History

    • Accepted
      28 Nov 2006
    • Received
      25 July 2006
    Instituto de Medicina Tropical de São Paulo Av. Dr. Enéas de Carvalho Aguiar, 470, 05403-000 - São Paulo - SP - Brazil, Tel. +55 11 3061-7005 - São Paulo - SP - Brazil
    E-mail: revimtsp@usp.br