The research ethics committee. Source: Study protocol, 2015, Table S1. Description of values of AICM applied in the statistics (Bayesian inference) in the study data. Source: Study protocol, 2016. (PDF 1549 kb

A Gessain

A Ilinskaya

A Segurado

ABF Carneiro-Proietti

ACA Mota-Miranda

Akim Felipe Santos Nobre

B Tallet

BJ Poiesz

Bruna Teles Pinheiro

CA Costa

Carlos Araujo da Costa

Cássia Cristine Costa Pereira

Danilo Souza de Almeida

DB Reiss

E Wattel

Edivaldo Costa Jr

Edna Aoba Yassui Ishikawa

EL Santos

F Sanger

GS Pontes

I Dourado

Ingrid Christiane Silva

K Katoh

K Verdonck

KS Jones

L-T Nguyen

LB Cook

Louise de Souza Canto Ferreira

M Kearse

Marcos William Leão de Araújo

Maria de Nazaré do Socorro de Almeida Viana

Mariza da Silva Borges

Maísa Silva de Sousa

MC Macedo

ND Wolfe

NR Faria

O Cassar

OC Ferreira Jr

P Lemey

P Tuke

R Ishak

S Kashima

SK Chien-Wen

Stephen Francis Ferrari

T Kosako

TJ Palker

V ACR

Y Yamano

Virology Journal

This research was supported by the UFPA Pro-Rectory for Extension and the
Brazilian National Council for Research and Development — CNPq (MCTI/
CNPQ/Universal 14/2014 _PROJ_459352/2014–8).Universidade Federal do Pará. Núcleo de Medicina Tropical. Postgraduate Program in Tropical Diseases. Belém, PA, Brazil.Universidade Federal do Pará. Núcleo de Medicina Tropical. Postgraduate Program in Tropical Diseases. Belém, PA, Brazil.Ministério da Saúde. Secretaria de Vigilância em Saúde. Instituto Evandro Chagas. Ananindeua, PA, Brasil.Universidade Federal do Pará. Núcleo de Medicina Tropical. Postgraduate Program in Tropical Diseases. Belém, PA, Brazil.Universidade Federal do Pará. Núcleo de Medicina Tropical. Postgraduate Program in Tropical Diseases. Belém, PA, Brazil.Universidade Federal do Pará. Núcleo de Medicina Tropical. Postgraduate Program in Tropical Diseases. Belém, PA, Brazil.Universidade Federal do Pará. Núcleo de Medicina Tropical. Postgraduate Program in Tropical Diseases. Belém, PA, Brazil.Universidade Federal do Pará. Núcleo de Medicina Tropical. Postgraduate Program in Tropical Diseases. Belém, PA, Brazil.Universidade Federal do Pará. Faculty of Pharmacy. Belém, PA, Brazil.Universidade Federal do Pará. Faculty of Nursing. Belém, PA, Brazil.Universidade Federal do Pará. Núcleo de Medicina Tropical. Postgraduate Program in Tropical Diseases. Belém, PA, Brazil.Universidade Federal do Pará. Núcleo de Medicina Tropical. Postgraduate Program in Tropical Diseases. Belém, PA, Brazil.Universidade Federal de Sergipe. Department of Ecology. São Cristóvão, SE, Brazil.Universidade Federal do Pará. Núcleo de Medicina Tropical. Postgraduate Program in Tropical Diseases. Belém, PA, Brazil.BACKGROUND:
The human T-lymphotropic virus type 1 (HTLV-1) affects 2-5 million people worldwide, and is associated with a number of degenerative and infectious diseases. The Envelope glycoproteins (gp) are highly conserved among the different HTLV-1 isolates, although nucleotide substitutions in the region that codifies these proteins may influence both the infectivity and the replication of the virus. The gp46 gene has functional domains which have been associated with the inhibition of the formation of the syncytium, cell-cell transmission, and the production of antibodies. The present study investigated the genetic stability of the gp46 gene of HTLV-1 in an endemic region of Brazilian Amazonia.
METHODS: Index case (IC - a sample of a given family group) carriers of HTLV-1 were investigated in the metropolitan region of Belém (Pará, Brazil) between January 2010 (registered retrospectively) and December 2015. The sequences that codify the gp46 were amplified by PCR, purified and sequenced (MF084788-MF084825). The gene was characterized using bioinformatics and Bayesian Inference. RESULTS: The 40 patients analyzed had a mean age of 45.2 years and 70% presented some type of symptom, with a predominance of pain and sensitivity, dysautonomia, and motor disorders. All patients presented the aA (Transcontinental Cosmopolitan) genotype, with an extremely low mutation rate, which is characteristic of the codifying region (aA - 1.83 × 10-4 mutations per site per year). The gp46 gene had a nucleotide diversity of between 0.00% and 2.0%. Amino acid mutations were present in 66.6% of the samples of individuals with signs/symptoms or diseases associated with HTLV-1 (p = 0.0091). Of the three most frequent mutations, the previously undescribed N93D mutant was invariably associated with symptomatic cases.
CONCLUSIONS: The aA HTLV-1 subtype is predominant in the metropolitan region of Belém and presented a high degree of genetic stability in the codifying region. The rare N93D amino acid mutation may be associated with the clinical manifestations of this viral infection.
IMPORTANCE: Little is known of the phylogeny of HTLV-1 in the endemic region of Brazilian Amazonia, and few complete gene sequences are available for the gp46 glycoprotein from the local population. The nucleotide sequences of the viral gp46 gene recorded in the present study confirmed the genetic stability of the region, and pointed to a homogeneous viral group, with local geographic characteristics. Further research will be necessary to more fully understand the molecular diversity of this protein, given the potential of this codifying region as a model for an effective HTLV-1 vaccine. The identification of a rare mutation (N93D), present only in symptomatic patients, should also be investigated further as a potential clinical marker

Viana, Maria de Nazaré do Socorro de Almeida

Nobre, Akim Felipe Santos

Costa Júnior, Edivaldo

Silva, Ingrid Christiane

Pinheiro, Bruna Teles

Pereira, Cássia Cristine Costa

Ferreira, Louise de Souza Canto

Almeida, Danilo de Souza

Araújo, Marcos William Leão de

Borges, Mariza da Silva

Costa, Carlos Araujo da

Ishikawa, Edna Aoba Yassui

Ferrari, Stephen Francis

Sousa, Maísa Silva de

LAReferencia - Red Federada de Repositorios Institucionales de Publicaciones Científicas Latinoamericanas

Stability of the HTLV-1 glycoprotein 46 (gp46) gene in an endemic region of the Brazilian Amazon and the presence of a significant mutation (N93D) in symptomatic patients

Crossref

Maria Socorro de Almeida Viana (5162771)

Akim Felipe Santos Nobre (4984526)

Edivaldo Costa Jr (5162753)

Ingrid Silva (5162756)

Bruna Teles Pinheiro (4984535)

Cássia Cristine Costa Pereira (5162759)

Louise de Souza Canto Ferreira (421925)

Danilo Souza de Almeida (5162765)

Marcos William Leão de Araújo (5162762)

Mariza da Silva Borges (5162768)

Carlos Araujo da Costa (421923)

Edna Aoba Yassui Ishikawa (421931)

Stephen Francis Ferrari (771917)

Maísa Silva de Sousa (421933)

FigShare

Additional file 1: of Stability of the HTLV-1 glycoprotein 46 (gp46) gene in an endemic region of the Brazilian Amazon and the presence of a significant mutation (N93D) in symptomatic patients

Abstract Background The human T-lymphotropic virus type 1 (HTLV-1) affects 2–5 million people worldwide, and is associated with a number of degenerative and infectious diseases. The Envelope glycoproteins (gp) are highly conserved among the different HTLV-1 isolates, although nucleotide substitutions in the region that codifies these proteins may influence both the infectivity and the replication of the virus. The gp46 gene has functional domains which have been associated with the inhibition of the formation of the syncytium, cell-cell transmission, and the production of antibodies. The present study investigated the genetic stability of the gp46 gene of HTLV-1 in an endemic region of Brazilian Amazonia. Methods Index case (IC - a sample of a given family group) carriers of HTLV-1 were investigated in the metropolitan region of Belém (Pará, Brazil) between January 2010 (registered retrospectively) and December 2015. The sequences that codify the gp46 were amplified by PCR, purified and sequenced (MF084788–MF084825). The gene was characterized using bioinformatics and Bayesian Inference. Results The 40 patients analyzed had a mean age of 45.2 years and 70% presented some type of symptom, with a predominance of pain and sensitivity, dysautonomia, and motor disorders. All patients presented the aA (Transcontinental Cosmopolitan) genotype, with an extremely low mutation rate, which is characteristic of the codifying region (aA – 1.83 × 10–4 mutations per site per year). The gp46 gene had a nucleotide diversity of between 0.00% and 2.0%. Amino acid mutations were present in 66.6% of the samples of individuals with signs/symptoms or diseases associated with HTLV-1 (p = 0.0091). Of the three most frequent mutations, the previously undescribed N93D mutant was invariably associated with symptomatic cases. Conclusions The aA HTLV-1 subtype is predominant in the metropolitan region of Belém and presented a high degree of genetic stability in the codifying region. The rare N93D amino acid mutation may be associated with the clinical manifestations of this viral infection. Importance Little is known of the phylogeny of HTLV-1 in the endemic region of Brazilian Amazonia, and few complete gene sequences are available for the gp46 glycoprotein from the local population. The nucleotide sequences of the viral gp46 gene recorded in the present study confirmed the genetic stability of the region, and pointed to a homogeneous viral group, with local geographic characteristics. Further research will be necessary to more fully understand the molecular diversity of this protein, given the potential of this codifying region as a model for an effective HTLV-1 vaccine. The identification of a rare mutation (N93D), present only in symptomatic patients, should also be investigated further as a potential clinical marker. Trial registration ISRCTN 12345678, registered 28 September 2014

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Additional file 1: of Stability of the HTLV-1 glycoprotein 46 (gp46) gene in an endemic region of the Brazilian Amazon and the presence of a significant mutation (N93D) in symptomatic patients

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