Contagens de células T CD4+ na co-infecção HIV-1 e HTLV-1: alta prevalência da paraparesia espástica tropical/mielopatia associada ao HTLV-1

INTRODUCTION: HIV positive patients co-infected with HTLV-1 may have an increase in their T CD4+ cell counts, thus rendering this parameter useless as an AIDS-defining event. OBJECTIVE: To study the effects induced by the co-infection of HIV-1 and HTLV-1 upon CD4+ cells. MATERIAL AND METHODS: Since 1997, our group has been following a cohort of HTLV-1-infected patients, in order to study the interaction of HTLV-1 with HIV and/or with hepatitis C virus (HCV), as well as HTLV-1-only infected asymptomatic carriers and those with tropical spastic paraparesis/HTLV-1 associated myelopathy (TSP/HAM). One hundred and fifty HTLV-1-infected subjects have been referred to our clinic at the Institute of Infectious Diseases "Emílio Ribas", São Paulo. Twenty-seven of them were also infected with HIV-1 and HTLV-1-infection using two ELISAs and confirmed and typed by Western Blot (WB) or polymerase chain reaction (PCR). All subjects were evaluated by two neurologists, blinded to the patient's HTLV status, and the TSP/HAM diagnostic was based on the World Health Organization (WHO) classification. AIDS-defining events were in accordance with the Centers for Disease Control (CDC) classification of 1988. The first T CD4+ cells count available before starting anti-retroviral therapy are shown compared to the HIV-1-infected subjects at the moment of AIDS defining event. RESULTS: A total of 27 HIV-1/HTLV-1 co-infected subjects were identified in this cohort; 15 already had AIDS and 12 remained free of AIDS. The median of T CD4+ cell counts was 189 (98-688) cells/mm³ and 89 (53-196) cells/mm³ for co-infected subjects who had an AIDS-defining event, and HIV-only infected individuals, respectively (p = 0.036). Eight of 27 co-infected subjects (30%) were diagnosed as having a TSP/HAM simile diagnosis, and three of them had opportunistic infections but high T CD4+ cell counts at the time of their AIDS- defining event. DISCUSSION: Our results indicate that higher T CD4+ cells count among HIV-1/HTLV-1-coinfected subjects was found in 12% of the patients who presented an AIDS-defining event. These subjects also showed a TSP/HAM simile picture when it was the first manifestation of disease; this incidence is 20 times higher than that for HTLV-1-only infected subjects in endemic areas.INTRODUÇÃO: A possibilidade que a co-infecção pelo vírus da leucemia de células T humana do tipo 1 (HTLV-1) em indivíduos infectados pelo vírus da imunodeficiência humana do tipo 1 poderia falsamente elevar o número de linfócitos T CD4+ no momento do evento definidor de aids, inferindo que essa contagem poderia ser um marcador laboratorial incompleto nos pacientes com a co-infecção HIV-1/HTLV-1. OBJETIVO: Estudar a interação entre o HIV-1 e a co-infecção como o HTLV-1. MATERIAL E MÉTODO: Desde 1997, nosso grupo tem seguido uma coorte de pacientes para estudar a interação entre HIV e/ou vírus da hepatite C (HCV), como também pacientes assintomáticos ou com TSP/HAM. 150 pacientes infectados pelo HTLV-1, encaminhados à clínica de HTLV do Instituto de Infectologia Emilio Ribas, São Paulo, Brasil, foram estudados. Vinte e sete deles estavam co-infectados pelo HIV-1 e HTLV-1, usando dois ELISAs e confirmados tipados pelo WB ou PCR. Todos os pacientes foram avaliados por dois neurologistas, cegos para o status de HTLV e o diagnóstico de TSP/HAM foi baseado na classificação da Organização Mundial de Saúde, 1988. A primeira contagem de células T disponível antes da terapia anti-retroviral foi mostrada para comparar com os pacientes infectados pelo HIV no momento do evento definidor de aids de acordo com Classificação do Centro de controle de Doenças, 1988. RESULTADOS: Um total de 27 HIV-1/HTLV-1 co-infectados foram identificados na coorte, 15 já apresentavam aids e 12 permaneceram sem evento de aids. A mediana de células T CD4 foi de 189 (98-688) células/mm³ e 89 (53-196) células/mm³ nos co-infectados que tinham evento definidor de aids e naqueles com a infecção somente pelo HIV, respectivamente (p = 0,036). Oito dos 27 co-infectados (30%) foram diagnosticados tendo TSP/HAM símile, e três deles mostraram elevada contagem de células T CD4 e apresentaram infecções oportunistas no momento do evento definidor de aids. DISCUSSÃO: Nossos resultados indicam que a contagem de células T CD4+ entre os indivíduos com HIV-1/HTLV-1 foi somente discrepante em 12% desses pacientes e podem ser relacionados à progressão da infecção HTLV-1, e todos mostraram um quadro de TSP/HAM símile como a primeira manifestação de doença. Entretanto, essa taxa de ataque foi 20 vezes mais alta que a observada em pacientes somente infectados pelo HTLV-1 em área endêmica

Priming of microglia in a DNA-repair deficient model of accelerated aging

AbstractAging is associated with reduced function, degenerative changes, and increased neuroinflammation of the central nervous system (CNS). Increasing evidence suggests that changes in microglia cells contribute to the age-related deterioration of the CNS. The most prominent age-related change of microglia is enhanced sensitivity to inflammatory stimuli, referred to as priming. It is unclear if priming is due to intrinsic microglia ageing or induced by the ageing neural environment. We have studied this in Ercc1 mutant mice, a DNA repair-deficient mouse model that displays features of accelerated aging in multiple tissues including the CNS. In Ercc1 mutant mice, microglia showed hallmark features of priming such as an exaggerated response to peripheral lipopolysaccharide exposure in terms of cytokine expression and phagocytosis. Specific targeting of the Ercc1 deletion to forebrain neurons resulted in a progressive priming response in microglia exemplified by phenotypic alterations. Summarizing, these data show that neuronal genotoxic stress is sufficient to switch microglia from a resting to a primed state

The FANCM:p.Arg658* truncating variant is associated with risk of triple-negative breast cancer

Abstract: Breast cancer is a common disease partially caused by genetic risk factors. Germline pathogenic variants in DNA repair genes BRCA1, BRCA2, PALB2, ATM, and CHEK2 are associated with breast cancer risk. FANCM, which encodes for a DNA translocase, has been proposed as a breast cancer predisposition gene, with greater effects for the ER-negative and triple-negative breast cancer (TNBC) subtypes. We tested the three recurrent protein-truncating variants FANCM:p.Arg658*, p.Gln1701*, and p.Arg1931* for association with breast cancer risk in 67,112 cases, 53,766 controls, and 26,662 carriers of pathogenic variants of BRCA1 or BRCA2. These three variants were also studied functionally by measuring survival and chromosome fragility in FANCM−/− patient-derived immortalized fibroblasts treated with diepoxybutane or olaparib. We observed that FANCM:p.Arg658* was associated with increased risk of ER-negative disease and TNBC (OR = 2.44, P = 0.034 and OR = 3.79; P = 0.009, respectively). In a country-restricted analysis, we confirmed the associations detected for FANCM:p.Arg658* and found that also FANCM:p.Arg1931* was associated with ER-negative breast cancer risk (OR = 1.96; P = 0.006). The functional results indicated that all three variants were deleterious affecting cell survival and chromosome stability with FANCM:p.Arg658* causing more severe phenotypes. In conclusion, we confirmed that the two rare FANCM deleterious variants p.Arg658* and p.Arg1931* are risk factors for ER-negative and TNBC subtypes. Overall our data suggest that the effect of truncating variants on breast cancer risk may depend on their position in the gene. Cell sensitivity to olaparib exposure, identifies a possible therapeutic option to treat FANCM-associated tumors

Molecular diversity of the envelope and proviral load cell lymphotropic virus human T-cell type 2 (HTLV-2) in the test samples indeterminate Western-Blot

O Vírus Linfotrópico de Células T Humanas do tipo 2 (HTLV-2) é considerado pouco patogênico, mas o diagnóstico sorológico é importante para aconselhamento e acompanhamento. Os testes confirmatórios mais utilizados são o Western-Blot (WB) e a reação em cadeia de polimerase (PCR). Entretanto, em populações de alto risco como usuários de drogas intravenosas e a população indígena, cerca de 50% dos resultados indeterminados pelo WB resultaram como positivos para a infecção do HTLV-2, quando testadas pela PCR. Uma hipótese para a insensibilidade do teste WB utilizado no Brasil seria pelo uso de proteínas recombinantes procedentes de cepas que não circulam em nosso país. Outra possibilidade é o nível de imunossupressão, que pode acarretar uma menor produção de anticorpos anti-HTLV-2 circulantes. A carga proviral do HTLV-2 pode ser também um fator da pouca estimulação do sistema imune, o que resulta baixa quantidade de anticorpos circulantes. Este estudo testou três hipóteses e os resultados mostraram uma alta homologia na região do envelope viral quando alinhada com a seqüência de aminoácidos da proteína K55 utilizada no WB, independente do perfil do teste. A carga proviral do HTLV-2, assim como o estado de imunessupressão dos pacientes não foi importante para perfis indeterminados do Western-Blot.Despite the human T-cell lymphotropic virus type 2 (HTLV-2) is considered low pathogenic, the serological diagnosis is important for counseling and monitoring. The most used confirmatory tests are Western Blot (WB) and PCR. However, in high-risk populations, about 50% of the indeterminate WB results when tested by PCR, in our study, confirmed the presence of HTLV-2. A hypothesis for the insensitivity of the WB used in Brazil would be the use of recombinant proteins from strains that do not circulate in our country. Another possibility is the level of immunosuppression, which may lead to lower production of anti-HTLV-2 circulating. The viral load of HTLV-2 can also be a factor of little stimulation of the immune system, resulting low amount of antibodies. This study tested the three hypothesis and we showed that high homology in the region of immunogenic viral envelope when aligned with the sequence of amino acids of the protein K55 (HTLV-2) of WB kit, the proviral load and immunessupression state were not important for inconclusive WB profiles

Neither Molecular Diversity of the Envelope, Immunosuppression Status, Nor Proviral Load Causes Indeterminate HTLV Western Blot Profiles in Samples From Human T-Cell Lymphotropic Virus Type 2 (HTLV-2)-Infected Individuals

Although human T-cell lymphotropic virus type 2 (HTLV-2) is considered of low pathogenicity, serological diagnosis is important for counseling and monitoring. The confirmatory tests most used are Western blot (WB) and PCR. However, in high-risk populations, about 50% of the indeterminate WB were HTLV-2 positives by PCR. The insensitivity of the WB might be due to the use of recombinant proteins of strains that do not circulate in our country. Another possibility may be a high level of immunosuppression, which could lead to low production of virus, resulting in low stimulation of antibody. We found one mutation, proline to serine in the envelope region in the position 184, presented at least 1/3 of the samples, independent the indeterminate WB profile. In conclusion, we found no correlation of immune state, HTLV-2 proviral load, or env diversity in the K55 region and WB indeterminate results. We believe that the only WB kit available in the market is probably more accurate to detect HTLV-1 antibodies, and some improvement for HTLV-2 detection should be done in the future, especially among high-risk population. J. Med. Virol. 82:837-842,2010. (C) 2010 Wiley-Liss, Inc.FAPESP[07/52298-2]FAPESP[2008/56427-4

T CD4+ cells count among patients co-infected with human immunodeficiency virus type 1 (HIV-1) and human T-cell leukemia virus type 1 (HTLV-1): high prevalence of tropical spastic paraparesis/HTLV-1-associated myelopathy (TSP/HAM) Contagens de células T CD4+ na co-infecção HIV-1 e HTLV-1: alta prevalência da paraparesia espástica tropical/mielopatia associada ao HTLV-1

INTRODUCTION: HIV positive patients co-infected with HTLV-1 may have an increase in their T CD4+ cell counts, thus rendering this parameter useless as an AIDS-defining event. OBJECTIVE: To study the effects induced by the co-infection of HIV-1 and HTLV-1 upon CD4+ cells. MATERIAL AND METHODS: Since 1997, our group has been following a cohort of HTLV-1-infected patients, in order to study the interaction of HTLV-1 with HIV and/or with hepatitis C virus (HCV), as well as HTLV-1-only infected asymptomatic carriers and those with tropical spastic paraparesis/HTLV-1 associated myelopathy (TSP/HAM). One hundred and fifty HTLV-1-infected subjects have been referred to our clinic at the Institute of Infectious Diseases "Emílio Ribas", São Paulo. Twenty-seven of them were also infected with HIV-1 and HTLV-1-infection using two ELISAs and confirmed and typed by Western Blot (WB) or polymerase chain reaction (PCR). All subjects were evaluated by two neurologists, blinded to the patient's HTLV status, and the TSP/HAM diagnostic was based on the World Health Organization (WHO) classification. AIDS-defining events were in accordance with the Centers for Disease Control (CDC) classification of 1988. The first T CD4+ cells count available before starting anti-retroviral therapy are shown compared to the HIV-1-infected subjects at the moment of AIDS defining event. RESULTS: A total of 27 HIV-1/HTLV-1 co-infected subjects were identified in this cohort; 15 already had AIDS and 12 remained free of AIDS. The median of T CD4+ cell counts was 189 (98-688) cells/mm³ and 89 (53-196) cells/mm³ for co-infected subjects who had an AIDS-defining event, and HIV-only infected individuals, respectively (p = 0.036). Eight of 27 co-infected subjects (30%) were diagnosed as having a TSP/HAM simile diagnosis, and three of them had opportunistic infections but high T CD4+ cell counts at the time of their AIDS- defining event. DISCUSSION: Our results indicate that higher T CD4+ cells count among HIV-1/HTLV-1-coinfected subjects was found in 12% of the patients who presented an AIDS-defining event. These subjects also showed a TSP/HAM simile picture when it was the first manifestation of disease; this incidence is 20 times higher than that for HTLV-1-only infected subjects in endemic areas.<br>INTRODUÇÃO: A possibilidade que a co-infecção pelo vírus da leucemia de células T humana do tipo 1 (HTLV-1) em indivíduos infectados pelo vírus da imunodeficiência humana do tipo 1 poderia falsamente elevar o número de linfócitos T CD4+ no momento do evento definidor de aids, inferindo que essa contagem poderia ser um marcador laboratorial incompleto nos pacientes com a co-infecção HIV-1/HTLV-1. OBJETIVO: Estudar a interação entre o HIV-1 e a co-infecção como o HTLV-1. MATERIAL E MÉTODO: Desde 1997, nosso grupo tem seguido uma coorte de pacientes para estudar a interação entre HIV e/ou vírus da hepatite C (HCV), como também pacientes assintomáticos ou com TSP/HAM. 150 pacientes infectados pelo HTLV-1, encaminhados à clínica de HTLV do Instituto de Infectologia Emilio Ribas, São Paulo, Brasil, foram estudados. Vinte e sete deles estavam co-infectados pelo HIV-1 e HTLV-1, usando dois ELISAs e confirmados tipados pelo WB ou PCR. Todos os pacientes foram avaliados por dois neurologistas, cegos para o status de HTLV e o diagnóstico de TSP/HAM foi baseado na classificação da Organização Mundial de Saúde, 1988. A primeira contagem de células T disponível antes da terapia anti-retroviral foi mostrada para comparar com os pacientes infectados pelo HIV no momento do evento definidor de aids de acordo com Classificação do Centro de controle de Doenças, 1988. RESULTADOS: Um total de 27 HIV-1/HTLV-1 co-infectados foram identificados na coorte, 15 já apresentavam aids e 12 permaneceram sem evento de aids. A mediana de células T CD4 foi de 189 (98-688) células/mm³ e 89 (53-196) células/mm³ nos co-infectados que tinham evento definidor de aids e naqueles com a infecção somente pelo HIV, respectivamente (p = 0,036). Oito dos 27 co-infectados (30%) foram diagnosticados tendo TSP/HAM símile, e três deles mostraram elevada contagem de células T CD4 e apresentaram infecções oportunistas no momento do evento definidor de aids. DISCUSSÃO: Nossos resultados indicam que a contagem de células T CD4+ entre os indivíduos com HIV-1/HTLV-1 foi somente discrepante em 12% desses pacientes e podem ser relacionados à progressão da infecção HTLV-1, e todos mostraram um quadro de TSP/HAM símile como a primeira manifestação de doença. Entretanto, essa taxa de ataque foi 20 vezes mais alta que a observada em pacientes somente infectados pelo HTLV-1 em área endêmica

Low DNA HTLV-2 proviral load among women in Sao Paulo city

Background: HTLV-2 infections are almost always asymptomatic, and diseases associated with the infection are rarely reported. Little information is available on the relationship between HTLV-2 proviral load and gender or expression of disease, especially among patients with HlV-1 co-infection. Methods: We studied 77 HTLV-2-infected subjects followed in our clinic for the last 9 years; 53 (69%) of them were co-infected with HIV-1. HTLV-2 DNA proviral load (PVL) was measured by real time PCR, a test with a sensitivity of 10 in 10(4) PBMCs. Results: Six of 53 HTLV-2/HIV-1 cases had a myelopathy (all of them had undetectable PVL of HTLV-2). Only 3 of 35 women (2 out of 3 co-infected with HIV) had a detectable PVL, whereas 10 of 42 men had a detectable PVL. Regardless of their HIV status women had significantly lower PVL than men (10 vs. 43 CopieS/10(4) PBMCs, p < 0.05). Conclusions: We noticed the occurrence of myelopathy in HTLV-2/HIV-1 co-infected patients, with undetectable HTLV-2 viral load. There was a sex difference in viral load for HTLV-2, what may be the result in mode of transmission or acquisition of the virus. (c) 2008 Elsevier B. V. All rights reserved