Human T-cell leukemia virus type 1 (HTLV-1) is the causative agent of a neural chronic inflammation, called HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP) and of a malignant ...lymphoproliferation, called the adult T-cell leukemia/lymphoma (ATLL). The mechanisms through which the HTLV-1 induces these diseases are still unclear, but they might rely on immune alterations. HAM/TSP is associated with an impaired production of pro-inflammatory cytokines and chemokines, such as IFN-γ, TNF-α, CXCL9, or CXCL10. ATLL is associated with high levels of IL-10 and TGF-β. These immunosuppressive cytokines could promote a protumoral micro-environment. Moreover, HTLV-1 infection impairs the IFN-I production and signaling, and favors the IL-2, IL-4, and IL-6 expression. This contributes both to immune escape and to infected cells proliferation. Here, we review the landscape of cytokine dysregulations induced by HTLV-1 infection and the role of these cytokines in the HTLV-1-associated diseases progression.
HTLV-1-Associated Myelopathy/Tropical Spastic Paraparesis (HAM/TSP) is an incapacitating neuroinflammatory disorder for which no disease-modifying therapy is available, but corticosteroids provide ...some clinical benefit. Although HAM/TSP pathogenesis is not fully elucidated, older age, female sex and higher proviral load are established risk factors. We investigated systemic cytokines and a novel chronic inflammatory marker, GlycA, as possible biomarkers of immunopathogenesis and therapeutic response in HAM/TSP, and examined their interaction with established risk factors.
We recruited 110 People living with HTLV-1 (PLHTLV-1, 67 asymptomatic individuals and 43 HAM/TSP patients) with a total of 946 person-years of clinical follow-up. Plasma cytokine levels (IL-2, IL-4, IL-6, IL-10, IL-17A, IFN-γ, TNF) and GlycA were quantified by Cytometric Bead Array and
NMR, respectively. Cytokine signaling and prednisolone response were validated in an independent cohort by nCounter digital transcriptomics. We used multivariable regression, machine learning algorithms and Bayesian network learning for biomarker identification.
We found that systemic IL-6 was positively correlated with both age (r = 0.50, p < 0.001) and GlycA (r = 0.45, p = 0.00049) in asymptomatics, revealing an 'inflammaging" signature which was absent in HAM/TSP. GlycA levels were higher in women (p = 0.0069), but cytokine levels did not differ between the sexes. IFN-γ (p = 0.007) and IL-17A (p = 0.0001) levels were increased in untreated HAM/TSP Multivariable logistic regression identified IL-17A and proviral load as independent determinants of clinical status, resulting in modest accuracy of predicting HAM/TSP status (64.1%), while a machine learning-derived decision tree classified HAM/TSP patients with 90.7% accuracy. Pre-treatment GlycA and TNF levels significantly predicted clinical worsening (measured by Osame Motor Disability Scale), independent of proviral load. In addition, a poor prednisolone response was significantly correlated with higher post-treatment IFN-γ levels. Likewise, a transcriptomic IFN signaling score, significantly correlated with previously proposed HAM/TSP biomarkers (CASP5/CXCL10/FCGR1A/STAT1), was efficiently blunted by in vitro prednisolone treatment of PBMC from PLHTLV-1 and incident HAM/TSP.
An age-related increase in systemic IL-6/GlycA levels reveals inflammaging in PLHTLV-1, in the absence of neurological disease. IFN-γ and IL-17A are biomarkers of untreated HAM/TSP, while pre-treatment GlycA and TNF predict therapeutic response to prednisolone pulse therapy, paving the way for a precision medicine approach in HAM/TSP.
People living with Human Immunodeficiency Virus (HIV) are under risk for co-infection with SARS-CoV-2. This population may be more prone to complications from COVID-19 due to persistent inflammation ...caused by HIV and higher incidence of metabolic syndromes, cardiovascular diseases, and malignancies, as well as being considered elderly at 50 years of age. The objective of this study was to report SARS-CoV-2 infection frequency, clinical evolution, and mortality in HIV-positive patients on antiretroviral therapy.
The period of inquiry ranged from January to September 2020. Due to the social distance and the suspension of in-person medical care during the time of the investigation, we sent electronic questions about demographic, epidemiological, and clinical data to 403 HIV-infected patients.
Among 260 patients who answered the questionnaire, thirty-nine patients (15%) had suggestive symptoms and were tested for SARS-CoV-2 infection. Of this, 11 had positive results (32.4%) and no patient died of COVID-19 complications. Nine were male (3.4%), and the mean age of the patients with positive results was 43.2 years (± 9.6). 107 patients (41.1%) were over 50 years of age and their mean T-CD4+ cell count was 768. Eleven patients (4.2%) had a detectable HIV RNA viral load and 127 (48.8%) had comorbidities. These variables were not associated with an increased risk for infection.
The frequency of SARS-COV2 infection among HIV-infected is similar to the general population, and the clinical course is associated with the presence of comorbidities and not due to the HIV infection. However, new studies should be done to assess if this vulnerable population could answer the vaccine anti-SARS-Cov2.
Few studies have reported the prognosis of human immunodeficiency virus (HIV)‐positive patients followed for a long time in Brazil, particularly those including pre and post‐HAART eras. The ...polymorphisms of interferon (IFN)‐λ4 have been postulated as possibly associated with the pathogenesis of HIV infection. The aim of this study was to describe the incidence and mortality from a cohort of HIV‐positive patients as well as whether IFN‐λ4 gene polymorphisms (SNP rs8099917 and SNP rs12979860) were associated with HIV/acquired immune deficiency syndrome (AIDS) progression. We followed 402 patients for up to 30 years; 347 of them began follow‐up asymptomatic, without any AIDS‐defining opportunistic disease and/or a lymphocytes T CD4+ count of 350 cells/mm3 or lower. We determined the probability of the asymptomatic subjects to remain AIDS‐free, and the risk of death for those entering the study already with an AIDS diagnosis, as well as for subjects developing AIDS during follow‐up. We compared the prognosis of patients with two different polymorphisms for the genes encoding for IFN‐λ4, variants rs8099917 and rs12979860. The follow‐up time of the 347 asymptomatic‐at‐entry subjects was 3687 person‐years. IFN‐λ4 rs8099917 polymorphisms were not associated with AIDS progression, but IFN‐λ4 rs12979860 wild type genotype (CC) was associated with higher mortality compared to CT and TT, with an increased probability of death from AIDS (P = .01). In conclusion, genetic variations in IFN‐λ4 on rs12979860 polymorphisms in HIV‐infected patients may drive mortality risk.
Highlights
This study described the incidence and mortality from a cohort of HIV‐positive patients as well as whether IFN‐λ4 gene polymorphisms (SNP rs8099917 and SNP rs12979860) were associated with HIV/acquired immune deficiency syndrome (AIDS) progression. The results showed that genetic variations in IFN‐λ4 on rs12979860 polymorphisms in HIV‐infected patients may drive mortality risk.
Introdução: O distúrbio neurocognitivo associado ao HIV (HAND) é caracterizado pelo comprometimento progressivo das funções neurológicas, cuja incidência varia entre 15 a 50% das pessoas vivendo com ...HIV/AIDS (PVHA). Dados clínicos, laboratoriais e fatores sociodemográficos podem corroborar no entendimento da HAND, sendo um passo fundamental para aprimorar o diagnóstico e prognóstico, tratamento e o acompanhamento dos pacientes desta coorte. O objetivo deste estudo é identificar fatores clínicos, laboratoriais e sociodemográficos de PVHA, que possam estar associados a HAND. Metodologia: Foram incluídos 24 participantes provenientes do ambulatório de Imunodeficiências Secundárias (ADEE 3002) do Hospital das Clínicas da Faculdade de Medicina da Universidade de São Paulo (HCFMUSP) neste estudo. Os dados demográficos foram coletados no momento da apresentação da pesquisa e assinatura do TCLE e os dados clínicos e laboratoriais de interesse foram coletados através do HCMED. A análise estatística foi feita através do software GraphPad Prism® v.9. Utilizou-se os testes Shapiro-Wilk para analisar a normalidade dos dados, Teste T independente com correção de Welch para a comparação entre os grupos e o teste exato de Fisher para a análise de dados baseados em frequências. Resultados: A análise dos dados sociodemográficos revelou que a média de idade dos participantes foi de 46,8 anos (± 9,8), com uma predominância de 79,2% de mulheres e 20,8% de homens. A escolaridade média foi de 11,1 anos (± 3,7). Em relação aos dados laboratoriais, não foram observadas diferenças estatísticas significativas. No entanto, houve uma tendência de diminuição na contagem de linfócitos T CD4+ no grupo HAND (688, ± 286 cels/mm3) em relação ao grupo normal (1011 ± 474 cels/mm3), assim como no nadir das células T CD4+, no grupo HAND (254 ± 204 cels/mm3) em comparação com o grupo normal (405 ± 290 cels/mm3). Quanto aos demais parâmetros clínicos analisados (tempo de tratamento, regime antirretroviral, e comorbidades) entre as categorias de classificação neurocognitiva, também não foram encontradas diferenças estatísticas. Conclusão: Após análise exploratória das características sociodemográficas e clínicas em PVHA, esses achados sugerem que os fatores clínicos investigados podem não estar diretamente associados ao desenvolvimento da HAND, ou seja, é multifatorial, requer estudos adicionais para uma compreensão mais aprofundada dessa relação e ou um biomarcador.
This study aimed to report cancer incidence and mortality in a Brazilian human immunodeficiency virus (HIV) cohort of 31?years duration and compare cancer deaths with deaths due to noncancer causes. ...We also investigated risk factors for the development of acquired immunodeficiency syndrome (AIDS)-defining and non-AIDS-defining cancers. We searched for any information related to the diagnosis of cancer in a period ranging from 1989 to 2020. We also collected data on sociodemographic and clinical information and risk factors. Statistical analysis included parametric and nonparametric tests and the building of survival curves. We used the statistical software GraphPad software (version 9) and STATA software (version 14) for the elaboration of statistics. Fifty-five new cases of cancer occurred in a total of 677 HIV patients included in our cohort over 31?years, an incidence of 8.12%. The most important risk factors associated with cancer were smoking (p = 0.03), infection with oncoviruses like human papillomavirus (p < 0.001), and hepatitis C (p = 0.04). Eleven patients (1.6%) died from cancer. The most frequent diagnoses of fatal cancer were liver cancer and lymphoma (three cases each). The mean follow-up time of patients dying from cancer was 14?years; patients dying from noncancer causes were 24 (3.55%), and their mean follow-up time was 11?years. We had low overall mortality in our cohort of HIV patients (5.2%), mostly due to noncancer causes, which may be due to the fact that most of our patients begin follow-up asymptomatic. Cancer deaths were 31.4% of all deaths; half of those cancers were AIDS-defining.
Introdução: A frequência de distúrbios neurocognitivos (HAND) atinge até 50% da população vivendo com infecção pelo HIV e as mulheres parecem ser mais afetadas. O escore CPE tem demonstrado ...correlação com a diminuição da carga viral liquórica do HIV e melhora cognitiva. Em adição, diversos estudos relataram uma associação entre o uso de Efavirenz com o declínio neurocognitivo. Objetivo: Relacionar o regime de TARV, uso do efavirenz e a efetividade de penetração no SNC (CPE) com o desfecho de alterações neurocognitivas em mulheres vivendo com HIV (MVHIV). Método: No total, 43 MVHIV acompanhadas no Hospital das Clínicas de São Paulo realizaram a avaliação neuropsicológica de 2019 a 2020. Os dados sobre o regime da TARV foram coletados em prontuários. O CPE foi determinado a partir do protocolo de manejo clínico para pessoas vivendo com HIV (dados pareados). Este desfecho compreende a categoria de comprometimento neurocognitivo assintomático (ANI), alteração neurocognitiva leve/moderada (MND) e demência associada ao HIV (HAD). Resultados: Das 43 mulheres avaliadas, 17 (39,5%) apresentaram alteração cognitiva. 20,9% tem a forma ANI, 16,2% a forma MND e 2,2% a forma HAD. A média de idade, escolaridade e tempo de diagnóstico foi semelhante nos grupos. 88,4% dos indivíduos (38/43) apresentavam carga viral indetectável. 65,1% estavam em tratamento sem uso de efavirenz no momento da avaliação neuropsicológica e 48,8% foram tratados com TARV de eficácia de penetração no SNC superior a 6, porém não houve diferenças entre os grupos. Em ambas as variáveis não houve diferença estatística. Conclusão: O tratamento combinado com efavirenz e demais TARVs, bem como a eficácia da penetração no SNC, não esteve relacionado às alterações neuropsicológicas em mulheres brasileiras infectadas pelo HIV da coorte em estudo. O que sugere que a causa da HAND pode ser multifatorial e outros fatores como escolaridade, comorbidades, neuroinfecções e início da terapia tardia devem ser considerados. Ag. Financiadora: FAPESP E CNPQ. Nr. Processo: 2018/07239-2; GRANT JC: 301275/2019-0.
To evaluate the trend of pneumonia mortality in Brazilian children aged 4 years and younger from 1991 to 2007.
We conducted a retrospective study based on the database of the IT Department of the ...Brazilian Unified Health System (DATASUS), from which we obtained the number of deaths from pneumonia and the population aged 4 years and younger living in the five Brazilian regions and in the whole country. Mortality rate was calculated according to the number of deaths from pneumonia divided by the population, multiplied by 1,000 for the age group under 1 year old and by 10,000 in the age group from 1 to 4 years. The linear regression test was used to evaluate the time trend of mortality.
There was a significant decrease in pneumonia mortality rates during the study period in both age groups and all regions of the country. In Brazil, the mean annual reduction in mortality rates in the population under 1 year old and between 1 and 4 years was 0.12 and 0.07, respectively. The South and Southeast regions showed the greatest reductions (-0.14 and -0.18 for < 1 year and -0.07 and -0.09 for 1 to 4 years). The smallest decreases were in the North and Northeast regions (-0.04 and -0.07) in children younger than 1 year, and in the North and Central West (-0.03 and -0.04) in the age group between 1 and 4 years.
There was a significant reduction in pneumonia mortality in children aged 4 years and younger across the country from 1991 to 2007; however, a discrepancy between the different regions remains evident.
Persistent viruses are hard to be eradicated, even using effective medications, and can persist for a long time in humans, sometimes regardless of treatment. Hepatitis B virus, hepatitis C virus, ...human immunodeficiency virus, and human T cell lymphotropic virus infections, the most common in our era, are still a challenge despite the increased knowledge about their biology. Most of them are highly pathogenic, some causing acute disease or, more often, leading to chronic persistent infections, and some of the occult, carrying a high risk of morbidity and mortality. However, if such infections were discovered early, they might be eradicated in the near future with effective medications and/or vaccines. This perspective review points out some specific characteristics of the most important chronic persistent viruses. It seems that in the next few years, these persistent viruses may have control by vaccination, epidemiological strategies, and/or treatment.
Abstract
Background
Mother-to-child transmission (MTCT) of human T-lymphotropic virus type 1 (HTLV-1) is an important route of transmission that can cause lifelong infection. There is high morbidity ...and mortality due to adult T-cell leukemia/lymphoma, HTLV-1–associated myelopathy (HAM), and other inflammatory disorders. These conditions develop in nearly 10% of people with HTLV-1 infection, with a higher risk if infection occurs early in life. Identification of risk factors can inform targeted measures to reduce HTLV-1 MTCT. This study aimed to investigate the potential of cesarean delivery to prevent HTLV-1 MTCT.
Methods
We performed a review of the cases of women and their offspring under regular follow-up at the HTLV-1 outpatient clinic at the Institute of Infectious Diseases Emilio Ribas.
Results
A total of 177 HTLV-1–infected women and 369 adult offspring were investigated. Overall, 15% of the children were positive for HTLV-1 and 85% were negative. Regarding vertical transmission, we found that a breastfeeding duration of >6 months was associated with MTCT. Moreover, maternal proviral load was not associated with transmission, but high educational level and cesarean delivery were identified as protective factors.
Conclusions
HTLV-1 MTCT was associated with mother's age at delivery of >25 years, low educational level, prolonged breastfeeding, and vaginal delivery.
Cesarean delivery has high potential in preventing mother-to-child transmission of human T- lymphotropic virus. Cesarean delivery implementation policies should be established to reduce the rate of neonatal infection during delivery. Formula feeding should be encouraged.
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