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1.
BMC Infect Dis ; 21(1): 49, 2021 Jan 11.
Artigo em Inglês | MEDLINE | ID: mdl-33430790

RESUMO

BACKGROUND: The World Health Organization (WHO) has endorsed the next-generation Xpert MTB/RIF Ultra (Ultra) cartridge, and Uganda is currently transitioning from the older generation Xpert MTB/RIF (Xpert) cartridge to Ultra as the initial diagnostic test for pulmonary tuberculosis (TB). We assessed the diagnostic accuracy of Ultra for pulmonary TB among adults in Kampala, Uganda. METHODS: We sampled adults referred for Xpert testing at two hospitals and a health center over a 12-month period. We enrolled adults with positive Xpert and a random 1:1 sample with negative Xpert results. Expectorated sputum was collected for Ultra, and for solid and liquid culture testing for Xpert-negative patients. We measured sensitivity and specificity of Ultra overall and by HIV status, prior history of TB, and hospitalization, in reference to Xpert and culture results. We also assessed how classification of results in the new "trace" category affects Ultra accuracy. RESULTS: Among 698 participants included, 211 (30%) were HIV-positive and 336 (48%) had TB. The sensitivity of Ultra was 90.5% (95% CI 86.8-93.4) and specificity was 98.1% (95% CI 96.1-99.2). There were no significant differences in sensitivity and specificity by HIV status, prior history of TB or hospitalization. Xpert and Ultra results were concordant in 670 (96%) participants, with Ultra having a small reduction in specificity (difference 1.9, 95% CI 0.2 to 3.6, p=0.01). When "trace" results were considered positive for all patients, sensitivity increased by 2.1% (95% CI 0.3 to 3.9, p=0.01) without a significant reduction in specificity (- 0.8, 95% CI - 0.3 to 2.0, p=0.08). CONCLUSIONS: After 1 year of implementation, Ultra had similar performance to Xpert. Considering "trace" results to be positive in all patients increased case detection without significant loss of specificity. Longitudinal studies are needed to compare the benefit of greater diagnoses to the cost of overtreatment.


Assuntos
Confiabilidade dos Dados , Mycobacterium tuberculosis/genética , Técnicas de Amplificação de Ácido Nucleico/métodos , Tuberculose Pulmonar/diagnóstico , Tuberculose Pulmonar/epidemiologia , Adulto , Estudos Transversais , Feminino , HIV/genética , Infecções por HIV/diagnóstico , Infecções por HIV/virologia , Humanos , Masculino , Prevalência , Sensibilidade e Especificidade , Escarro/microbiologia , Tuberculose Pulmonar/microbiologia , Uganda/epidemiologia
2.
Curr Opin HIV AIDS ; 16(1): 54-62, 2021 01.
Artigo em Inglês | MEDLINE | ID: mdl-33165007

RESUMO

PURPOSE OF REVIEW: The aim of this review is to summarize the clinical outcomes of people living with HIV (PWH) coinfected with SARS-CoV-2 during the first six months of the COVID-19 pandemic. RECENT FINDINGS: Several reports from single centers have described increased, decreased, or no difference in outcomes of COVID-19 in PWH. These studies have come from a range of locations, each with different underlying HIV prevalence and access to various antiretroviral therapy (ART) regimens. Differences in healthcare quality, access and policies may also affect reported outcomes in PWH across different locations, making interpretation of results more challenging. Meanwhile, different components of ART have been proposed to protect against SARS-CoV-2 acquisition or disease progression. SUMMARY: The current review considers 6 months of data across geographic regions with a range of healthcare quality and access and ART regimens to generate a wider view of COVID-19 outcomes in PWH. Taken together, these studies indicate that HIV infection may be associated with increased risk of COVID-19 diagnosis, but comorbidities appear to play a larger role than HIV-specific variables in outcomes of COVID-19 among PWH. ART does not appear to protect from COVID-19 disease acquisition, progression or death.


Assuntos
/virologia , Coinfecção/virologia , Infecções por HIV/virologia , HIV/fisiologia , /fisiologia , Animais , Coinfecção/epidemiologia , HIV/genética , Infecções por HIV/epidemiologia , Humanos , Pandemias , /genética
3.
Curr Opin HIV AIDS ; 16(1): 63-73, 2021 01.
Artigo em Inglês | MEDLINE | ID: mdl-33186229

RESUMO

PURPOSE OF REVIEW: We examine the interplay between the HIV and COVID-19 epidemics, including the impact of HIV on COVID-19 susceptibility and severe disease, the effect of the COVID-19 epidemic on HIV prevention and treatment, and the influence of the HIV epidemic on responses to COVID-19. RECENT FINDINGS: Evidence to date does not suggest that people living with HIV (PLWH) have a markedly higher susceptibility to SARS-CoV-2 infection, with disparities in the social determinants of health and comorbidities likely having a greater influence. The majority of literature has not supported a higher risk for severe disease among PLWH in Europe and the United States, although a large, population-based study in South Africa reported a higher rate of death due to COVID-19. Higher rates of comorbidities associated with COVID-19 disease severity among PLWH is an urgent concern. COVID-19 is leading to decreased access to HIV prevention services and HIV testing, and worsening HIV treatment access and virologic suppression, which could lead to worsening HIV epidemic control. CONCLUSION: COVID-19 is threatening gains against the HIV epidemic, including the U.S. Ending the HIV Epidemic goals. The ongoing collision of these two global pandemics will continue to need both study and interventions to mitigate the effects of COVID-19 on HIV efforts worldwide.


Assuntos
/virologia , Infecções por HIV/virologia , HIV/fisiologia , /fisiologia , /complicações , /mortalidade , Europa (Continente)/epidemiologia , HIV/genética , Infecções por HIV/complicações , Infecções por HIV/epidemiologia , Infecções por HIV/mortalidade , Humanos , Pandemias , África do Sul/epidemiologia , Estados Unidos/epidemiologia
4.
Curr Opin HIV AIDS ; 16(1): 11-24, 2021 01.
Artigo em Inglês | MEDLINE | ID: mdl-33186230

RESUMO

PURPOSE OF REVIEW: The aim of this review was to compare and contrast the application of molecular epidemiology approaches for the improved management and understanding of the HIV versus SARS-CoV-2 epidemics. RECENT FINDINGS: Molecular biology approaches, including PCR and whole genome sequencing (WGS), have become powerful tools for epidemiological investigation. PCR approaches form the basis for many high-sensitivity diagnostic tests and can supplement traditional contact tracing and surveillance strategies to define risk networks and transmission patterns. WGS approaches can further define the causative agents of disease, trace the origins of the pathogen, and clarify routes of transmission. When coupled with clinical datasets, such as electronic medical record data, these approaches can investigate co-correlates of disease and pathogenesis. In the ongoing HIV epidemic, these approaches have been effectively deployed to identify treatment gaps, transmission clusters and risk factors, though significant barriers to rapid or real-time implementation remain critical to overcome. Likewise, these approaches have been successful in addressing some questions of SARS-CoV-2 transmission and pathogenesis, but the nature and rapid spread of the virus have posed additional challenges. SUMMARY: Overall, molecular epidemiology approaches offer unique advantages and challenges that complement traditional epidemiological tools for the improved understanding and management of epidemics.


Assuntos
/virologia , Infecções por HIV/virologia , HIV/genética , /genética , /epidemiologia , HIV/classificação , HIV/isolamento & purificação , Infecções por HIV/epidemiologia , Humanos , Epidemiologia Molecular , Pandemias , /isolamento & purificação
5.
Curr Opin HIV AIDS ; 16(1): 48-53, 2021 01.
Artigo em Inglês | MEDLINE | ID: mdl-33278160

RESUMO

PURPOSE OF REVIEW: The global pandemic caused by the severe acute respiratory virus coronavirus 2 (SARS-CoV-2) has a male bias in mortality likely driven by both gender and sex-based differences between male and female individuals. This is consistent with sex and gender-based features of HIV infection and overlap between the two diseases will highlight potential mechanistic pathways of disease and guide research questions and policy interventions. In this review, the emerging findings from SARS-CoV-2 infection will be placed in the context of sex and gender research in the more mature HIV epidemic. RECENT FINDINGS: This review will focus on the new field of literature on prevention, immunopathogenesis and treatment of SARS-CoV-2 referencing relevant articles in HIV for context from a broader time period, consistent with the evolving understanding of sex and gender in HIV infection. Sex-specific features of epidemiology and immunopathogenesis reported in COVID-19 disease will be discussed and potential sex and gender-specific factors of relevance to prevention and treatment will be emphasized. SUMMARY: Multilayered impacts of sex and gender on HIV infection have illuminated pathways of disease and identified important goals for public health interventions. SARS-CoV-2 has strong evidence for a male bias in disease severity and exploring that difference will yield important insights.


Assuntos
/virologia , /fisiologia , Animais , Feminino , HIV/genética , HIV/fisiologia , Infecções por HIV/virologia , Humanos , Masculino , Pandemias , Fatores Sexuais
6.
Methods Mol Biol ; 2197: 113-131, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-32827134

RESUMO

Reliable detection and quantification of antigen-specific T cells are critical for assessing the immunogenicity of vaccine candidates. In this chapter, we describe the use of ELISpot and flow cytometry-based assays for efficient detection, mapping, and functional characterization of memory T lymphocytes in different tissues of rhesus macaques immunized with plasmid DNA. Flow cytometric assays provide a large amount of information, both phenotypic and functional, about individual cells, while the ELISpot is well suited for high throughput sample screening.


Assuntos
Infecções por HIV/prevenção & controle , HIV/genética , HIV/imunologia , Síndrome de Imunodeficiência Adquirida dos Símios/prevenção & controle , Vírus da Imunodeficiência Símia/genética , Vírus da Imunodeficiência Símia/imunologia , Vacinas de DNA/imunologia , Animais , Biomarcadores , Modelos Animais de Doenças , ELISPOT , Epitopos de Linfócito T/imunologia , Citometria de Fluxo , Interações Hospedeiro-Patógeno/imunologia , Humanos , Imunofenotipagem , Subpopulações de Linfócitos T/imunologia , Subpopulações de Linfócitos T/metabolismo
7.
Proc Natl Acad Sci U S A ; 117(52): 32880-32882, 2020 12 29.
Artigo em Inglês | MEDLINE | ID: mdl-33318172

RESUMO

In vivo clonal expansion of HIV-infected T cells is an important mechanism of viral persistence. In some cases, clonal expansion is driven by HIV proviral DNA integrated into one of a handful of genes. To investigate this phenomenon in vitro, we infected primary CD4+ T cells with an HIV construct expressing GFP and, after nearly 2 mo of culture and multiple rounds of activation, analyzed the resulting integration site distribution. In each of three replicates from each of two donors, we detected large clusters of integration sites with multiple breakpoints, implying clonal selection. These clusters all mapped to a narrow region within the STAT3 gene. The presence of hybrid transcripts splicing HIV to STAT3 sequences supports a model of LTR-driven STAT3 overexpression as a driver of preferential growth. Thus, HIV integration patterns linked to selective T cell outgrowth can be reproduced in cell culture. The single report of an HIV provirus in a case of AIDS-associated B-cell lymphoma with an HIV provirus in the same part of STAT3 also has implications for HIV-induced malignancy.


Assuntos
Proliferação de Células , HIV/fisiologia , Provírus/fisiologia , Linfócitos T/virologia , Integração Viral , Células Cultivadas , Evolução Clonal , DNA Viral/genética , HIV/genética , Humanos , Provírus/genética , Fator de Transcrição STAT3/genética , Linfócitos T/fisiologia
8.
PLoS One ; 15(12): e0243934, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33338033

RESUMO

BACKGROUND: Although the clinical benefits of medical genetic testing have been proven, there has been limited evidence on its economic impact in Thai setting. Thus, this study aimed to evaluate the economic impact of genetic testing services provided by the Center for Medical Genomics (CMG) in Thailand. METHODS: Cost-benefit analysis was conducted from provider and societal perspectives. Cost and output data of genetic testing services provided by the CMG during 2014 to 2018 and published literature reviews were applied to estimate the costs and benefits. Monetary benefits related to genetic testing services were derived through human capital approach. RESULTS: The total operation cost was 126 million baht over five years with an average annual cost of 21 million baht per year. The net benefit, benefit-to-cost ratio, and return on investment were 5,477 million baht, 43 times, and 42 times, respectively. Productivity gain was the highest proportion (50.57%) of the total benefit. CONCLUSIONS: The provision of genetic testing services at the CMG gained much more benefits than the cost. This study highlighted a good value for money in the establishment of medical genomics settings in Thailand and other developing countries.


Assuntos
Efeitos Psicossociais da Doença , Análise Custo-Benefício/economia , Testes Genéticos/economia , Infecções por HIV/economia , Genômica/economia , HIV/genética , HIV/patogenicidade , Infecções por HIV/epidemiologia , Infecções por HIV/genética , Infecções por HIV/virologia , Custos de Cuidados de Saúde/normas , Sequenciamento de Nucleotídeos em Larga Escala/economia , Humanos , Tailândia/epidemiologia
9.
BMC Infect Dis ; 20(1): 815, 2020 Nov 10.
Artigo em Inglês | MEDLINE | ID: mdl-33167892

RESUMO

BACKGROUND: The availability of effective, oral direct acting antivirals (DAAs) for hepatitis C virus (HCV) treatment has put elimination of HCV as a public health challenge within reach. However, little is known about the characteristics of transmission networks of people who inject drugs (PWID). METHODS: Sequencing of a segment of the HCV genome was performed on samples collected from a community-based cohort of PWID between August 2005 and December 2016. Phylogenetic trees were inferred, and clusters were identified (70% bootstrap threshold; 0.04 maximum genetic distance threshold). We describe sex, race, age difference, and HIV infection status of potential transmission partners. Logistic regression was used to assess factors associated with being in an HCV cluster. RESULTS: Of 508 HCV genotype 1 viremic PWID, 8% (n = 41) were grouped into 20 clusters, consisting of 19 pairs and 1 triad. In adjusted analyses, female sex (odds ratio [OR] 2.3 [95% confidence interval (CI) 1.2-4.5]) and HIV infection (OR 5.7 [CI 2.7-11.9]) remained independently associated with being in an HCV infection cluster. CONCLUSIONS: Molecular epidemiological analysis reveals that, in this cohort of PWID in Baltimore, HIV infection and female sex were associated with HCV clustering. Combination HCV prevention interventions targeting HIV infected PWID and addressing HCV infection prevention needs of women have potential to advance HCV elimination efforts.


Assuntos
Infecções por HIV/epidemiologia , HIV/genética , Hepacivirus/genética , Hepatite C/epidemiologia , Filogenia , Abuso de Substâncias por Via Intravenosa/epidemiologia , Idoso , Idoso de 80 Anos ou mais , Antivirais/uso terapêutico , Baltimore/epidemiologia , Análise por Conglomerados , Feminino , Seguimentos , Genótipo , Infecções por HIV/transmissão , Infecções por HIV/virologia , Hepatite C/transmissão , Hepatite C/virologia , Humanos , Masculino , Pessoa de Meia-Idade , Prevalência , Estudos Prospectivos , Fatores Sexuais , Parceiros Sexuais , Viremia/epidemiologia
10.
BMC Infect Dis ; 20(1): 788, 2020 Oct 23.
Artigo em Inglês | MEDLINE | ID: mdl-33096990

RESUMO

BACKGROUND: Tuberculous meningitis (TBM) represents a diagnostic and management challenge to clinicians. The "Thwaites' system" and "Lancet consensus scoring system" are utilized to differentiate TBM from bacterial meningitis but their utility in subacute and chronic meningitis where TBM is an important consideration is unknown. METHODS: A multicenter retrospective study of adults with subacute and chronic meningitis, defined by symptoms greater than 5 days and less than 30 days for subacute meningitis (SAM) and greater than 30 days for chronic meningitis (CM). The "Thwaites' system" and "Lancet consensus scoring system" scores and the diagnostic accuracy by sensitivity, specificity, and area under the curve of receiver operating curve (AUC-ROC) were calculated. The "Thwaites' system" and "Lancet consensus scoring system" suggest a high probability of TBM with scores ≤4, and with scores of ≥12, respectively. RESULTS: A total of 395 patients were identified; 313 (79.2%) had subacute and 82 (20.8%) with chronic meningitis. Patients with chronic meningitis were more likely caused by tuberculosis and had higher rates of HIV infection (P < 0.001). A total of 162 patients with TBM and 233 patients with non-TBM had unknown (140, 60.1%), fungal (41, 17.6%), viral (29, 12.4%), miscellaneous (16, 6.7%), and bacterial (7, 3.0%) etiologies. TMB patients were older and presented with lower Glasgow coma scores, lower CSF glucose and higher CSF protein (P < 0.001). Both criteria were able to distinguish TBM from bacterial meningitis; only the Lancet score was able to differentiate TBM from fungal, viral, and unknown etiologies even though significant overlap occurred between the etiologies (P < .001). Both criteria showed poor diagnostic accuracy to distinguish TBM from non-TBM etiologies (AUC-ROC was <. 5), but Lancet consensus scoring system was fair in diagnosing TBM (AUC-ROC was .738), sensitivity of 50%, and specificity of 89.3%. CONCLUSION: Both criteria can be helpful in distinguishing TBM from bacterial meningitis, but only the Lancet consensus scoring system can help differentiate TBM from meningitis caused by fungal, viral and unknown etiologies even though significant overlap occurs and the overall diagnostic accuracy of both criteria were either poor or fair.


Assuntos
Infecções Oportunistas Relacionadas com a AIDS/diagnóstico , Criptococose/diagnóstico , Cryptococcus neoformans/imunologia , HIV/genética , Meningite Fúngica/diagnóstico , Meningite Viral/diagnóstico , Mycobacterium tuberculosis/genética , Projetos de Pesquisa , Tuberculose Meníngea/diagnóstico , Infecções Oportunistas Relacionadas com a AIDS/virologia , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Área Sob a Curva , Doença Crônica , Criptococose/microbiologia , Diagnóstico Diferencial , Feminino , Humanos , Masculino , Meningite Fúngica/líquido cefalorraquidiano , Meningite Fúngica/microbiologia , Meningite Viral/líquido cefalorraquidiano , Meningite Viral/virologia , Pessoa de Meia-Idade , Mycobacterium tuberculosis/isolamento & purificação , Estudos Retrospectivos , Sensibilidade e Especificidade , Tuberculose Meníngea/líquido cefalorraquidiano , Tuberculose Meníngea/microbiologia , Adulto Jovem
11.
PLoS One ; 15(9): e0237469, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32870911

RESUMO

BACKGROUND: It is estimated that approximately half of new HIV diagnoses among heterosexual migrants in Victoria, Australia, were acquired post-migration. We investigated the characteristics of phylogenetic clusters in notified cases of HIV among heterosexual migrants. METHODS: Partial HIV pol sequences obtained from routine clinical genotype tests were linked to Victorian HIV notifications with the following exposures listed on the notification form: heterosexual sexual contact, injecting drug use, bisexual sexual contact, male-to male sexual contact or heterosexual sexual contact in combination with injecting drug use, unknown exposure. Those with heterosexual sexual contact as the only exposure were the focus of this study, with the other exposures included to better understand transmission networks. Additional reference sequences were extracted from the Los Alamos database. Maximum likelihood methods were used to infer the phylogeny and the robustness of the resulting tree was assessed using bootstrap analysis. Phylogenetic clusters were defined on the basis of bootstrap and genetic distance. RESULTS: HIV pol sequences were available for 332 of 445 HIV notifications attributed to only heterosexual sexual contact in Victoria from 2005-2014. Forty-three phylogenetic clusters containing at least one heterosexual migrant were detected, 30 (70%) of which were pairs. The characteristics of these phylogenetic clusters varied considerably by cluster size. Pairs were more likely to be composed of people living with HIV from a single country of birth (p = 0.032). Larger clusters (n≥3) were more likely to contain people born in Australian/New Zealand (p = 0.002), migrants from more than one country of birth (p = 0.013) and viral subtype-B, the most common subtype in Australia (p = 0.006). Pairs were significantly more likely to contain females (p = 0.037) and less likely to include HIV diagnoses with male-to-male sexual contact reported as a possible exposure (p<0.001) compared to larger clusters (n≥3). CONCLUSION: Migrants appear to be at elevated risk of HIV acquisition, in part due to intimate relationships between migrants from the same country of origin, and in part due to risks associated with the broader Australian HIV epidemic. However, there was no evidence of large transmission clusters driven by heterosexual transmission between migrants. A multipronged approach to prevention of HIV among migrants is warranted.


Assuntos
Infecções por HIV/epidemiologia , HIV/genética , Filogenia , Adulto , Austrália/epidemiologia , Análise por Conglomerados , Feminino , HIV/isolamento & purificação , Infecções por HIV/diagnóstico , HIV-1/genética , HIV-1/isolamento & purificação , Heterossexualidade , Humanos , Masculino , Pessoa de Meia-Idade , Migrantes , Produtos do Gene pol do Vírus da Imunodeficiência Humana/genética
12.
Med Sci (Paris) ; 36(8-9): 783-796, 2020.
Artigo em Francês | MEDLINE | ID: mdl-32773024

RESUMO

SARS-CoV-2 is a new human coronavirus (CoV), which emerged in People's Republic of China at the end of 2019 and is responsible for the global Covid-19 pandemic that caused more than 540 000 deaths in six months. Understanding the origin of this virus is an important issue and it is necessary to determine the mechanisms of its dissemination in order to be able to contain new epidemics. Based on phylogenetic inferences, sequence analysis and structure-function relationships of coronavirus proteins, informed by the knowledge currently available, we discuss the different scenarios evoked to account for the origin - natural or synthetic - of the virus. On the basis of currently available data, it is impossible to determine whether SARS-CoV-2 is the result of a natural zoonotic emergence or an accidental escape from experimental strains. Regardless of its origin, the study of the evolution of the molecular mechanisms involved in the emergence of this pandemic virus is essential to develop therapeutic and vaccine strategies.


Assuntos
Betacoronavirus/genética , Doenças Transmissíveis Emergentes/virologia , Infecções por Coronavirus/virologia , Coronavirus/classificação , Evolução Molecular , Pandemias , Filogenia , Pneumonia Viral/virologia , RNA Viral/genética , Sequência de Aminoácidos , Animais , Betacoronavirus/classificação , Betacoronavirus/isolamento & purificação , Derramamento de Material Biológico , China/epidemiologia , Infecções por Coronaviridae/transmissão , Infecções por Coronaviridae/veterinária , Infecções por Coronaviridae/virologia , Infecções por Coronavirus/epidemiologia , Infecções por Coronavirus/transmissão , Reservatórios de Doenças , Mutação com Ganho de Função , Genoma Viral , HIV/genética , Especificidade de Hospedeiro , Humanos , Mamíferos/virologia , Pneumonia Viral/epidemiologia , Pneumonia Viral/transmissão , Vírus Reordenados/genética , Alinhamento de Sequência , Homologia de Sequência de Aminoácidos , Glicoproteína da Espícula de Coronavírus/química , Glicoproteína da Espícula de Coronavírus/genética , Glicoproteína da Espícula de Coronavírus/fisiologia , Zoonoses
13.
Proc Natl Acad Sci U S A ; 117(36): 22436-22442, 2020 09 08.
Artigo em Inglês | MEDLINE | ID: mdl-32820072

RESUMO

Cholesterol-PIE12-trimer (CPT31) is a potent d-peptide HIV entry inhibitor that targets the highly conserved gp41 N-peptide pocket region. CPT31 exhibited strong inhibitory breadth against diverse panels of primary virus isolates. In a simian-HIV chimeric virus AD8 (SHIVAD8) macaque model, CPT31 prevented infection from a single high-dose rectal challenge. In chronically infected animals, CPT31 monotherapy rapidly reduced viral load by ∼2 logs before rebound occurred due to the emergence of drug resistance. In chronically infected animals with viremia initially controlled by combination antiretroviral therapy (cART), CPT31 monotherapy prevented viral rebound after discontinuation of cART. These data establish CPT31 as a promising candidate for HIV prevention and treatment.


Assuntos
Fármacos Anti-HIV , Infecções por HIV , HIV , Vírus da Imunodeficiência Símia , Internalização do Vírus/efeitos dos fármacos , Animais , Fármacos Anti-HIV/química , Fármacos Anti-HIV/farmacologia , Fármacos Anti-HIV/uso terapêutico , Avaliação Pré-Clínica de Medicamentos , Feminino , HIV/efeitos dos fármacos , HIV/genética , Proteína gp41 do Envelope de HIV/antagonistas & inibidores , Infecções por HIV/tratamento farmacológico , Infecções por HIV/prevenção & controle , Infecções por HIV/virologia , Macaca mulatta , Masculino , Vírus da Imunodeficiência Símia/efeitos dos fármacos , Vírus da Imunodeficiência Símia/genética
14.
Nat Commun ; 11(1): 3849, 2020 07 31.
Artigo em Inglês | MEDLINE | ID: mdl-32737300

RESUMO

Kaposi's sarcoma-associated herpesvirus (KSHV) and Epstein-Barr Virus (EBV) establish life-long infections and are associated with malignancies. Striking geographic variation in incidence and the fact that virus alone is insufficient to cause disease, suggests other co-factors are involved. Here we present epidemiological analysis and genome-wide association study (GWAS) in 4365 individuals from an African population cohort, to assess the influence of host genetic and non-genetic factors on virus antibody responses. EBV/KSHV co-infection (OR = 5.71(1.58-7.12)), HIV positivity (OR = 2.22(1.32-3.73)) and living in a more rural area (OR = 1.38(1.01-1.89)) are strongly associated with immunogenicity. GWAS reveals associations with KSHV antibody response in the HLA-B/C region (p = 6.64 × 10-09). For EBV, associations are identified for VCA (rs71542439, p = 1.15 × 10-12). Human leucocyte antigen (HLA) and trans-ancestry fine-mapping substantiate that distinct variants in HLA-DQA1 (p = 5.24 × 10-44) are driving associations for EBNA-1 in Africa. This study highlights complex interactions between KSHV and EBV, in addition to distinct genetic architectures resulting in important differences in pathogenesis and transmission.


Assuntos
Anticorpos Antivirais/biossíntese , Resistência à Doença/genética , Infecções por Vírus Epstein-Barr/genética , Infecções por Henipavirus/genética , Interações Hospedeiro-Patógeno/genética , Sarcoma de Kaposi/genética , Adolescente , Adulto , Antígenos Virais/genética , Antígenos Virais/imunologia , Proteínas do Capsídeo/genética , Proteínas do Capsídeo/imunologia , Coinfecção , Infecções por Vírus Epstein-Barr/epidemiologia , Infecções por Vírus Epstein-Barr/imunologia , Infecções por Vírus Epstein-Barr/virologia , Antígenos Nucleares do Vírus Epstein-Barr/genética , Antígenos Nucleares do Vírus Epstein-Barr/imunologia , Feminino , Expressão Gênica , Estudo de Associação Genômica Ampla , HIV/genética , HIV/imunologia , HIV/patogenicidade , Cadeias alfa de HLA-DQ/genética , Cadeias alfa de HLA-DQ/imunologia , Infecções por Henipavirus/epidemiologia , Infecções por Henipavirus/imunologia , Infecções por Henipavirus/virologia , Herpesvirus Humano 4/genética , Herpesvirus Humano 4/imunologia , Herpesvirus Humano 4/patogenicidade , Herpesvirus Humano 8/genética , Herpesvirus Humano 8/imunologia , Herpesvirus Humano 8/patogenicidade , Interações Hospedeiro-Patógeno/imunologia , Humanos , Incidência , Masculino , Pessoa de Meia-Idade , População Rural , Sarcoma de Kaposi/epidemiologia , Sarcoma de Kaposi/imunologia , Sarcoma de Kaposi/virologia , Uganda/epidemiologia , População Urbana
15.
Inflamm Res ; 69(9): 801-812, 2020 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-32656668

RESUMO

During the current COVID-19 pandemic, the global ratio between the dead and the survivors is approximately 1 to 10, which has put humanity on high alert and provided strong motivation for the intensive search for vaccines and drugs. It is already clear that if we follow the most likely scenario, which is similar to that used to create seasonal influenza vaccines, then we will need to develop improved vaccine formulas every year to control the spread of the new, highly mutable coronavirus SARS-CoV-2. In this article, using well-known RNA viruses (HIV, influenza viruses, HCV) as examples, we consider the main successes and failures in creating primarily highly effective vaccines. The experience accumulated dealing with the biology of zoonotic RNA viruses suggests that the fight against COVID-19 will be difficult and lengthy. The most effective vaccines against SARS-CoV-2 will be those able to form highly effective memory cells for both humoral (memory B cells) and cellular (cross-reactive antiviral memory T cells) immunity. Unfortunately, RNA viruses constantly sweep their tracks and perhaps one of the most promising solutions in the fight against the COVID-19 pandemic is the creation of 'universal' vaccines based on conservative SARS-CoV-2 genome sequences (antigen-presenting) and unmethylated CpG dinucleotides (adjuvant) in the composition of the phosphorothioate backbone of single-stranded DNA oligonucleotides (ODN), which can be effective for long periods of use. Here, we propose a SARS-CoV-2 vaccine based on a lasso-like phosphorothioate oligonucleotide construction containing CpG motifs and the antigen-presenting unique ACG-containing genome sequence of SARS-CoV-2. We found that CpG dinucleotides are the most rare dinucleotides in the genomes of SARS-CoV-2 and other known human coronaviruses, and hypothesized that their higher frequency could be responsible for the unwanted increased lethality to the host, causing a 'cytokine storm' in people who overexpress cytokines through the activation of specific Toll-like receptors in a manner similar to TLR9-CpG ODN interactions. Interestingly, the virus strains sequenced in China (Wuhan) in February 2020 contained on average one CpG dinucleotide more in their genome than the later strains from the USA (New York) sequenced in May 2020. Obviously, during the first steps of the microevolution of SARS-CoV-2 in the human population, natural selection tends to select viral genomes containing fewer CpG motifs that do not trigger a strong innate immune response, so the infected person has moderate symptoms and spreads SARS-CoV-2 more readily. However, in our opinion, unmethylated CpG dinucleotides are also capable of preparing the host immune system for the coronavirus infection and should be present in SARS-CoV-2 vaccines as strong adjuvants.


Assuntos
Betacoronavirus/genética , Infecções por Coronavirus/imunologia , Oligodesoxirribonucleotídeos/imunologia , Pneumonia Viral/imunologia , Vacinas Virais , Adjuvantes Imunológicos , Linfócitos B/virologia , Betacoronavirus/imunologia , Infecções por Coronavirus/prevenção & controle , Infecções por Coronavirus/virologia , Citocinas/imunologia , Genoma Viral , HIV/genética , Hepacivirus/genética , Humanos , Imunidade Humoral , Memória Imunológica , Inflamação , Mutação , Orthomyxoviridae/genética , Pandemias/prevenção & controle , Oligonucleotídeos Fosforotioatos/imunologia , Pneumonia Viral/prevenção & controle , Pneumonia Viral/virologia , Linfócitos T/virologia
16.
J Vis Exp ; (160)2020 06 17.
Artigo em Inglês | MEDLINE | ID: mdl-32628155

RESUMO

In situ hybridization is a powerful technique to identify specific RNA or DNA sequences within individual cells in tissue sections, providing important insights into physiological processes and disease pathogenesis. In situ hybridization (ISH) has been used for many years to assess the location of cells infected by viruses, but recently a next-generation ISH approach was developed with a unique probe design strategy that allows simultaneous signal amplification and background suppression to achieve single-molecule visualization while preserving tissue morphology. This next-generation ISH is based on an approach like branched PCR, but performed in situ and is more facile, sensitive, and reproducible than classical ISH methods or in situ PCR approaches in routinely detecting RNA or DNA in formalin-fixed paraffin embedded (FFPE) tissues. For the last several years our laboratory has been applying this ISH platform for the detection of human immunodeficiency (HIV) and simian immunodeficiency (SIV) viral RNA (vRNA) and/or viral DNA (vDNA) positive cells within a multitude of FFPE tissues. With this detailed technical manuscript, we would like to share our knowledge and advice with all individuals interested in using next-generation ISH in their research.


Assuntos
DNA Viral/genética , HIV/genética , Hibridização In Situ , RNA Viral/genética , Vírus da Imunodeficiência Símia/genética , Animais , Epitopos/metabolismo , Humanos , Processamento de Imagem Assistida por Computador , Inclusão em Parafina , Peptídeo Hidrolases/metabolismo , Processamento de Sinais Assistido por Computador , Fixação de Tecidos
17.
Am J Ophthalmol ; 218: 268-278, 2020 10.
Artigo em Inglês | MEDLINE | ID: mdl-32621897

RESUMO

PURPOSE: Despite well-known ocular complications of HIV-related immune suppression, few studies have examined the prevalence and consequences of visual impairment among aging long-term survivors of HIV. DESIGN: Retrospective cohort study. METHODS: Aging HIV-infected (HIV+) men who have sex with men (MSM) and HIV-uninfected (HIV-) MSM controls reported their difficulty performing 6 vision-dependent tasks (difficulty defined as: no, a little, moderate, and extreme difficulty). Relationships were examined using logistic regression, regressing each outcome separately on categorical visual function responses, with missing data multiply imputed. RESULTS: There were 634 age-matched pairs for a total sample of 1,268 MSM of 1,700 MSM with available data. The median age was 60 years old (interquartile range [IQR], 54, 66), and 23% were African American. Among HIV+ men, 95% were virally suppressed (viral load <400 copies/mL). HIV+ men were more likely to report moderate or extreme difficulty performing at least 1 task (21% for HIV+ compared to 13% for HIV-; P < .01). Participants reporting extreme vision-related difficulty performing at least 1 task had 11.2 times the odds of frailty (95% confidence interval [CI], 5.2-23.9), 2.6 times the odds of a slow gait speed (95% CI, 1.4-4.8), and 3.2 times the odds of impaired instrumental activities of daily living (95% CI: 1.6-6.3) compared to those reporting no vision-related difficulty on any task. CONCLUSIONS: Perceived vision difficulty was more common among older HIV+ MSM than age-matched HIV- MSM controls and was associated with higher risk of depression and physical function loss among MSM.


Assuntos
Envelhecimento/fisiologia , Infecções por HIV/epidemiologia , Sobreviventes/estatística & dados numéricos , Transtornos da Visão/epidemiologia , Pessoas com Deficiência Visual/estatística & dados numéricos , Idoso , Estudos Transversais , HIV/genética , Infecções por HIV/diagnóstico , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Multicêntricos como Assunto , Prevalência , RNA Viral/sangue , Estudos Retrospectivos , Perfil de Impacto da Doença , Inquéritos e Questionários , Carga Viral , Transtornos da Visão/diagnóstico
18.
Viruses ; 12(7)2020 07 14.
Artigo em Inglês | MEDLINE | ID: mdl-32674515

RESUMO

Next-generation sequencing (NGS) offers a powerful opportunity to identify low-abundance, intra-host viral sequence variants, yet the focus of many bioinformatic tools on consensus sequence construction has precluded a thorough analysis of intra-host diversity. To take full advantage of the resolution of NGS data, we developed HAplotype PHylodynamics PIPEline (HAPHPIPE), an open-source tool for the de novo and reference-based assembly of viral NGS data, with both consensus sequence assembly and a focus on the quantification of intra-host variation through haplotype reconstruction. We validate and compare the consensus sequence assembly methods of HAPHPIPE to those of two alternative software packages, HyDRA and Geneious, using simulated HIV and empirical HIV, HCV, and SARS-CoV-2 datasets. Our validation methods included read mapping, genetic distance, and genetic diversity metrics. In simulated NGS data, HAPHPIPE generated pol consensus sequences significantly closer to the true consensus sequence than those produced by HyDRA and Geneious and performed comparably to Geneious for HIV gp120 sequences. Furthermore, using empirical data from multiple viruses, we demonstrate that HAPHPIPE can analyze larger sequence datasets due to its greater computational speed. Therefore, we contend that HAPHPIPE provides a more user-friendly platform for users with and without bioinformatics experience to implement current best practices for viral NGS assembly than other currently available options.


Assuntos
Biologia Computacional/métodos , Sequenciamento de Nucleotídeos em Larga Escala/métodos , Vírus/genética , Betacoronavirus/genética , Infecções por Coronavirus/virologia , Genoma Viral , Genômica/métodos , HIV/genética , Haplótipos , Hepacivirus/genética , Humanos , Pandemias , Pneumonia Viral/virologia
19.
Hum Genet ; 139(6-7): 865-875, 2020 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-32409920

RESUMO

Genome-wide association studies (GWAS) have been successful in identifying and confirming novel genetic variants that are associated with diverse HIV phenotypes. However, these studies have predominantly focused on European cohorts. HLA molecules have been consistently associated with HIV outcomes, some of which have been found to be population specific, underscoring the need for diversity in GWAS. Recently, there has been a concerted effort to address this gap that leads to health care (disease prevention, diagnosis, treatment) disparities with marginal improvement. As precision medicine becomes more utilized, non-European individuals will be more and more disadvantaged, as the genetic variants identified in genomic research based on European populations may not accurately reflect that of non-European individuals. Leveraging pre-existing, large, multiethnic cohorts, such as the UK Biobank, 23andMe, and the National Institute of Health's All of Us Research Program, can contribute in raising genomic research in non-European populations and ultimately lead to better health outcomes.


Assuntos
Marcadores Genéticos , Predisposição Genética para Doença , Genética Populacional , Infecções por HIV/genética , HIV/genética , Genética Humana , Polimorfismo de Nucleotídeo Único , Estudo de Associação Genômica Ampla , HIV/isolamento & purificação , Infecções por HIV/epidemiologia , Infecções por HIV/virologia , Humanos
20.
Sex Transm Infect ; 96(5): 337-341, 2020 08.
Artigo em Inglês | MEDLINE | ID: mdl-32245779

RESUMO

OBJECTIVE: To provide insight on viral kinetics and genetic diversity of HIV in seminal plasma at baseline and 1 month after initiating antiretroviral therapy (ART). PATIENTS AND METHODS: Blood and seminal samples from patients with newly diagnosed HIV were obtained before ART initiation (T0) and 1 month after ART initiation (T1). HIV env genetic diversity was studied using deep sequencing Nextera and V3 chemistry in a MiSeq Illumina platform. The number of viral quasispecies (5% cut-off) and Shannon Index were used to analyse diversity. RESULTS: Forty-seven ART-naive patients were recruited between September 2016 and November 2018. At enrolment, the number of quasispecies in blood (median 4 (IQR 2-5)) was lower than in the seminal compartment (median 6, (IQR 4-8)) (p<0.01); the Shannon Index was also higher (p<0.001) in the seminal compartment than in blood (1.77 vs 0.64). At T1, for the 13 patients with detectable HIV in both blood/seminal plasma, viral diversity remained higher (p=0.139) in seminal plasma (median 2 (IQR 1-4.5)) than in blood (median 1 (IQR 1-1.5)) Integrase inhibitors (INI)-based regimens achieved higher levels of undetectability and led more frequently to lower variability (p<0.001) than protease inhibitors (PI) or non-nucleoside reverse transcriptase inhibitors (NNRTI). CONCLUSION: We provide here further evidence of a larger genetic diversity in seminal plasma, both at diagnosis and short term after ART initiation. Our results strengthen previous findings on HIV diversity in seminal plasma. In addition, INIs decrease variability more rapidly than PI and NNRTI in both blood and seminal plasma.


Assuntos
Antirretrovirais/uso terapêutico , Sangue/virologia , Variação Genética , Infecções por HIV/tratamento farmacológico , HIV/genética , Sêmen/virologia , Produtos do Gene env do Vírus da Imunodeficiência Humana/genética , Adulto , Infecções por HIV/sangue , Infecções por HIV/metabolismo , Inibidores de Integrase de HIV/uso terapêutico , Inibidores da Protease de HIV/uso terapêutico , Humanos , Masculino , Inibidores da Transcriptase Reversa/uso terapêutico
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