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1.
Artigo em Inglês | MEDLINE | ID: mdl-32053203

RESUMO

BACKGROUND: Validated biomarkers to evaluate HIV-1 cure strategies are currently lacking, therefore requiring analytical treatment interruption (ATI) in study participants. Little is known about the safety of ATI and its long-term impact on patient health. OBJECTIVES: ATI safety was assessed and potential biomarkers predicting viral rebound were evaluated. METHODS: PBMCs, plasma and CSF were collected from 11 HIV-1-positive individuals at four different timepoints during ATI (NCT02641756). Total and integrated HIV-1 DNA, cell-associated (CA) HIV-1 RNA transcripts and restriction factor (RF) expression were measured by PCR-based assays. Markers of neuroinflammation and neuronal injury [neurofilament light chain (NFL) and YKL-40 protein] were measured in CSF. Additionally, neopterin, tryptophan and kynurenine were measured, both in plasma and CSF, as markers of immune activation. RESULTS: Total HIV-1 DNA, integrated HIV-1 DNA and CA viral RNA transcripts did not differ pre- and post-ATI. Similarly, no significant NFL or YKL-40 increases in CSF were observed between baseline and viral rebound. Furthermore, markers of immune activation did not increase during ATI. Interestingly, the RFs SLFN11 and APOBEC3G increased after ATI before viral rebound. Similarly, Tat-Rev transcripts were increased preceding viral rebound after interruption. CONCLUSIONS: ATI did not increase viral reservoir size and it did not reveal signs of increased neuronal injury or inflammation, suggesting that these well-monitored ATIs are safe. Elevation of Tat-Rev transcription and induced expression of the RFs SLFN11 and APOBEC3G after ATI, prior to viral rebound, indicates that these factors could be used as potential biomarkers predicting viral rebound.

2.
J Int AIDS Soc ; 23(2): e25453, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-32107887

RESUMO

INTRODUCTION: Viral remission after analytical treatment interruption (ATI), termed post-treatment control, has been described in a small proportion of HIV-positive patients. This phenomenon has been separately associated to both low levels of HIV-1 proviral DNA as well as cell-associated RNA. We investigated whether the combination of both parameters could help predict delayed viral rebound after treatment interruption (TI). METHODS: We conducted an open single-arm ATI study in four Belgian HIV reference centres from January 2016 to July 2018. Eligible participants were adults who had fewer than 50 HIV-1 RNA copies/mL for more than two years, more than 500 CD4 cells/µL for more than three months, and were in general good health. Consenting participants who had fewer than 66 copies total HIV-1 DNA (t-DNA) and fewer than 10 copies cell-associated HIV-1 unspliced RNA (US-RNA) per million peripheral blood mononuclear cells (PBMCs), interrupted therapy and were monitored closely. Antiretroviral therapy (ART) was resumed after two consecutive viral loads exceeding 1000 copies or one exceeding 10,000 copies/mL. The primary outcome was the proportion of participants with fewer than 50 HIV-1 RNA copies/mL 48 weeks after TI. Secondary outcomes were time to viral rebound, the frequency of serious adverse events (AEs) and evolution of t-DNA and US-RNA after TI. RESULTS: All 16 consenting participants who interrupted therapy experienced rapid viral rebound two to eight weeks after TI. No serious AEs were observed. Levels of t-DNA and US-RNA increased after TI but returned to pre-ATI levels after treatment restart. None of the studied demographic, clinical and biological parameters were predictive of time of viral rebound. CONCLUSIONS: The combination of low levels of t-DNA and US-RNA in PBMCs, corresponding respectively to a small and transcriptionally silent viral reservoir, is not predictive of viral remission after TI in patients on ART.

4.
Cell Host Microbe ; 26(3): 347-358.e7, 2019 Sep 11.
Artigo em Inglês | MEDLINE | ID: mdl-31471273

RESUMO

Viral rebound upon stopping combined antiretroviral therapy poses a major barrier toward an HIV cure. Cellular and anatomical sources responsible for reinitiating viral replication remain a subject of ardent debate, despite extensive research efforts. To unravel the source of rebounding viruses, we conducted a large-scale HIV-STAR (HIV-1 sequencing before analytical treatment interruption to identify the anatomically relevant HIV reservoir) clinical trial. We collected samples from 11 participants and compared the genetic composition of (pro)viruses collected under treatment from different cellular and anatomical compartments with that of plasma viruses sampled during analytical treatment interruption. We found a remarkably heterogeneous source of viral rebound. In addition, irrespective of the compartment or cell subset, genetically identical viral expansions played a significant role in viral rebound. Our study suggests that although there does not seem to be a primary source for rebound HIV, cellular proliferation is an important driver of HIV persistence and should therefore be considered in future curative strategies.


Assuntos
Infecções por HIV/virologia , HIV-1/genética , Dispositivos de Acesso Vascular/virologia , Antirretrovirais/uso terapêutico , Medula Óssea/virologia , Proliferação de Células , Líquido Cefalorraquidiano/virologia , Feminino , Genes Virais , HIV-1/isolamento & purificação , Humanos , Cinética , Linfonodos/virologia , Tecido Linfoide/virologia , Masculino , Plasma , Carga Viral , Replicação Viral
5.
Sci Rep ; 8(1): 17274, 2018 11 22.
Artigo em Inglês | MEDLINE | ID: mdl-30467426

RESUMO

HIV-1 DNA quantification serves as an important reservoir biomarker in HIV cure trials. However, the high genetic diversity of HIV-1 represented by different subtypes may bring inaccuracy in quantifying HIV-1 DNA and a sensitive and validated assay covering diverse HIV-1 subtypes is lacking. Therefore, we cross-validated total HIV-1 DNA assays described in literature using a three-step comparative analysis. First, a bioinformatics tool was developed in-house to perform an in silico evaluation of 67 HIV-1 DNA assays. Secondly, these selected assays were in vitro validated using a panel of different HIV-1 subtypes and, finally, ex vivo assessed on selected patient samples with different HIV-1 subtypes. Our results show that quantification of HIV-1 DNA substantially differs between assays and we advise five best performing HIV-1 DNA assays for ddPCR and qPCR (Schvachsa_2007, Viard_2004, Heeregrave_2009, Van_der_Sluis_2013, Yu_2008 and Yun_2002). This in-depth analysis of published HIV-1 DNA assays indicates that not all assays guarantee an optimal measurement of HIV-1 DNA, especially when looking across subtypes. Using an in-depth cross-validation, we were able to validate HIV-1 DNA assays that are suitable for quantification of HIV-1 DNA in a wide variety of HIV-1 infected patients.


Assuntos
Infecções por HIV/virologia , HIV-1/genética , Reação em Cadeia da Polimerase/métodos , Simulação por Computador , DNA Viral/análise , Variação Genética , Infecções por HIV/genética , Repetição Terminal Longa de HIV , Humanos , Kit de Reagentes para Diagnóstico , Carga Viral
6.
Acta Clin Belg ; 72(2): 138-141, 2017 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-27593992

RESUMO

We describe a 43-year-old patient with subacute appearance of neurological and atypical complaints of anergia, anorexia and weight loss six months earlier. In spite of several admissions in different hospitals, no underlying somatic cause could be found and he was admitted to a psychiatric hospital with a tentative diagnosis of major depressive disorder. Subsequently, he was referred to the unit of medically unexplained physical symptoms within the department of general internal medicine for assessment by the psychiatrist, involved in this programme. Based on clinical suspicion and red flag symptoms such as involuntary weight loss, a broader internal medicine reassessment, including FDG whole-body PET-CT was requested. Neurological clinical exam showed minor deviations, but neither brain imaging nor a lumbar puncture were contributory. However, FDG PET-CT revealed abnormal moderately to intensely FDG positive lymph nodes in the retroperitoneum. Laparoscopic lymph node biopsy indicated germ cell tumour metastasis. Anti-NMDA antibody positivity allowed a diagnosis of paraneoplastic anti-NMDA encephalitis. Treatment of the underlying disease, a pure seminoma stadium II, consisting of orchidectomy and chemotherapy, resulted in a spectacular regression of 'psychosomatic' symptoms with long-term ability to return to work, and documented disappearance of the anti-NMDA antibody response.


Assuntos
Encefalite Antirreceptor de N-Metil-D-Aspartato/diagnóstico , Seminoma/diagnóstico , Neoplasias Testiculares/diagnóstico , Adulto , Encefalite Antirreceptor de N-Metil-D-Aspartato/etiologia , Humanos , Metástase Linfática , Masculino , Transtornos Psicofisiológicos/diagnóstico por imagem , Espaço Retroperitoneal/patologia , Seminoma/complicações , Seminoma/patologia , Neoplasias Testiculares/complicações , Neoplasias Testiculares/patologia
7.
Sci Rep ; 6: 38329, 2016 12 02.
Artigo em Inglês | MEDLINE | ID: mdl-27910923

RESUMO

To understand the persistence of latently HIV-1 infected cells in virally suppressed infected patients, a number of in vitro models of HIV latency have been developed. In an attempt to mimic the in vivo situation as closely as possible, several models use primary cells and replication-competent viruses in combination with antiretroviral compounds to prevent ongoing replication. Latency is subsequently measured by HIV RNA and/or protein production after cellular activation. To discriminate between pre- and post-integration latency, integrase inhibitors are routinely used, preventing novel integrations upon cellular activation. Here, we show that this choice of antiretrovirals may still cause a bias of pre-integration latency in these models, as unintegrated HIV DNA can form and directly contribute to the levels of HIV RNA and protein production. We further show that the addition of reverse transcriptase inhibitors effectively suppresses the levels of episomal HIV DNA (as measured by 2-LTR circles) and decreases the levels of HIV transcription. Consequently, we show that latency levels described in models that only use integrase inhibitors may be overestimated. The inclusion of additional control conditions, such as 2-LTR quantification and the addition of reverse transcriptase inhibitors, is crucial to fully elucidate the actual levels of post-integration latency.


Assuntos
Inibidores de Integrase de HIV/farmacologia , Inibidores da Protease de HIV/farmacologia , HIV-1/efeitos dos fármacos , Inibidores da Transcriptase Reversa/farmacologia , Proteínas Virais/genética , Latência Viral/efeitos dos fármacos , Benzoxazinas/farmacologia , Linfócitos T CD4-Positivos/imunologia , Linfócitos T CD4-Positivos/virologia , DNA Viral/antagonistas & inibidores , DNA Viral/biossíntese , DNA Viral/genética , Genes Reporter , Proteínas de Fluorescência Verde/genética , Proteínas de Fluorescência Verde/metabolismo , Infecções por HIV/tratamento farmacológico , Infecções por HIV/imunologia , Infecções por HIV/virologia , HIV-1/fisiologia , Humanos , Ativação Linfocitária , Modelos Biológicos , Nevirapina/farmacologia , Cultura Primária de Células , Raltegravir Potássico/farmacologia , Ritonavir/farmacologia , Proteínas Virais/antagonistas & inibidores , Proteínas Virais/biossíntese , Integração Viral/efeitos dos fármacos , Replicação Viral/efeitos dos fármacos
8.
AIDS Rev ; 18(4): 171-183, 2016.
Artigo em Inglês | MEDLINE | ID: mdl-27438577

RESUMO

Due to the scarcity of HIV-1 latently infected cells in patients, in vitro primary latency models are now commonly used to study the HIV-1 reservoir. To this end, a number of experimental systems have been developed. Most of these models differ based on the nature of the primary CD4+ T-cell type, the used HIV strains, activation methods, and latency assessment strategies. Despite these differences, most models share some common characteristics. Here, we provide a systematic review covering the primary HIV latency models that have been used to date with the aim to compare these models and identify minimal requirements for such experiments. A systematic search on PubMed and Web of Science databases generated a short list of 17 unique publications that propose new in vitro latency models. Based on the described methods, we propose and discuss a generalized workflow, visualizing all the necessary steps to perform such an in vitro study, with the key choices and validation steps that need to be made; from cell type selection until the model readout.


Assuntos
Infecções por HIV/virologia , HIV-1/fisiologia , Latência Viral/fisiologia , Humanos , Modelos Biológicos , Linfócitos T/fisiologia , Linfócitos T/virologia
9.
Clin Rheumatol ; 35(6): 1649-53, 2016 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-26712500

RESUMO

We describe the case of a 26-year-old African female who was treated successfully with belimumab in a case of severe membranous lupus nephritis and retinal vasculitis, resistant to first line therapy. She presented initially with chronic dacryoadenitis and screening showed nephrotic-range proteinuria. Biopsy of the kidney confirmed the diagnosis of membranous lupus nephritis. Clinical features (joint pain, dacryoadenitis, retinal vasculitis and lupus nephritis) in combination with serology (positive anti-double-stranded DNA (ds-DNA) antibodies, hypocomplementemia) confirmed the diagnosis of systemic lupus erythematosus (SLE). Treatment was immediately initiated with glucocorticosteroids (GCS), mycophenolate mofetil (MMF) and hydroxychloroquine sulphate (Plaquenil®). Tacrolimus was associated but no effect was observed with the proteinuria remaining in the nephrotic range and secondary effects of the glucocorticosteroids becoming a real concern. The patient was started on add-on belimumab with quasi-immediate effect on the proteinuria, making it possible to decrease the dosage of the other immunosuppressants and gradually stop them, even the GCS. The patient is currently in complete remission after 3 years of treatment with belimumab. We were able to stop immunosuppressive treatment but will keep her on antimalarial treatment as the most recent guidelines in treatment of SLE recommend.


Assuntos
Anticorpos Monoclonais Humanizados/uso terapêutico , Imunossupressores/uso terapêutico , Nefrite Lúpica/tratamento farmacológico , Nefrite Lúpica/patologia , Adulto , Emigrantes e Imigrantes , Feminino , Humanos , Rim/patologia , Proteinúria/tratamento farmacológico , Indução de Remissão
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