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1.
Artif Cells Nanomed Biotechnol ; 49(1): 204-218, 2021 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-33645342

RESUMEN

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is a zoo tonic, highly pathogenic virus. The new type of coronavirus with contagious nature spread from Wuhan (China) to the whole world in a very short time and caused the new coronavirus disease (COVID-19). COVID-19 has turned into a global public health crisis due to spreading by close person-to-person contact with high transmission capacity. Thus, research about the treatment of the damages caused by the virus or prevention from infection increases everyday. Besides, there is still no approved and definitive, standardized treatment for COVID-19. However, this disaster experienced by human beings has made us realize the significance of having a system ready for use to prevent humanity from viral attacks without wasting time. As is known, nanocarriers can be targeted to the desired cells in vitro and in vivo. The nano-carrier system targeting a specific protein, containing the enzyme inhibiting the action of the virus can be developed. The system can be used by simple modifications when we encounter another virus epidemic in the future. In this review, we present a potential treatment method consisting of a nanoparticle-ribozyme conjugate, targeting ACE-2 receptors by reviewing the virus-associated ribozymes, their structures, types and working mechanisms.


Asunto(s)
/tratamiento farmacológico , Nanopartículas/administración & dosificación , ARN Catalítico/uso terapéutico , ARN Viral/antagonistas & inhibidores , /efectos de los fármacos , /antagonistas & inhibidores , Ensayos Clínicos como Asunto , Portadores de Fármacos , Composición de Medicamentos , Diseño de Fármacos , Infecciones por VIH/tratamiento farmacológico , VIH-1/efectos de los fármacos , VIH-1/genética , Humanos , Coronavirus del Síndrome Respiratorio de Oriente Medio/efectos de los fármacos , Coronavirus del Síndrome Respiratorio de Oriente Medio/genética , Modelos Moleculares , Conformación de Ácido Nucleico , Interferencia de ARN , ARN Catalítico/administración & dosificación , ARN Catalítico/química , ARN Catalítico/clasificación , ARN no Traducido/clasificación , ARN no Traducido/genética , ARN no Traducido/uso terapéutico , Virus del SRAS/efectos de los fármacos , Virus del SRAS/genética , /fisiología , Glicoproteína de la Espiga del Coronavirus/fisiología , Replicación Viral/efectos de los fármacos
2.
N Engl J Med ; 384(12): 1089-1100, 2021 03 25.
Artículo en Inglés | MEDLINE | ID: mdl-33761206

RESUMEN

BACKGROUND: A safe, effective vaccine is essential to eradicating human immunodeficiency virus (HIV) infection. A canarypox-protein HIV vaccine regimen (ALVAC-HIV plus AIDSVAX B/E) showed modest efficacy in reducing infection in Thailand. An analogous regimen using HIV-1 subtype C virus showed potent humoral and cellular responses in a phase 1-2a trial in South Africa. Efficacy data and additional safety data were needed for this regimen in a larger population in South Africa. METHODS: In this phase 2b-3 trial, we randomly assigned 5404 adults without HIV-1 infection to receive the vaccine (2704 participants) or placebo (2700 participants). The vaccine regimen consisted of injections of ALVAC-HIV at months 0 and 1, followed by four booster injections of ALVAC-HIV plus bivalent subtype C gp120-MF59 adjuvant at months 3, 6, 12, and 18. The primary efficacy outcome was the occurrence of HIV-1 infection from randomization to 24 months. RESULTS: In January 2020, prespecified criteria for nonefficacy were met at an interim analysis; further vaccinations were subsequently halted. The median age of the trial participants was 24 years; 70% of the participants were women. The incidence of adverse events was similar in the vaccine and placebo groups. During the 24-month follow-up, HIV-1 infection was diagnosed in 138 participants in the vaccine group and in 133 in the placebo group (hazard ratio, 1.02; 95% confidence interval, 0.81 to 1.30; P = 0.84). CONCLUSIONS: The ALVAC-gp120 regimen did not prevent HIV-1 infection among participants in South Africa despite previous evidence of immunogenicity. (HVTN 702 ClinicalTrials.gov number, NCT02968849.).


Asunto(s)
Vacunas contra el SIDA , Adyuvantes Inmunológicos , Infecciones por VIH/prevención & control , VIH-1 , Inmunogenicidad Vacunal , Polisorbatos , Escualeno , Vacunas contra el SIDA/inmunología , Adolescente , Adulto , Virus de la Viruela de los Canarios , Método Doble Ciego , Femenino , Vectores Genéticos , VIH-1/genética , Humanos , Inmunización Secundaria , Masculino , Sudáfrica , Insuficiencia del Tratamiento , Adulto Joven
3.
Nat Commun ; 12(1): 1474, 2021 03 05.
Artículo en Inglés | MEDLINE | ID: mdl-33674572

RESUMEN

The establishment of a long-lived viral reservoir is the key obstacle for achieving an HIV-1 cure. However, the anatomic, virologic, and immunologic features of the viral reservoir in tissues during antiretroviral therapy (ART) remain poorly understood. Here we present a comprehensive necroscopic analysis of the SIV/SHIV viral reservoir in multiple lymphoid and non-lymphoid tissues from SIV/SHIV-infected rhesus macaques suppressed with ART for one year. Viral DNA is observed broadly in multiple tissues and is comparable in animals that had initiated ART at week 1 or week 52 of infection. In contrast, viral RNA is restricted primarily to lymph nodes. Ongoing viral RNA transcription is not the result of unsuppressed viral replication, as single-genome amplification and subsequent phylogenetic analysis do not show evidence of viral evolution. Gag-specific CD8+ T cell responses are predominantly observed in secondary lymphoid organs in animals chronically infected prior to ART and these responses are dominated by CD69+ populations. Overall, we observe that the viral reservoir in rhesus macaques is widely distributed across multiple tissue sites and that lymphoid tissues act as a site of persistent viral RNA transcription under conditions of long-term ART suppression.


Asunto(s)
Antirretrovirales/uso terapéutico , Infecciones por VIH/virología , Ganglios Linfáticos/virología , ARN Viral/genética , Síndrome de Inmunodeficiencia Adquirida del Simio/virología , Virus de la Inmunodeficiencia de los Simios/inmunología , Animales , Linfocitos T CD8-positivos , ADN Viral , Modelos Animales de Enfermedad , Femenino , Infecciones por VIH/tratamiento farmacológico , VIH-1/genética , Ganglios Linfáticos/inmunología , Tejido Linfoide/virología , Macaca mulatta , Filogenia , Síndrome de Inmunodeficiencia Adquirida del Simio/tratamiento farmacológico , Síndrome de Inmunodeficiencia Adquirida del Simio/inmunología , Virus de la Inmunodeficiencia de los Simios/efectos de los fármacos , Virus de la Inmunodeficiencia de los Simios/genética , Carga Viral , Replicación Viral
4.
BMC Infect Dis ; 21(1): 214, 2021 Feb 25.
Artículo en Inglés | MEDLINE | ID: mdl-33632139

RESUMEN

BACKGROUND: HIV-1C has been shown to have a greater risk of virological failure and reduced susceptibility towards boosted protease inhibitors (bPIs), a component of second-line combination antiretroviral therapy (cART) in South Africa. This study entailed an evaluation of HIV-1 drug resistance-associated mutations (RAMs) among minor viral populations through high-throughput sequencing genotypic resistance testing (HTS-GRT) in patients on the South African national second-line cART regimen receiving bPIs. METHODS: During 2017 and 2018, 67 patient samples were sequenced using high-throughput sequencing (HTS), of which 56 samples were included in the final analysis because the patient's treatment regimen was available at the time of sampling. All patients were receiving bPIs as part of their cART. Viral RNA was extracted, and complete pol genes were amplified and sequenced using Illumina HiSeq2500, followed by bioinformatics analysis to quantify the RAMs according to the Stanford HIV Drug Resistance Database. RESULTS: Statistically significantly higher PI RAMs were observed in minor viral quasispecies (25%; 14/56) compared to non-nucleoside reverse transcriptase inhibitors (9%; 5/56; p = 0.042) and integrase inhibitor RAM (4%; 2/56; p = 0.002). The majority of the drug resistance mutations in the minor viral quasispecies were observed in the V82A mutation (n = 13) in protease and K65R (n = 5), K103N (n = 7) and M184V (n = 5) in reverse transcriptase. CONCLUSIONS: HTS-GRT improved the identification of PI and reverse transcriptase inhibitor (RTI) RAMs in second-line cART patients from South Africa compared to the conventional GRT with ≥20% used in Sanger-based sequencing. Several RTI RAMs, such as K65R, M184V or K103N and PI RAM V82A, were identified in < 20% of the population. Deep sequencing could be of greater value in detecting acquired resistance mutations early.


Asunto(s)
Farmacorresistencia Viral/genética , Infecciones por VIH/tratamiento farmacológico , Inhibidores de la Proteasa del VIH/uso terapéutico , VIH-1/efectos de los fármacos , Cuasiespecies/efectos de los fármacos , Antirretrovirales/uso terapéutico , Farmacorresistencia Viral/efectos de los fármacos , Genes pol/genética , Genotipo , Infecciones por VIH/virología , VIH-1/genética , VIH-1/aislamiento & purificación , Humanos , Mutación , Cuasiespecies/genética , ARN Viral/genética , Sudáfrica/epidemiología
5.
Viruses ; 13(2)2021 01 26.
Artículo en Inglés | MEDLINE | ID: mdl-33530363

RESUMEN

The transcription of the HIV-1 provirus results in only one type of transcript-full length genomic RNA. To make the mRNA transcripts for the accessory proteins Tat and Rev, the genomic RNA must completely splice. The mRNA transcripts for Vif, Vpr, and Env must undergo splicing but not completely. Genomic RNA (which also functions as mRNA for the Gag and Gag/Pro/Pol precursor polyproteins) must not splice at all. HIV-1 can tolerate a surprising range in the relative abundance of individual transcript types, and a surprising amount of aberrant and even odd splicing; however, it must not over-splice, which results in the loss of full-length genomic RNA and has a dramatic fitness cost. Cells typically do not tolerate unspliced/incompletely spliced transcripts, so HIV-1 must circumvent this cell policing mechanism to allow some splicing while suppressing most. Splicing is controlled by RNA secondary structure, cis-acting regulatory sequences which bind splicing factors, and the viral protein Rev. There is still much work to be done to clarify the combinatorial effects of these splicing regulators. These control mechanisms represent attractive targets to induce over-splicing as an antiviral strategy. Finally, splicing has been implicated in latency, but to date there is little supporting evidence for such a mechanism. In this review we apply what is known of cellular splicing to understand splicing in HIV-1, and present data from our newer and more sensitive deep sequencing assays quantifying the different HIV-1 transcript types.


Asunto(s)
VIH-1/genética , Empalme del ARN , ARN Mensajero/metabolismo , ARN Viral/metabolismo , Empalme Alternativo , Exones , Regulación Viral de la Expresión Génica , Conformación de Ácido Nucleico , ARN Mensajero/química , ARN Mensajero/genética , ARN Viral/química , ARN Viral/genética , Secuencias Reguladoras de Ácidos Nucleicos , Latencia del Virus/genética , Productos del Gen rev del Virus de la Inmunodeficiencia Humana/genética , Productos del Gen rev del Virus de la Inmunodeficiencia Humana/metabolismo
6.
Viruses ; 13(2)2021 01 29.
Artículo en Inglés | MEDLINE | ID: mdl-33572956

RESUMEN

Integrase strand transfer inhibitors (INSTIs) are currently recommended for the first line treatment of human immunodeficiency virus type one (HIV-1) infection. The first-generation INSTIs are effective but can select for resistant viruses. Recent advances have led to several potent second-generation INSTIs that are effective against both wild-type (WT) HIV-1 integrase and many of the first-generation INSTI-resistant mutants. The emergence of resistance to these new second-generation INSTIs has been minimal, which has resulted in alternative treatment strategies for HIV-1 patients. Moreover, because of their high antiviral potencies and, in some cases, their bioavailability profiles, INSTIs will probably have prominent roles in pre-exposure prophylaxis (PrEP). Herein, we review the current state of the clinically relevant INSTIs and discuss the future outlook for this class of antiretrovirals.


Asunto(s)
Inhibidores de Integrasa VIH/farmacología , VIH-1/efectos de los fármacos , ADN Viral/metabolismo , Farmacorresistencia Viral , Infecciones por VIH/tratamiento farmacológico , Integrasa de VIH/química , Integrasa de VIH/genética , Integrasa de VIH/metabolismo , Inhibidores de Integrasa VIH/química , Inhibidores de Integrasa VIH/uso terapéutico , VIH-1/enzimología , VIH-1/genética , Humanos , Mutación , Profilaxis Pre-Exposición , Replicación Viral
7.
Viruses ; 13(2)2021 01 30.
Artículo en Inglés | MEDLINE | ID: mdl-33573241

RESUMEN

During the last two decades, progresses in bioimaging and the development of various strategies to fluorescently label the viral components opened a wide range of possibilities to visualize the early phase of Human Immunodeficiency Virus 1 (HIV-1) life cycle directly in infected cells. After fusion of the viral envelope with the cell membrane, the viral core is released into the cytoplasm and the viral RNA (vRNA) is retro-transcribed into DNA by the reverse transcriptase. During this process, the RNA-based viral complex transforms into a pre-integration complex (PIC), composed of the viral genomic DNA (vDNA) coated with viral and host cellular proteins. The protective capsid shell disassembles during a process called uncoating. The viral genome is transported into the cell nucleus and integrates into the host cell chromatin. Unlike biochemical approaches that provide global data about the whole population of viral particles, imaging techniques enable following individual viruses on a single particle level. In this context, quantitative microscopy has brought original data shedding light on the dynamics of the viral entry into the host cell, the cytoplasmic transport, the nuclear import, and the selection of the integration site. In parallel, multi-color imaging studies have elucidated the mechanism of action of host cell factors implicated in HIV-1 viral cycle progression. In this review, we describe the labeling strategies used for HIV-1 fluorescence imaging and report on the main advancements that imaging studies have brought in the understanding of the infection mechanisms from the viral entry into the host cell until the provirus integration step.


Asunto(s)
Infecciones por VIH/virología , VIH-1/fisiología , Internalización del Virus , Animales , Núcleo Celular/virología , VIH-1/química , VIH-1/genética , Humanos , Microscopía Fluorescente , Integración Viral
8.
PLoS One ; 16(2): e0247396, 2021.
Artículo en Inglés | MEDLINE | ID: mdl-33606823

RESUMEN

Among various delivery systems for vaccine and drug delivery, cell-penetrating peptides (CPPs) have been known as a potent delivery system because of their capability to penetrate cell membranes and deliver some types of cargoes into cells. Several CPPs were found in the proteome of viruses such as Tat originated from human immunodeficiency virus-1 (HIV-1), and VP22 derived from herpes simplex virus-1 (HSV-1). In the current study, a wide-range of CPPs was identified in the proteome of SARS-CoV-2, a new member of coronaviruses family, using in silico analyses. These CPPs may play a main role for high penetration of virus into cells and infection of host. At first, we submitted the proteome of SARS-CoV-2 to CellPPD web server that resulted in a huge number of CPPs with ten residues in length. Afterward, we submitted the predicted CPPs to C2Pred web server for evaluation of the probability of each peptide. Then, the uptake efficiency of each peptide was investigated using CPPred-RF and MLCPP web servers. Next, the physicochemical properties of the predicted CPPs including net charge, theoretical isoelectric point (pI), amphipathicity, molecular weight, and water solubility were calculated using protparam and pepcalc tools. In addition, the probability of membrane binding potential and cellular localization of each CPP were estimated by Boman index using APD3 web server, D factor, and TMHMM web server. On the other hand, the immunogenicity, toxicity, allergenicity, hemolytic potency, and half-life of CPPs were predicted using various web servers. Finally, the tertiary structure and the helical wheel projection of some CPPs were predicted by PEP-FOLD3 and Heliquest web servers, respectively. These CPPs were divided into: a) CPP containing tumor homing motif (RGD) and/or tumor penetrating motif (RXXR); b) CPP with the highest Boman index; c) CPP with high half-life (~100 hour) in mammalian cells, and d) CPP with +5.00 net charge. Based on the results, we found a large number of novel CPPs with various features. Some of these CPPs possess tumor-specific motifs which can be evaluated in cancer therapy. Furthermore, the novel and potent CPPs derived from SARS-CoV-2 may be used alone or conjugated to some sequences such as nuclear localization sequence (NLS) for vaccine and drug delivery.


Asunto(s)
/química , Péptidos de Penetración Celular/química , Biología Computacional , Simulación por Computador , Sistemas de Liberación de Medicamentos , Proteoma , /química , Animales , /metabolismo , Péptidos de Penetración Celular/genética , Péptidos de Penetración Celular/metabolismo , VIH-1/química , VIH-1/genética , Herpesvirus Humano 1/química , Herpesvirus Humano 1/genética , Humanos , /metabolismo , Proteínas Estructurales Virales/química , Proteínas Estructurales Virales/genética , Productos del Gen tat del Virus de la Inmunodeficiencia Humana/química , Productos del Gen tat del Virus de la Inmunodeficiencia Humana/genética
9.
BMC Bioinformatics ; 22(1): 54, 2021 Feb 08.
Artículo en Inglés | MEDLINE | ID: mdl-33557755

RESUMEN

BACKGROUND: The high variability in envelope regions of some viruses such as HIV allow the virus to establish infection and to escape subsequent immune surveillance. This variability, as well as increasing incorporation of N-linked glycosylation sites, is fundamental to this evasion. It also creates difficulties for multiple sequence alignment methods (MSA) that provide the first step in their analysis. Existing MSA tools often fail to properly align highly variable HIV envelope sequences requiring extensive manual editing that is impractical with even a moderate number of these variable sequences. RESULTS: We developed an automated library building tool NGlyAlign, that organizes similar N-linked glycosylation sites as block constraints and statistically conserved global sites as single site constraints to automatically enforce partial columns in consistency-based MSA methods such as Dialign. This combined method accurately aligns variable HIV-1 envelope sequences. We tested the method on two datasets: a set of 156 founder and chronic gp160 HIV-1 subtype B sequences as well as a set of reference sequences of gp120 in the highly variable region 1. On measures such as entropy scores, sum of pair scores, column score, and similarity heat maps, NGlyAlign+Dialign proved superior against methods such as T-Coffee, ClustalOmega, ClustalW, Praline, HIValign and Muscle. The method is scalable to large sequence sets producing accurate alignments without requiring manual editing. As well as this application to HIV, our method can be used for other highly variable glycoproteins such as hepatitis C virus envelope. CONCLUSIONS: NGlyAlign is an automated tool for mapping and building glycosylation motif libraries to accurately align highly variable regions in HIV sequences. It can provide the basis for many studies reliant on single robust alignments. NGlyAlign has been developed as an open-source tool and is freely available at https://github.com/UNSW-Mathematical-Biology/NGlyAlign_v1.0 .


Asunto(s)
Biblioteca de Genes , Infecciones por VIH , VIH-1 , Glicosilación , Proteína gp120 de Envoltorio del VIH/genética , VIH-1/genética , Humanos , Alineación de Secuencia
10.
BMC Infect Dis ; 21(1): 160, 2021 Feb 08.
Artículo en Inglés | MEDLINE | ID: mdl-33557775

RESUMEN

BACKGROUND: The widespread use of antiretroviral therapy (ART) has resulted in the development of transmitted drug resistance (TDR), which reduces ART efficacy. We explored TDR prevalence and its associated risk factors in newly diagnosed individuals in Guangxi. METHODS: We enrolled 1324 participants who were newly diagnosed with HIV-1 and had not received ART at voluntary counselling and testing centres (VCT) in Guangxi, China, who had not received ART. Phylogenetic relationship, transmission cluster, and genotypic drug resistance analyses were performed using HIV-1 pol sequences. We analysed the association of demographic and virological factors with TDR. RESULTS: In total, 1151 sequences were sequenced successfully, of which 83 (7.21%) showed evidence of TDR. Multivariate logistic regression analysis revealed that there was significant difference between the prevalence of TDR and unmarried status (adjusted odds ratio (aOR) = 2.41, 95% CI: 1.23-4.71), and CRF08_BC subtype (aOR = 2.03, 95% CI: 1.13-3.64). Most cases of TDR were related to resistance to non-nucleoside reverse transcriptase inhibitors (4.87%) and V179E was the most common mutation detected. We identified a total of 119 HIV transmission clusters (n = 585, 50.8%), of which 18 (15.1%) clusters showed evidence of TDR (36, 41.86%). Three clusters were identified that included drug-resistant individuals having a transmission relationship with each other. The following parameters were associated with TDR transmission risk: Unmarried status, educational level of junior high school or below, and CRF08_BC subtype may be a risk of the transmission of TDR. CONCLUSIONS: Our findings indicated that moderate TDR prevalence and highlighted the importance of continuous TDR monitoring and designing of strategies for TDR mitigation.


Asunto(s)
Farmacorresistencia Viral/genética , Infecciones por VIH/diagnóstico , VIH-1/genética , Adulto , Antirretrovirales/uso terapéutico , China , Femenino , Genotipo , Infecciones por VIH/tratamiento farmacológico , Infecciones por VIH/transmisión , VIH-1/clasificación , VIH-1/aislamiento & purificación , Humanos , Modelos Logísticos , Masculino , Filogenia , Prevalencia , Factores de Riesgo , Productos del Gen pol del Virus de la Inmunodeficiencia Humana/genética
11.
AIDS ; 35(2): 227-234, 2021 02 02.
Artículo en Inglés | MEDLINE | ID: mdl-33394670

RESUMEN

OBJECTIVES: HIV-1 pretreatment drug resistance (PDR) is a global concern. Our aim was to evaluate high-throughput sequencing (HTS) for HIV-1 resistance testing and describe PDR in Sweden, where 75% of diagnosed individuals are foreign-born. DESIGN: Cross-sectional study. METHODS: Individuals entering HIV-1 care in Sweden 2017 to March 2019 (n = 400) were included if a viremic sample was available (n = 220). HTS was performed using an in-house assay. Drug resistance mutations (DRMs) (based on Stanford HIV DB vs. 8.7) at levels 1-5%, 5-19% and at least 20% of the viral population were described. Results from HTS and routine Sanger sequencing were compared. RESULTS: HTS was successful in 88% of patients, 92% when viral load was at least 1000 copies/ml. DRMs at any level in protease and/or reverse transcriptase were detected in 95 individuals (49%), whereas DRMs at least 20% in 35 (18%) individuals. DRMs at least 20% correlated well to findings in routine Sanger sequencing. Protease/reverse transcriptase (PR/RT) DRMs at least 20% were predicted by treatment exposure; adjusted OR 9.28 (95% CI 2.24-38.43; P = 0.002) and origin in Asia; adjusted OR 20.65 (95% CI 1.66-256.24; P = 0.02). Nonnucleoside reverse transcriptase inhibitor (NNRTI) DRMs at least 20% were common (16%) and over-represented in individuals originating from sub-Saharan Africa or Asia. Low-level integrase strand transfer inhibitor (INSTI) DRMs less than 20% were detected in 15 individuals (8%) with no association with INSTI exposure. CONCLUSION: Our HTS can efficiently detect PDR and findings of DRMs at least 20% compare well to routine Sanger sequencing. The high prevalence of PDR was because of NNRTI DRMs and associated with migration from areas with emerging PDR.


Asunto(s)
Fármacos Anti-VIH , Farmacorresistencia Viral , Infecciones por VIH , VIH-1 , África del Sur del Sahara , Fármacos Anti-VIH/uso terapéutico , Asia , Estudios Transversales , Genotipo , Infecciones por VIH/tratamiento farmacológico , Infecciones por VIH/epidemiología , VIH-1/efectos de los fármacos , VIH-1/genética , Secuenciación de Nucleótidos de Alto Rendimiento , Humanos , Mutación/efectos de los fármacos , Prevalencia , Suecia/epidemiología
12.
Viruses ; 13(2)2021 01 25.
Artículo en Inglés | MEDLINE | ID: mdl-33503987

RESUMEN

Molecular investigation of primary HIV infections (PHI) is crucial to describe current dynamics of HIV transmission. Aim of the study was to investigate HIV transmission clusters (TC) in PHI referred during the years 2013-2020 to the National Institute for Infectious Diseases in Rome (INMI), that is the Lazio regional AIDS reference centre, and factors possibly associated with inclusion in TC. These were identified by phylogenetic analysis, based on population sequencing of pol; a more in depth analysis was performed on TC of B subtype, using ultra-deep sequencing (UDS) of env. Of 270 patients diagnosed with PHI during the study period, 229 were enrolled (median follow-up 168 (IQR 96-232) weeks). Median age: 39 (IQR 32-48) years; 94.8% males, 86.5% Italians, 83.4% MSM, 56.8% carrying HIV-1 subtype B. Of them, 92.6% started early treatment within a median of 4 (IQR 2-7) days after diagnosis; median time to sustained suppression was 20 (IQR 8-32) weeks. Twenty TC (median size 3, range 2-9 individuals), including 68 patients, were identified. A diagnosis prior to 2015 was the unique factor associated with inclusion in a TC. Added value of UDS was the identification of shared quasispecies components in transmission pairs within TC.


Asunto(s)
Infecciones por VIH/epidemiología , Infecciones por VIH/transmisión , VIH-1/genética , Adulto , Femenino , Genotipo , Infecciones por VIH/diagnóstico , VIH-1/clasificación , VIH-1/aislamiento & purificación , Humanos , Italia/epidemiología , Masculino , Persona de Mediana Edad , Epidemiología Molecular , Filogenia , ARN Viral/genética , Productos del Gen env del Virus de la Inmunodeficiencia Humana/genética , Productos del Gen pol del Virus de la Inmunodeficiencia Humana/genética
13.
BMC Infect Dis ; 21(1): 60, 2021 Jan 13.
Artículo en Inglés | MEDLINE | ID: mdl-33435861

RESUMEN

BACKGROUND: Little evidence exists to comprehensively estimate adolescent viral suppression after initiation on antiretroviral therapy in sub-Saharan Africa. This study examines adolescent progression along the HIV care cascade to viral suppression for adolescents initiated on antiretroviral therapy in South Africa. METHODS: All adolescents ever initiated on antiretroviral therapy (n=1080) by 2015 in a health district of the Eastern Cape, South Africa, were interviewed in 2014-2015. Clinical records were extracted from 52 healthcare facilities through January 2018 (including records in multiple facilities). Mortality and loss to follow-up rates were corrected for transfers. Predictors of progression through the HIV care cascade were tested using sequential multivariable logistic regressions. Predicted probabilities for the effects of significant predictors were estimated by sex and mode of infection. RESULTS: Corrected mortality and loss to follow-up rates were 3.3 and 16.9%, respectively. Among adolescents with clinical records, 92.3% had ≥1 viral load, but only 51.1% of viral loads were from the past 12 months. Adolescents on ART for ≥2 years (AOR 3.42 [95%CI 2.14-5.47], p< 0.001) and who experienced decentralised care (AOR 1.39 [95%CI 1.06-1.83], p=0.018) were more likely to have a recent viral load. The average effect of decentralised care on recent viral load was greater for female (AOR 2.39 [95%CI 1.29-4.43], p=0.006) and sexually infected adolescents (AOR 3.48 [95%CI 1.04-11.65], p=0.043). Of the total cohort, 47.5% were recorded as fully virally suppressed at most recent test. Only 23.2% were recorded as fully virally suppressed within the past 12 months. Younger adolescents (AOR 1.39 [95%CI 1.06-1.82], p=0.017) and those on ART for ≥2 years (AOR 1.70 [95%CI 1.12-2.58], p=0.013) were more likely to be fully viral suppressed. CONCLUSIONS: Viral load recording and viral suppression rates remain low for ART-initiated adolescents in South Africa. Improved outcomes for this population require stronger engagement in care and viral load monitoring.


Asunto(s)
Fármacos Anti-VIH/uso terapéutico , Infecciones por VIH/tratamiento farmacológico , Infecciones por VIH/epidemiología , VIH-1/genética , Adolescente , Niño , Continuidad de la Atención al Paciente , Femenino , Estudios de Seguimiento , Infecciones por VIH/mortalidad , Infecciones por VIH/virología , Humanos , Modelos Logísticos , Estudios Longitudinales , Masculino , ARN Viral/genética , Estudios Retrospectivos , Sudáfrica/epidemiología , Respuesta Virológica Sostenida , Carga Viral/efectos de los fármacos , Adulto Joven
14.
Mol Genet Genomics ; 296(2): 409-422, 2021 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-33464395

RESUMEN

RNA debranching enzymes are 2'-5' phosphodiesterases found in all eukaryotes. Their main role is cleavage of intron RNA lariat branch points, promoting RNA turnover via exonucleases. Consistent with this role, cells with reduced RNA debranching enzyme activity accumulate intron RNA lariats. The Saccharomyces cerevisiae RNA debranching enzyme Dbr1p is also a host factor for the yeast long terminal repeat (LTR) retrotransposon Ty1, a model for many aspects of retroviral replication. Fittingly, the human RNA debranching enzyme Dbr1 is a host factor for the human immunodeficiency virus, HIV-1. The yeast and human RNA debranching enzymes act at the reverse transcription stages for Ty1 and HIV-1, respectively. Although efficient production of full-length Ty1 cDNA requires Dbr1p, the findings reported here indicate that production of the earliest distinct cDNA product, minus strand strong stop DNA (-sssDNA), is equivalent in wild type and dbr1∆ mutant cells. Several branched Ty1 RNAs are shown to accumulate in dbr1∆ cells during retrotransposition. These data are consistent with creation of Ty1 RNA branches prior to Ty1 reverse transcription and their removal by Dbr1p to allow efficient extension of early cDNA products. The data support the possibility that RNA branch formation and cleavage play broadly shared, but unknown roles in retroviral and LTR retrotransposon reverse transcription.


Asunto(s)
ARN Nucleotidiltransferasas/genética , Transcripción Reversa , Saccharomyces cerevisiae/enzimología , ADN de Cadena Simple/metabolismo , VIH-1/genética , Mutación , ARN Nucleotidiltransferasas/metabolismo , Retroelementos , Saccharomyces cerevisiae/genética , Replicación Viral
15.
Viruses ; 13(1)2021 Jan 16.
Artículo en Inglés | MEDLINE | ID: mdl-33467166

RESUMEN

HIV-1 subtype CRF01_AE is the second most predominant strain in Bulgaria, yet little is known about the molecular epidemiology of its origin and transmissibility. We used a phylodynamics approach to better understand this sub-epidemic by analyzing 270 HIV-1 polymerase (pol) sequences collected from persons diagnosed with HIV/AIDS between 1995 and 2019. Using network analyses at a 1.5% genetic distance threshold (d), we found a large 154-member outbreak cluster composed mostly of persons who inject drugs (PWID) that were predominantly men. At d = 0.5%, which was used to identify more recent transmission, the large cluster dissociated into three clusters of 18, 12, and 7 members, respectively, five dyads, and 107 singletons. Phylogenetic analysis of the Bulgarian sequences with publicly available global sequences showed that CRF01_AE likely originated from multiple Asian countries, with Vietnam as the likely source of the outbreak cluster between 1988 and 1990. Our findings indicate that CRF01_AE was introduced into Bulgaria multiple times since 1988, and infections then rapidly spread among PWID locally with bridging to other risk groups and countries. CRF01_AE continues to spread in Bulgaria as evidenced by the more recent large clusters identified at d = 0.5%, highlighting the importance of public health prevention efforts in the PWID communities.


Asunto(s)
Genotipo , Infecciones por VIH/epidemiología , Infecciones por VIH/transmisión , Infecciones por VIH/virología , VIH-1/clasificación , VIH-1/genética , Adolescente , Adulto , Anciano , Bulgaria/epidemiología , Femenino , Variación Genética , Infecciones por VIH/prevención & control , VIH-1/efectos de los fármacos , Humanos , Masculino , Persona de Mediana Edad , Epidemiología Molecular , Filogenia , Filogeografía , Vigilancia en Salud Pública , Virus Reordenados , Recombinación Genética , Adulto Joven
16.
Viruses ; 13(1)2021 Jan 12.
Artículo en Inglés | MEDLINE | ID: mdl-33445523

RESUMEN

The extraordinary genetic variability of human immunodeficiency virus type 1 (HIV-1) group M has led to the identification of 10 subtypes, 102 circulating recombinant forms (CRFs) and numerous unique recombinant forms. Among CRFs, 11 derived from subtypes B and C have been identified in China, Brazil, and Italy. Here we identify a new HIV-1 CRF_BC in Northern Spain. Originally, a phylogenetic cluster of 15 viruses of subtype C in protease-reverse transcriptase was identified in an HIV-1 molecular surveillance study in Spain, most of them from individuals from the Basque Country and heterosexually transmitted. Analyses of near full-length genome sequences from six viruses from three cities revealed that they were BC recombinant with coincident mosaic structures different from known CRFs. This allowed the definition of a new HIV-1 CRF designated CRF108_BC, whose genome is predominantly of subtype C, with four short subtype B fragments. Phylogenetic analyses with database sequences supported a Brazilian ancestry of the parental subtype C strain. Coalescent Bayesian analyses estimated the most recent common ancestor of CRF108_BC in the city of Vitoria, Basque Country, around 2000. CRF108_BC is the first CRF_BC identified in Spain and the second in Europe, after CRF60_BC, both phylogenetically related to Brazilian subtype C strains.


Asunto(s)
Genoma Viral , Genotipo , Infecciones por VIH/epidemiología , Infecciones por VIH/virología , VIH-1/clasificación , VIH-1/genética , Recombinación Genética , Variación Genética , Humanos , Epidemiología Molecular , Filogenia , Filogeografía , Vigilancia en Salud Pública , Análisis de Secuencia de ADN , España/epidemiología , Viremia
17.
BMC Infect Dis ; 21(1): 5, 2021 Jan 04.
Artículo en Inglés | MEDLINE | ID: mdl-33446115

RESUMEN

BACKGROUND: Dolutegravir (DTG)-based antiretroviral therapy (ART) is highly effective and well-tolerated in adults and is rapidly being adopted globally. We describe the design of the ODYSSEY trial which evaluates the efficacy and safety of DTG-based ART compared with standard-of-care in children and adolescents. The ODYSSEY trial includes nested pharmacokinetic (PK) sub-studies which evaluated pragmatic World Health Organization (WHO) weight-band-based DTG dosing and opened recruitment to children < 14 kg while dosing was in development. METHODS: ODYSSEY (Once-daily DTG based ART in Young people vS. Standard thErapY) is an open-label, randomised, non-inferiority, basket trial comparing the efficacy and safety of DTG + 2 nucleos(t) ides (NRTIs) versus standard-of-care (SOC) in HIV-infected children < 18 years starting first-line ART (ODYSSEY A) or switching to second-line ART (ODYSSEY B). The primary endpoint is clinical or virological failure by 96 weeks. RESULTS: Between September 2016 and June 2018, 707 children weighing ≥14 kg were enrolled; including 311 ART-naïve children and 396 children starting second-line. 47% of children were enrolled in Uganda, 21% Zimbabwe, 20% South Africa, 9% Thailand, 4% Europe. 362 (51%) participants were male; median age [range] at enrolment was 12.2 years [2.9-18.0]. 82 (12%) children weighed 14 to < 20 kg, 135 (19%) 20 to < 25 kg, 206 (29%) 25 to < 35 kg, 284 (40%) ≥35 kg. 128 (18%) had WHO stage 3 and 60 (8%) WHO stage 4 disease. Challenges encountered include: (i) running the trial across high- to low-income countries with differing frequencies of standard-of-care viral load monitoring; (ii) evaluating pragmatic DTG dosing in PK sub-studies alongside FDA- and EMA-approved dosing and subsequently transitioning participants to new recommended doses; (iii) delays in dosing information for children weighing 3 to < 14 kg and rapid recruitment of ART-naïve older/heavier children, which led to capping recruitment of participants weighing ≥35 kg in ODYSSEY A and extending recruitment (above 700) to allow for ≥60 additional children weighing between 3 to < 14 kg with associated PK; (iv) a safety alert associated with DTG use during pregnancy, which required a review of the safety plan for adolescent girls. CONCLUSIONS: By employing a basket design, to include ART-naïve and -experienced children, and nested PK sub-studies, the ODYSSEY trial efficiently evaluates multiple scientific questions regarding dosing and effectiveness of DTG-based ART in children. TRIAL REGISTRATION: NCT, NCT02259127 , registered 7th October 2014; EUDRACT, 2014-002632-14, registered 18th June 2014 ( https://www.clinicaltrialsregister.eu/ctr-search/trial/2014-002632-14/ES ); ISRCTN, ISRCTN91737921 , registered 4th October 2014.


Asunto(s)
Infecciones por VIH/tratamiento farmacológico , Inhibidores de Integrasa VIH/administración & dosificación , Inhibidores de Integrasa VIH/efectos adversos , VIH-1/genética , Compuestos Heterocíclicos con 3 Anillos/administración & dosificación , Compuestos Heterocíclicos con 3 Anillos/efectos adversos , Oxazinas/administración & dosificación , Oxazinas/efectos adversos , Piperazinas/administración & dosificación , Piperazinas/efectos adversos , Piridonas/administración & dosificación , Piridonas/efectos adversos , Adolescente , Peso Corporal , Niño , Preescolar , Estudios de Cohortes , Cálculo de Dosificación de Drogas , Europa (Continente)/epidemiología , Femenino , Infecciones por VIH/epidemiología , Infecciones por VIH/virología , Humanos , Masculino , ARN Viral/genética , Sudáfrica/epidemiología , Tailandia/epidemiología , Resultado del Tratamiento , Uganda/epidemiología , Carga Viral/efectos de los fármacos , Organización Mundial de la Salud , Zimbabwe/epidemiología
18.
Nat Commun ; 12(1): 165, 2021 01 08.
Artículo en Inglés | MEDLINE | ID: mdl-33420062

RESUMEN

The Intact Proviral DNA Assay (IPDA) was developed to address the critical need for a scalable method for intact HIV-1 reservoir quantification. This droplet digital PCR-based assay simultaneously targets two HIV-1 regions to distinguish genomically intact proviruses against a large background of defective ones, and its application has yielded insights into HIV-1 persistence. Reports of assay failures however, attributed to HIV-1 polymorphism, have recently emerged. Here, we describe a diverse North American cohort of people with HIV-1 subtype B, where the IPDA yielded a failure rate of 28% due to viral polymorphism. We further demonstrate that within-host HIV-1 diversity can lead the IPDA to underestimate intact reservoir size, and provide examples of how this phenomenon could lead to erroneous interpretation of clinical trial data. While the IPDA represents a major methodological advance, HIV-1 diversity should be addressed before its widespread adoption as a principal readout in HIV-1 remission trials.


Asunto(s)
Biodiversidad , ADN Viral/análisis , VIH-1/genética , Provirus/genética , Secuencia de Bases , Linfocitos T CD4-Positivos/virología , ADN Viral/genética , Infecciones por VIH/virología , Humanos , Filogenia , Reacción en Cadena de la Polimerasa/métodos
19.
BMC Infect Dis ; 21(1): 93, 2021 Jan 21.
Artículo en Inglés | MEDLINE | ID: mdl-33478415

RESUMEN

BACKGROUND: HIV-transmitted drug resistance (TDR) is found in antiretroviral therapy (ART)-naïve populations infected with HIV-1 with TDR mutations and is important for guiding future first- and second-line ART regimens. We investigated TDR and its effect on CD4 count in ART-naïve youths from the China-Myanmar border near the Golden Triangle to better understand TDR and effectively guide ART. METHODS: From 2009 to 2017, 10,832 HIV-1 infected individuals were newly reported along the Dehong border of China, 573 ART-naïve youths (16 ~ 25 y) were enrolled. CD4 counts were obtained from whole blood samples. HIV pol gene sequences were amplified from RNA extracted from plasma. The Stanford REGA program and jpHMM recombination prediction tool were used to determine genotypes. TDR mutations (TDRMs) were analyzed using the Stanford Calibrated Population Resistance tool. RESULTS: The most common infection route was heterosexuals (70.51%), followed by people who inject drugs (PWID, 19.20%) and men who have sex with men (MSM) (8.90%). The distribution of HIV genotypes mainly included the unique recombinant form (URF) (44.08%), 38.68% were CRFs, 13.24% were subtype C and 4.04% were subtype B. The prevalence of TDR increased significantly from 2009 to 2017 (3.48 to 9.48%) in ART-naïve youths (4.00 to 13.16% in Burmese subjects, 3.33 to 5.93% in Chinese subjects), and the resistance to non-nucleoside reverse transcriptase inhibitors (NNRTIs), nucleoside and nucleotide reverse transcriptase inhibitors (NRTIs), and protease inhibitors (PIs) were 3.49, 2.62, and 0.52%, respectively. Most (94.40%, n = 34) of HIV-1-infected patients with TDRM had mutation that conferred resistance to a single drug class. The most common mutations Y181I/C and K103N, were found in 7 and 9 youths, respectively. The mean CD4 count was significantly lower among individuals with TDRMs (373/mm3 vs. 496/mm3, p = 0.013). CONCLUSIONS: The increase in the prevalence of HIV-1 TDR increase and a low CD4 count of patients with TDRMs in the China-Myanmar border suggests the need for considering drug resistance before initiating ART in HIV recombination hotspots.


Asunto(s)
Fármacos Anti-VIH/farmacología , Farmacorresistencia Viral , Infecciones por VIH/epidemiología , Infecciones por VIH/virología , VIH-1/aislamiento & purificación , Adolescente , Adulto , Recuento de Linfocito CD4 , China/epidemiología , Farmacorresistencia Viral/genética , Femenino , Genes pol/genética , Genotipo , Infecciones por VIH/diagnóstico , Infecciones por VIH/transmisión , VIH-1/efectos de los fármacos , VIH-1/genética , Humanos , Masculino , Mutación , Mianmar/epidemiología , Prevalencia , Adulto Joven
20.
Viruses ; 13(2)2021 01 23.
Artículo en Inglés | MEDLINE | ID: mdl-33498793

RESUMEN

The ability to efficiently establish a new infection is a critical property for human immunodeficiency virus type 1 (HIV-1). Although the envelope protein of the virus plays an essential role in receptor binding and internalization of the infecting virus, the structural proteins, the polymerase and the assembly of new virions may also play a role in establishing and spreading viral infection in a new host. We examined Ugandan viruses from newly infected patients and focused on the contribution of the Gag-Pol genes to replication capacity. A panel of Gag-Pol sequences generated using single genome amplification from incident HIV-1 infections were cloned into a common HIV-1 NL4.3 pol/env backbone and the influence of Gag-Pol changes on replication capacity was monitored. Using a novel protein domain approach, we then documented diversity in the functional protein domains across the Gag-Pol region and identified differences in the Gag-p6 domain that were frequently associated with higher in vitro replication.


Asunto(s)
Infecciones por VIH/virología , VIH-1/fisiología , Replicación Viral , Productos del Gen gag del Virus de la Inmunodeficiencia Humana/genética , Productos del Gen pol del Virus de la Inmunodeficiencia Humana/genética , Adulto , Femenino , Proteasa del VIH/genética , VIH-1/genética , Humanos , Masculino , Persona de Mediana Edad , Dominios Proteicos , Uganda , Adulto Joven
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