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1.
Medicine (Baltimore) ; 98(43): e17585, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31651864

RESUMO

This study sought to examine the human immunodeficiency virus type 1 (HIV-1) genetic diversity on drug resistance among men who have sex with men (MSM) with virologic failure in antiretroviral therapy (ART), and investigate linking-associated factors for genetic transmission networks.Seven hundred and thirty-four HIV-positive MSM with virologic failure in ART were recruited into our study from 2011 to 2017. HIV-1 pol gene sequences were used for phylogenetic and genotypic drug resistance analyses. The drug resistance mutations were determined using the Stanford University HIV Drug Resistance Database. The genetic transmission networks were analyzed for CRF01_AE and CRF07_BC sequences by the genetic distance-based method.Of 734 subjects, 372 (50.68%) showed drug resistance, in which CRF01_AE and CRF07_BC were the predominating subtypes. Drug resistance more frequently occurred in non-nucleoside reverse transcriptase inhibitors (NNRTIs) treatment (48.64%), and followed by nucleoside reverse transcriptase inhibitors (NRTIs) (36.51%) and PIs (4.03%). The most common drug resistance-associated mutations in protease inhibitors (PIs), NRTIs and NNRTIs were K20I/R, M184V/I and K103N/KN, respectively. For 283CRF01_AE sequences, 64 (22.61%) fell into clusters at a genetic distance of 0.011, resulting in 17 clusters ranging in size from 2 to 16 individuals. For 230 CRF07_BC sequences, 66 (28.69%) were connected to at least one other sequence with 0.005 genetic distances, resulting in 8 clusters ranging in size from 2 to 52 individuals. Individuals who showed drug resistance to ART were less likely to fall into clusters than those who did not. The genetic linkage was robust by the exclusion of sites associated with drug resistance.CRF01_AE and CRF07_BC were the main strains among MSM with virologic failure in ART, and the drug resistance more frequently occurred in NNRTIs, followed by NRTIs and PIs. Genetic transmission networks revealed a complexity of transmission pattern, suggesting early-diagnosis and in-time intervention among MSM.


Assuntos
Fármacos Anti-HIV/efeitos adversos , Farmacorresistência Viral/genética , Infecções por HIV/tratamento farmacológico , HIV-1/genética , Inibidores da Transcriptase Reversa/efeitos adversos , Adolescente , Adulto , China , Homossexualidade Masculina , Humanos , Masculino , Minorias Sexuais e de Gênero/estatística & dados numéricos , Falha de Tratamento , Adulto Jovem
3.
Cell Host Microbe ; 26(3): 299-300, 2019 09 11.
Artigo em Inglês | MEDLINE | ID: mdl-31513765

RESUMO

In this issue of Cell Host & Microbe, Buffalo et al. describe a cryo-EM structure of SIV Nef complexed with AP-2 and tetherin. The structure helps explain why human tetherin is Nef-resistant and why lentiviruses that successfully emerged in humans (HIV-1 and HIV-2) had to evolve novel anti-tetherin strategies.


Assuntos
HIV-1 , Vírus da Imunodeficiência Símia , Antígenos CD , Antígeno 2 do Estroma da Médula Óssea , Proteínas Ligadas por GPI , Humanos , Produtos do Gene nef do Vírus da Imunodeficiência Humana
4.
Zhonghua Liu Xing Bing Xue Za Zhi ; 40(8): 982-987, 2019 Aug 10.
Artigo em Chinês | MEDLINE | ID: mdl-31484265

RESUMO

Objective: To understand the distribution of HIV-1 genotypes and the status of drug resistance among people living with HIV who had prepared to initiate antiretroviral therapy (ART) in Dehong Dai and Jingpo autonomous prefecture (Dehong). Methods: A total of 170 adults with HIV were recruited in Dehong from January to June 2017, before initiating ART. HIV-1 pol genes were amplified and used to analyze the HIV-1 genotypes and drug resistance. Results: A total of 147 samples were successfully sequenced. Based on the phylogenetic analysis, 12 HIV-1 genotypes were found among the subjects, including three predominant genotypes such as subtype C (29.9%, 44/147), unique recombinant forms (URFs) (27.2%, 40/147) and CRF01_AE (19.7%, 29/147). Circulating recombinant forms (CRFs) which were newly identified in this area in recent years were also found among these subjects, including CRF62_BC, CRF64_BC, CRF86_BC and CRF96_cpx. The distribution of HIV-1 genotypes between heterosexual transmission or intravenous drug use, showed statistical difference. Surveillance drug resistance mutations (SDRMs) were found among 8.8% (13/147) of the subjects. Proportion of drug resistant strains among injecting drug users (25.0%, 8/32) was higher than that among those heterosexual transmitted individuals (4.6%, 5/109, χ(2)=10.166, P=0.002). Conclusions: Among people living with HIV-1 who had prepared to initiate ART, their HIV-1 genetics were highly complicated, with moderate prevalence rate of HIV-1 drug-resistant strains.


Assuntos
Fármacos Anti-HIV/uso terapêutico , Farmacorresistência Viral/genética , Infecções por HIV/tratamento farmacológico , Infecções por HIV/virologia , HIV-1/genética , Adulto , Análise do Polimorfismo de Comprimento de Fragmentos Amplificados , Fármacos Anti-HIV/farmacologia , Terapia Antirretroviral de Alta Atividade , China/epidemiologia , Genes pol , Genótipo , Infecções por HIV/epidemiologia , HIV-1/efeitos dos fármacos , Humanos , Filogenia
6.
N Engl J Med ; 381(13): 1240-1247, 2019 09 26.
Artigo em Inglês | MEDLINE | ID: mdl-31509667

RESUMO

The safety of CRISPR (clustered regularly interspaced short palindromic repeats)-based genome editing in the context of human gene therapy is largely unknown. CCR5 is a reasonable but not absolutely protective target for a cure of human immunodeficiency virus type 1 (HIV-1) infection, because CCR5-null blood cells are largely resistant to HIV-1 entry. We transplanted CRISPR-edited CCR5-ablated hematopoietic stem and progenitor cells (HSPCs) into a patient with HIV-1 infection and acute lymphoblastic leukemia. The acute lymphoblastic leukemia was in complete remission with full donor chimerism, and donor cells carrying the ablated CCR5 persisted for more than 19 months without gene editing-related adverse events. The percentage of CD4+ cells with CCR5 ablation increased by a small degree during a period of antiretroviral-therapy interruption. Although we achieved successful transplantation and long-term engraftment of CRISPR-edited HSPCs, the percentage of CCR5 disruption in lymphocytes was only approximately 5%, which indicates the need for further research into this approach. (Funded by the Beijing Municipal Science and Technology Commission and others; ClinicalTrials.gov number, NCT03164135.).


Assuntos
Sistemas CRISPR-Cas , Edição de Genes/métodos , Infecções por HIV/terapia , HIV-1 , Transplante de Células-Tronco Hematopoéticas , Células-Tronco Hematopoéticas , Receptores CCR5/genética , Adulto , Antirretrovirais/uso terapêutico , Contagem de Células Sanguíneas , Contagem de Linfócito CD4 , Infecções por HIV/complicações , Infecções por HIV/tratamento farmacológico , HIV-1/genética , Humanos , Masculino , Leucemia-Linfoma Linfoblástico de Células Precursoras/complicações , Carga Viral
7.
Nat Med ; 25(9): 1377-1384, 2019 09.
Artigo em Inglês | MEDLINE | ID: mdl-31501601

RESUMO

People living with HIV (PLWH) have expressed concern about the life-long burden and stigma associated with taking pills daily and can experience medication fatigue that might lead to suboptimal treatment adherence and the emergence of drug-resistant viral variants, thereby limiting future treatment options1-3. As such, there is strong interest in long-acting antiretroviral (ARV) agents that can be administered less frequently4. Herein, we report GS-CA1, a new archetypal small-molecule HIV capsid inhibitor with exceptional potency against HIV-2 and all major HIV-1 types, including viral variants resistant to the ARVs currently in clinical use. Mechanism-of-action studies indicate that GS-CA1 binds directly to the HIV-1 capsid and interferes with capsid-mediated nuclear import of viral DNA, HIV particle production and ordered capsid assembly. GS-CA1 selects in vitro for unfit GS-CA1-resistant capsid variants that remain fully susceptible to other classes of ARVs. Its high metabolic stability and low solubility enabled sustained drug release in mice following a single subcutaneous dosing. GS-CA1 showed high antiviral efficacy as a long-acting injectable monotherapy in a humanized mouse model of HIV-1 infection, outperforming long-acting rilpivirine. Collectively, these results demonstrate the potential of ultrapotent capsid inhibitors as new long-acting agents for the treatment of HIV-1 infection.


Assuntos
Proteínas do Capsídeo/antagonistas & inibidores , Infecções por HIV/tratamento farmacológico , HIV-1/efeitos dos fármacos , Bibliotecas de Moléculas Pequenas/farmacologia , Animais , Fármacos Anti-HIV/farmacologia , Capsídeo/efeitos dos fármacos , Capsídeo/metabolismo , Proteínas do Capsídeo/genética , DNA Viral/efeitos dos fármacos , Preparações de Ação Retardada , Farmacorresistência Viral/efeitos dos fármacos , Infecções por HIV/genética , Infecções por HIV/virologia , HIV-1/genética , HIV-1/patogenicidade , HIV-2/efeitos dos fármacos , HIV-2/patogenicidade , Humanos , Adesão à Medicação , Camundongos
8.
Expert Opin Drug Metab Toxicol ; 15(10): 813-829, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31556749

RESUMO

Introduction: Non-nucleoside reverse transcriptase inhibitors (NNRTIs) are essential components of highly active antiretroviral therapy against HIV-1 infections. Here, we provide a comprehensive overview of approved and emerging NNRTIs. Areas covered: This review covers the latest trend of NNRTIs regarding their pharmacodynamics, pharmacokinetics, mechanisms of drug action, drug resistance as well as new applications such as two-drug regimens and long-acting formulations. Expert opinion: Since the first NNRTI, nevirapine, was approved in 1996, antiviral drug discovery led to the approval of seven NNRTIs, including nevirapine, delavirdine (discontinued), etravirine, elsulfavirine, efavirenz, rilpivirine, and doravirine. The latter three compounds with favorable pharmacodynamic profiles and minimal adverse effects are often combined with one integrase inhibitor or two NRTIs in once-daily fixed-dose tablets. NNRTI-anchored regimens have been approved as initial therapies in treatment-naïve patients (efficacy: 72% to 86%) or maintaining therapies in virologically-suppressed patients (efficacy: 91% to 95%). Future development of NNRTIs includes: (i) better resistance and cross-resistance profiles; (ii) reduction of drug burden by optimizing two-drug or three-drug combinations; and (iii) improvement of patient adherence by novel long-acting formulations with weekly or monthly administration. Overall, NNRTIs play an important role in the management of HIV-1 infections, especially in resource-limited countries.


Assuntos
Fármacos Anti-HIV/administração & dosagem , Infecções por HIV/tratamento farmacológico , Inibidores da Transcriptase Reversa/administração & dosagem , Fármacos Anti-HIV/efeitos adversos , Fármacos Anti-HIV/farmacocinética , Terapia Antirretroviral de Alta Atividade/métodos , Preparações de Ação Retardada , Farmacorresistência Viral , HIV-1/efeitos dos fármacos , Humanos , Adesão à Medicação , Inibidores da Transcriptase Reversa/efeitos adversos , Inibidores da Transcriptase Reversa/farmacocinética
9.
Int. j. STD AIDS ; 30(9): 930-933, Aug. 2019. ilus
Artigo em Inglês | Sec. Est. Saúde SP, SESSP-IIERPROD, Sec. Est. Saúde SP | ID: biblio-1016472

RESUMO

We report the case of a previously healthy 29-year-old man who has sex with men who was admitted with sub-acute onset of headache, seizures and altered mental status. Physical examination revealed oral thrush, mental confusion and right hemiparesis. An unenhanced computed tomography of the brain revealed multiple rounded hemorrhages associated with perilesional edema and no enhancement was seen after contrast infusion. A rapid test for HIV-1 was positive and the CD4 T-lymphocyte count was 120 cells/mm3. Pyrimethamine, sulfadiazine plus folinic acid and dexamethasome were started. After two weeks of treatment, the clinical condition and neuroimaging of the patient remained unaltered. A stereotactic brain biopsy was performed and the Histopathologic examination confirmed the diagnosis of hemorrhagic toxoplasmosis. After a longer course of anti-Toxoplasma treatment due to an incomplete clinical and radiological response, the patient was discharged home. Hemorrhagic toxoplasmosis is a rare presentation of cerebral toxoplasmosis and should be considered in the differential diagnosis of hemorrhagic cerebral lesions in HIV-infected patients in order to initiate specific treatment promptly


Assuntos
Humanos , Masculino , Adulto , HIV-1 , Toxoplasmose Cerebral
10.
J Enzyme Inhib Med Chem ; 34(1): 1451-1456, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31409143

RESUMO

Herein, we report the effect of nine FDA approved protease inhibitor drugs against a new HIV-1 subtype C mutant protease, E35D↑G↑S. The mutant has five mutations, E35D, two insertions, position 36 (G and S), and D60E. Kinetics, inhibition constants, vitality, Gibbs free binding energies are reported. The variant showed a decreased affinity for substrate and low catalytic efficiency compared to the wild type. There was a significant decrease in the binding of seven FDA approved protease inhibitors against the mutant (p < .0001). Amprenavir and ritonavir showed the least decrease, but still significant reduced activity in comparison to the wildtype (4 and 5 folds, respectively, p = .0021 and .003, respectively). Nelfinavir and atazanavir were the worst inhibitors against the variant as seen from the IC50, with values of 1401 ± 3.0 and 685 ± 3.0 nM, respectively. Thermodynamics data showed less favourable Gibbs free binding energies for the protease inhibitors to the mutant.


Assuntos
Inibidores da Protease de HIV/farmacologia , Protease de HIV/efeitos dos fármacos , HIV-1/enzimologia , Termodinâmica , Protease de HIV/genética , Protease de HIV/metabolismo , Inibidores da Protease de HIV/química , Concentração Inibidora 50 , Cinética , Simulação de Acoplamento Molecular , Mutação
12.
Medicine (Baltimore) ; 98(32): e16357, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31393344

RESUMO

Achieving and maintaining viral suppression in young adults (18-24 years) living with HIV is challenging. Overall HIV viral suppression rates are lower in young as compared to older adults. Longitudinal data provide valuable insight on dynamics of viral suppression and variables of potential influence on HIV virological failure (VF), but is scarce in young adults living with HIV on combination antiretroviral therapy (cART). We evaluated longitudinal virological outcomes of behaviorally young adults (18-24 years) living with HIV in the Netherlands over a period of 15 years.We analyzed data from the Dutch national HIV database of 816 young adults living with HIV on cART in the Netherlands from 2000 to 2015. VF was defined as 2 consecutive detectable plasma HIV-1 viral load (VL) measurements > 200 copies/ml. Generalized linear mixed model analyses were used to assess HIV VF over time and identify risk factors associated with VF.VF during the study follow-up occurred at least once in 26% of cases. The probability of experiencing VF decreased over the study period per calendar year (OR 0.78, 95% confidence interval [CI];0.72; 0.85). Factors significantly associated with VF were being infected through heterosexual contact (OR 5.20, CI 1.39;19.38) and originating from Latin America or the Caribbean (OR 6.59, CI 2.08;20.92). Smaller, yet significant risk factors for VF were being infected through a blood transfusion or a needle accident (OR9.93, CI 1.34;73.84, and having started with cART with a nadir CD4 count >500 cells/µl (OR 11.36, CI 2.03;63.48).In our large cohort of young adults, the risk of VF has diminished over 15 years. Specific subgroups were identified to be at risk for suboptimal treatment.


Assuntos
Antirretrovirais/uso terapêutico , Infecções por HIV/tratamento farmacológico , Adolescente , Antirretrovirais/administração & dosagem , Contagem de Linfócito CD4 , Grupos de Populações Continentais , Quimioterapia Combinada , Feminino , Infecções por HIV/etiologia , HIV-1 , Humanos , Estudos Longitudinais , Masculino , Países Baixos , Fatores de Risco , Comportamento Sexual , Falha de Tratamento , Carga Viral , Adulto Jovem
13.
Medicine (Baltimore) ; 98(32): e16813, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31393412

RESUMO

Dolutegravir (DTG) has shown effectiveness in combination with rilpivirine in with experience of antiretroviral therapy (ART) and with 3TC in naïve patients (GEMINI trial). The main objectives of this real-life study were to analyze the effectiveness and safety of 3TC plus DTG in virologically suppressed HIV-1 patients and to conduct a pharmacoeconomic analysis.We conducted an observational, retrospective and multicenter study of HIV+ patients pretreated for at least 6 months with ART that was then simplified to 3TC + DTG for any reason. We gathered data on viral loads (VLs) during exposure to the DT, calculating the rate with VL < 50 copies/mL at week 48, and on associated adverse effects.The 177 HIV+ patients were collected, 77.4% male, with average age of 48.5 years and mean count of 252.2cell/µL CD4+ nadir lymphocytes; 96.6% had VL < 50 copies/mL and 674 cells/µL CD4+ lymphocytes. Median time since HIV diagnosis was 15 years, and median ART duration was 13 years, and 34.5% of patients were on mono- or dual-therapy before the switch. At week 48, 82.4% of patients had VL < 50 cop/µL using an intention-to-treat (ITT) analysis, 89.6% according to mITT, and 96.7% according to Per-Protocol analysis. 3.3% patients had virological failure (VF). These effectiveness data and costs were compared with those for 2 reference triple therapies (DTG/ABC/3TC and EVG/cobi/FTC/TAF) in a cost minimization analysis, showing cost savings with administration of DTG+3TC (2741 &OV0556;/year vs DTG/ABC/3TC and 4164 &OV0556;/year vs EVG/cobi/FTC/TAF) and in a cost-effectiveness analysis, finding the DT to be the most cost-effective approach (ICER = -548 vs DTG/ABC/3TC and ICER = -4,627&OV0556; vs EVG/cobi/FTC/TAF)The combination of 3TC with DTG appears to be a safe and effective option for the simplification of ART in pretreated and virologically stable HIV-positive patients, being cost-effective and offering the same effectiveness as the triple therapy it replaces.


Assuntos
Fármacos Anti-HIV/uso terapêutico , Infecções por HIV/tratamento farmacológico , Compostos Heterocíclicos com 3 Anéis/uso terapêutico , Lamivudina/uso terapêutico , Adulto , Fármacos Anti-HIV/administração & dosagem , Fármacos Anti-HIV/efeitos adversos , Fármacos Anti-HIV/economia , Contagem de Linfócito CD4 , Análise Custo-Benefício , Quimioterapia Combinada , Farmacoeconomia , Honorários Farmacêuticos/estatística & dados numéricos , Feminino , HIV-1 , Compostos Heterocíclicos com 3 Anéis/administração & dosagem , Compostos Heterocíclicos com 3 Anéis/efeitos adversos , Compostos Heterocíclicos com 3 Anéis/economia , Humanos , Lamivudina/administração & dosagem , Lamivudina/efeitos adversos , Lamivudina/economia , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Carga Viral
14.
Pan Afr Med J ; 32: 215, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31404285

RESUMO

Introduction: Kaposi's sarcoma (KS) is a kind of cancer that causes flat or raised lesions containing Human herpes virus 8 (HHV8). The KS lesions are common among immunosuppressed HIV patients. Highly Active Antiretroviral (HHART) treats and prevents the development of KS. The objective of this study was to determine the presence of K1 and K15 (predominant alleles) genes in Kaposi's sarcoma-associated herpes virus (KSHV) among immunosuppressed patients due to HIV-1. Methods: This was a cross-sectional descriptive study where consecutive sampling technique was adopted to pick archived tissue blocks from the Thematic Unit of Anatomic Pathology, Department of Human Pathology, College of Health Sciences, University of Nairobi and Department of Laboratory Medicine, Histology Section, Kenyatta National Hospital. Results: Upon staining 81 tissue blocks with H & E, 84% (68/81) were diagnosed as KS and 16% (13/81) as KS-like. The K1 and K15 (P) genes were both detected at 88.9% (72/81) in the tissue blocks, with 95.8% (69/72) detection from KS and 4.2% (3/72) from the KS-like. Conclusion: The K1 and K15 (P) genes of KSHV were present among the immunosuppressed patients with Human Immunodeficiency Virus (HIV)-1. It is important to carry out K1 and K15 (P) genes detection on tissues that are diagnosed as KS or KS-like by histology technique.


Assuntos
Infecções por HIV/complicações , Sarcoma de Kaposi/genética , Proteínas Virais/genética , Síndrome de Imunodeficiência Adquirida/complicações , Síndrome de Imunodeficiência Adquirida/tratamento farmacológico , Síndrome de Imunodeficiência Adquirida/genética , Adolescente , Adulto , Terapia Antirretroviral de Alta Atividade/métodos , Estudos Transversais , Feminino , Infecções por HIV/tratamento farmacológico , Infecções por HIV/genética , HIV-1/isolamento & purificação , Humanos , Hospedeiro Imunocomprometido , Masculino , Pessoa de Meia-Idade , Sarcoma de Kaposi/epidemiologia , Sarcoma de Kaposi/etiologia , Adulto Jovem
15.
Curr Top Med Chem ; 19(18): 1650-1675, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31424369

RESUMO

Human immunodeficiency virus type-1 (HIV-1) is the causative agent responsible for the acquired immunodeficiency syndrome (AIDS) pandemic. More than 60 million infections and 25 million deaths have occurred since AIDS was first identified in the early 1980s. Advances in available therapeutics, in particular combination antiretroviral therapy, have significantly improved the treatment of HIV infection and have facilitated the shift from high mortality and morbidity to that of a manageable chronic disease. Unfortunately, none of the currently available drugs are curative of HIV. To deal with the rapid emergence of drug resistance, off-target effects, and the overall difficulty of eradicating the virus, an urgent need exists to develop new drugs, especially against targets critically important for the HIV-1 life cycle. Viral entry, which involves the interaction of the surface envelope glycoprotein, gp120, with the cellular receptor, CD4, is the first step of HIV-1 infection. Gp120 has been validated as an attractive target for anti-HIV-1 drug design or novel HIV detection tools. Several small molecule gp120 antagonists are currently under investigation as potential entry inhibitors. Pyrrole, piperazine, triazole, pyrazolinone, oxalamide, and piperidine derivatives, among others, have been investigated as gp120 antagonist candidates. Herein, we discuss the current state of research with respect to the design, synthesis and biological evaluation of oxalamide derivatives and five-membered heterocycles, namely, the pyrrole-containing small molecule as inhibitors of gp120 and HIV entry.


Assuntos
Amidas/farmacologia , Fármacos Anti-HIV/farmacologia , Proteína gp120 do Envelope de HIV/antagonistas & inibidores , Inibidores da Fusão de HIV/farmacologia , Pirróis/farmacologia , Bibliotecas de Moléculas Pequenas/farmacologia , Amidas/química , Fármacos Anti-HIV/química , Descoberta de Drogas , Proteína gp120 do Envelope de HIV/metabolismo , Inibidores da Fusão de HIV/química , Infecções por HIV/tratamento farmacológico , HIV-1/efeitos dos fármacos , Humanos , Pirróis/química , Bibliotecas de Moléculas Pequenas/química
16.
Curr Top Med Chem ; 19(18): 1599-1620, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31424370

RESUMO

Viral entry, the first process in the reproduction of viruses, primarily involves attachment of the viral envelope proteins to membranes of the host cell. The crucial components that play an important role in viral entry include viral surface glycoprotein gp120, viral transmembrane glycoprotein gp41, host cell glycoprotein (CD4), and host cell chemokine receptors (CCR5 and CXCR4). Inhibition of the multiple molecular interactions of these components can restrain viruses, such as HIV-1, from fusion with the host cell, blocking them from reproducing. This review article specifically focuses on the recent progress in the development of small-molecule HIV-1 entry inhibitors and incorporates important aspects of their structural modification that lead to the discovery of new molecular scaffolds with more potency.


Assuntos
Fármacos Anti-HIV/farmacologia , Proteína gp120 do Envelope de HIV/antagonistas & inibidores , Proteína gp41 do Envelope de HIV/antagonistas & inibidores , Inibidores da Fusão de HIV/farmacologia , HIV-1/efeitos dos fármacos , Bibliotecas de Moléculas Pequenas/farmacologia , Fármacos Anti-HIV/química , Proteína gp120 do Envelope de HIV/metabolismo , Proteína gp41 do Envelope de HIV/metabolismo , Inibidores da Fusão de HIV/química , Humanos , Bibliotecas de Moléculas Pequenas/química
17.
Curr Top Med Chem ; 19(18): 1621-1649, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31424371

RESUMO

The history of the human immunodeficiency virus (HIV)/AIDS therapy, which spans over 30 years, is one of the most dramatic stories of science and medicine leading to the treatment of a disease. Since the advent of the first AIDS drug, AZT or zidovudine, a number of agents acting on different drug targets, such as HIV enzymes (e.g. reverse transcriptase, protease, and integrase) and host cell factors critical for HIV infection (e.g. CD4 and CCR5), have been added to our armamentarium to combat HIV/AIDS. In this review article, we first discuss the history of the development of anti-HIV drugs, during which several problems such as drug-induced side effects and the emergence of drug-resistant viruses became apparent and had to be overcome. Nowadays, the success of Combination Antiretroviral Therapy (cART), combined with recently-developed powerful but nonetheless less toxic drugs has transformed HIV/AIDS from an inevitably fatal disease into a manageable chronic infection. However, even with such potent cART, it is impossible to eradicate HIV because none of the currently available HIV drugs are effective in eliminating occult "dormant" HIV cell reservoirs. A number of novel unique treatment approaches that should drastically improve the quality of life (QOL) of patients or might actually be able to eliminate HIV altogether have also been discussed later in the review.


Assuntos
Fármacos Anti-HIV/farmacologia , Descoberta de Drogas , Infecções por HIV/tratamento farmacológico , HIV-1/efeitos dos fármacos , Fármacos Anti-HIV/química , Farmacorresistência Viral/efeitos dos fármacos , Humanos
18.
Anal Bioanal Chem ; 411(23): 6111-6118, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31367804

RESUMO

Application of a protease inhibitor, 4-(2-aminoethyl) benzenesulfonyl fluoride (AEBSF), during the cell culture process was demonstrated to effectively reduce proteolytic activity at a specific amino acid site during the production of an HIV-1 broadly neutralizing antibody (bNAb). However, the addition of AEBSF could potentially introduce some modifications to the bNAb protein. Experimental design from sample preparation to LC-MS characterization was performed using middle-up and bottom-up approaches to identify AEBSF-modified species for the bNAb using an AEBSF supplementation in the cell culture media. Modified species along with the unmodified control sample were also subjected to binding activity assessment. The results showed that two amino acids (Tyr177 and Lys250) were susceptible to AEBSF modification in the bNAb test articles but at a negligible level and not in the CDR regions, which therefore did not reduce the in vitro binding activity of the bNAb.


Assuntos
Anticorpos Neutralizantes/imunologia , Anticorpos Anti-HIV/imunologia , HIV-1/imunologia , Imunoconjugados/imunologia , Inibidores de Proteases/imunologia , Sulfonas/imunologia , Sequência de Aminoácidos , Anticorpos Neutralizantes/química , Anticorpos Anti-HIV/química , Infecções por HIV/virologia , Humanos , Imunoconjugados/química , Inibidores de Proteases/química , Sulfonas/química , Espectrometria de Massas em Tandem
19.
BMC Evol Biol ; 19(1): 163, 2019 08 02.
Artigo em Inglês | MEDLINE | ID: mdl-31375065

RESUMO

BACKGROUND: Ancestral character states computed from the combination of phylogenetic trees with extrinsic traits are used to decipher evolutionary scenarios in various research fields such as phylogeography, epidemiology, and ecology. Despite the existence of powerful methods and software in ancestral character state inference, difficulties may arise when interpreting the outputs of such inferences. The growing complexity of data (trees, annotations), the diversity of optimization criteria for computing trees and ancestral character states, the combinatorial explosion of potential evolutionary scenarios if some ancestral characters states do not stand out clearly from others, requires the design of new methods to explore associations of phylogenetic trees with extrinsic traits, to ease the visualization and interpretation of evolutionary scenarios. RESULT: We developed PastView, a user-friendly interface that includes numerical and graphical features to help users to import and/or compute ancestral character states from discrete variables and extract ancestral scenarios as sets of successive transitions of character states from the tree root to its leaves. PastView provides summarized views such as transition maps and integrates comparative tools to highlight agreements or discrepancies between methods of ancestral annotations inference. CONCLUSION: The main contribution of PastView is to assemble known numerical and graphical methods into a multi-maps graphical user interface dedicated to the computing, searching and viewing of evolutionary scenarios based on phylogenetic trees and ancestral character states. PastView is available publicly as a standalone software on www.pastview.org .


Assuntos
Filogenia , Software , Interface Usuário-Computador , Albânia/epidemiologia , Dengue/epidemiologia , Vírus da Dengue/genética , Infecções por HIV/epidemiologia , HIV-1/genética , Humanos , Fenótipo , Filogeografia
20.
Cell Host Microbe ; 26(2): 151-153, 2019 08 14.
Artigo em Inglês | MEDLINE | ID: mdl-31415744

RESUMO

In this issue of Cell Host & Microbe, Summers et al. (2019) use protein engineering to generate a toolbox of HIV-1 capsid oligomers. In an accompanying Cell Reports paper, Huang et al. (2019) use these oligomers to determine how the capsid engages the kinesin-1 adaptor protein FEZ1.


Assuntos
Capsídeo , HIV-1 , Proteínas Adaptadoras de Transdução de Sinal , Proteínas do Capsídeo , Cinesina
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