Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 932
Filtrar
1.
J Colloid Interface Sci ; 592: 156-166, 2021 Jun 15.
Artigo em Inglês | MEDLINE | ID: mdl-33652169

RESUMO

The antiretroviral (ARV) cocktailrevolved the treatment of the human immunodeficiency virus (HIV) infection. Drug combinations have been also tested to treat other infectious diseases, including the recentcoronavirus disease 2019 (COVID-19) outbreak. To simplify administration fixed-dose combinationshave been introduced, however, oral anti-HIV therapy still struggles with low oral bioavailability of many ARVs.This work investigated the co-encapsulation of two clinically relevant ARV combinations,tipranavir (TPV):efavirenz (EFV) anddarunavir (DRV):efavirenz (EFV):ritonavir (RTV),within the core of ß-casein (bCN) micelles. Encapsulation efficiency in both systems was ~100%. Cryo-transmission electron microscopy and dynamic light scattering of the ARV-loaded colloidaldispersions indicatefull preservation of the spherical morphology, and x-ray diffraction confirm that the encapsulated drugs are amorphous. To prolong the physicochemical stabilitythe formulations were freeze-driedwithout cryo/lyoprotectant, and successfully redispersed, with minor changes in morphology.Then, theARV-loaded micelles were encapsulated within microparticles of Eudragit® L100, which prevented enzymatic degradation and minimized drug release under gastric-like pH conditionsin vitro. At intestinal pH, the coating polymer dissolved and released the nanocarriers and content. Overall, our results confirm the promise of this flexible and modular technology platform for oral delivery of fixed dose combinations.


Assuntos
Antirretrovirais , Caseínas , Infecções por HIV/tratamento farmacológico , HIV-1 , Micelas , Antirretrovirais/química , Antirretrovirais/farmacocinética , Antirretrovirais/farmacologia , Caseínas/química , Caseínas/farmacocinética , Caseínas/farmacologia , Preparações de Ação Retardada/química , Preparações de Ação Retardada/farmacocinética , Combinação de Medicamentos , Humanos
2.
Int J Nanomedicine ; 16: 1189-1206, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33623382

RESUMO

Introduction: Human immunodeficiency virus (HIV) remains a persistent global challenge, impacting 38 million people worldwide. Antiretrovirals (ARVs) including tenofovir (TFV), raltegravir (RAL), and dapivirine (DAP) have been developed to prevent and treat HIV-1 via different mechanisms of action. In parallel, a promising biological candidate, griffithsin (GRFT), has demonstrated outstanding preclinical safety and potency against HIV-1. While ARV co-administration has been shown to enhance virus inhibition, synergistic interactions between ARVs and the oxidation-resistant variant of GRFT (Q-GRFT) have not yet been explored. Here, we co-administered Q-GRFT with TFV, RAL, and DAP, in free and encapsulated forms, to identify unique protein-drug synergies. Methods: Nanoparticles (NPs) were synthesized using a single or double-emulsion technique and release from each formulation was assessed in simulated vaginal fluid. Next, each ARV, in free and encapsulated forms, was co-administered with Q-GRFT or Q-GRFT NPs to evaluate the impact of co-administration in HIV-1 pseudovirus assays, and the combination indices were calculated to identify synergistic interactions. Using the most synergistic formulations, we investigated the effect of agent incorporation in NP-fiber composites on release properties. Finally, NP safety was assessed in vitro using MTT assay. Results: All active agents were encapsulated in NPs with desirable encapsulation efficiency (15-100%), providing ~20% release over 2 weeks. The co-administration of free Q-GRFT with each free ARV resulted in strong synergistic interactions, relative to each agent alone. Similarly, Q-GRFT NP and ARV NP co-administration resulted in synergy across all formulations, with the most potent interactions between encapsulated Q-GRFT and DAP. Furthermore, the incorporation of Q-GRFT and DAP in NP-fiber composites resulted in burst release of DAP and Q-GRFT with a second phase of Q-GRFT release. Finally, all NP formulations exhibited safety in vitro. Conclusions: This work suggests that Q-GRFT and ARV co-administration in free or encapsulated forms may improve efficacy in achieving prophylaxis.


Assuntos
Antirretrovirais/uso terapêutico , Infecções por HIV/tratamento farmacológico , Lectinas/uso terapêutico , Fármacos Anti-HIV/farmacologia , Antirretrovirais/farmacologia , Morte Celular/efeitos dos fármacos , Linhagem Celular , Composição de Medicamentos , Liberação Controlada de Fármacos , Sinergismo Farmacológico , Feminino , HIV-1/efeitos dos fármacos , Humanos , Concentração Inibidora 50 , Lectinas/farmacologia , Nanopartículas/química , Nanopartículas/ultraestrutura , Tamanho da Partícula , Copolímero de Ácido Poliláctico e Ácido Poliglicólico/química , Pirimidinas/farmacologia , Raltegravir Potássico/farmacologia , Tenofovir/farmacologia
3.
Molecules ; 26(3)2021 Jan 25.
Artigo em Inglês | MEDLINE | ID: mdl-33503916

RESUMO

The use of antiretroviral drugs is accompanied by the emergence of HIV-2 resistances. Thus, it is important to elucidate the mechanisms of resistance to antiretroviral drugs. Here, we propose a structural analysis of 31 drug-resistant mutants of HIV-2 protease (PR2) that is an important target against HIV-2 infection. First, we modeled the structures of each mutant. We then located structural shifts putatively induced by mutations. Finally, we compared wild-type and mutant inhibitor-binding pockets and interfaces to explore the impacts of these induced structural deformations on these two regions. Our results showed that one mutation could induce large structural rearrangements in side-chain and backbone atoms of mutated residue, in its vicinity or further. Structural deformations observed in side-chain atoms are frequent and of greater magnitude, that confirms that to fight drug resistance, interactions with backbone atoms should be favored. We showed that these observed structural deformations modify the conformation, volume, and hydrophobicity of the binding pocket and the composition and size of the PR2 interface. These results suggest that resistance mutations could alter ligand binding by modifying pocket properties and PR2 stability by impacting its interface. Our results reinforce the understanding of the effects of mutations that occurred in PR2 and the different mechanisms of PR2 resistance.


Assuntos
Farmacorresistência Viral/genética , HIV-2/genética , Mutação/genética , Antirretrovirais/farmacologia , Sítios de Ligação/genética , Farmacorresistência Viral/efeitos dos fármacos , Inibidores da Protease de HIV/farmacologia , HIV-2/efeitos dos fármacos , Interações Hidrofóbicas e Hidrofílicas/efeitos dos fármacos , Ligantes , Ligação Proteica/genética
4.
Nat Commun ; 11(1): 5542, 2020 11 02.
Artigo em Inglês | MEDLINE | ID: mdl-33139735

RESUMO

The HIV-1 reservoir is the major hurdle to curing HIV-1. However, the impact of the viral genome on the HIV-1 reservoir, i.e. its heritability, remains unknown. We investigate the heritability of the HIV-1 reservoir size and its long-term decay by analyzing the distribution of those traits on viral phylogenies from both partial-pol and viral near full-length genome sequences. We use a unique nationwide cohort of 610 well-characterized HIV-1 subtype-B infected individuals on suppressive ART for a median of 5.4 years. We find that a moderate but significant fraction of the HIV-1 reservoir size 1.5 years after the initiation of ART is explained by genetic factors. At the same time, we find more tentative evidence for the heritability of the long-term HIV-1 reservoir decay. Our findings indicate that viral genetic factors contribute to the HIV-1 reservoir size and hence the infecting HIV-1 strain may affect individual patients' hurdle towards a cure.


Assuntos
Antirretrovirais/farmacologia , HIV-1/efeitos dos fármacos , HIV-1/genética , Adulto , Linfócitos T CD4-Positivos/virologia , Estudos de Coortes , DNA Viral/genética , Feminino , Genoma Viral , Infecções por HIV/virologia , Humanos , Masculino , Fatores de Tempo , Carga Viral
5.
Farm. hosp ; 44(4): 163-173, jul.-ago. 2020. tab, graf
Artigo em Espanhol | IBECS | ID: ibc-195093

RESUMO

La adherencia al tratamiento en el paciente con infección por el virus de la inmunodeficiencia humana sigue siendo foco de atención de profesionales sanitarios e investigadores. Sin embargo, el perfil del paciente y el arsenal terapéutico disponible han cambiado enormemente en la última década. La adherencia inadecuada, no solo al tratamiento antirretroviral sino también a otros fármacos prescritos, sigue siendo la principal causa de fracaso terapéutico. Existen diversos factores asociados a la mala adherencia y otros que facilitan la misma, de ahí la importancia de identificar y manejar las situaciones que puedan dificultar la adherencia e intentar corregirlas. Asimismo, se debe reevaluar periódicamente la adherencia durante el seguimiento del tratamiento antirretroviral y del resto de los fármacos prescritos. En la actualidad no existe un método único para medir la adherencia de forma fiable. Por ello se hace necesario utilizar varios métodos combinados de fácil realización. Adicionalmente, una buena relación entre el personal sanitario y los pacientes facilita la obtención de una adecuada información sobre la adherencia. Las intervenciones para mejorar la adherencia deben ser multidisciplinares, individualizadas y ajustadas a los nuevos patrones de transmisión de la infección, y es fundamental incluir el control de la adherencia a otros fármacos prescritos al paciente con el virus de la inmunodeficiencia humana. El presente documento actualiza las recomendaciones publicadas en 2008 tras una revisión de la literatura científica, lo que ha permitido emitir unas recomendaciones consensuadas para la mejora de la adherencia al tratamiento. El objetivo principal es ayudar a todos los profesionales sanitarios dedicados al control clínico y terapéutico de los pacientes con el virus de la inmunodeficiencia humana (médicos, farmacéuticos, enfermeras, psicólogos y trabajadores sociales) a mejorar la adherencia a toda la farmacoterapia que tengan prescrita


Adherence to treatment in patients living with HIV remains the focus of attention of health professionals and researchers. However, patient pro-files and the available therapeutic arsenal have changed greatly over the last decade. Inadequate adherence not only to antiretroviral therapy but also to other prescribed drugs remains the main cause of therapeutic failure. There are several factors associated with poor adherence and others that facilitate it, hence the importance of identifying, managing and correcting situations that may hinder adherence. Likewise, adherence should be periodically reassessed during the follow-up of ART and other prescribed drugs. It has so far proved impossible to find a single method capable of providing a reliable measurement of adherence. That is why it is necessary to use a combination of multiple easy-to-implement methods. Additionally a good relationship with the patient facilitates the conveyance of adequate information on adherence. It is currently considered that interventions to improve adherence should be multidisciplinary, individualized and adjusted to the new patterns of infection transmission, and that controlling adherence to other drugs prescribed to patients with HIV should be part of such interventions. This document provides an update on the recommendations published in 2008 based on a review of the scientific literature. The main goal is to help healthcare professionals dedicated to the clinical and therapeutic management of HIV patients (doctors, pharmacists, nurses, psychologists and social workers) improve adherence of such patients to all the drugs prescribed to them as treatment for their HIV infection


Assuntos
Humanos , Adolescente , Adulto Jovem , Adulto , Cooperação e Adesão ao Tratamento , Consenso , Síndromes de Imunodeficiência/tratamento farmacológico , Antirretrovirais/uso terapêutico , Síndrome de Imunodeficiência Adquirida/tratamento farmacológico , Antirretrovirais/farmacologia , Fatores de Risco
6.
Arch Virol ; 165(8): 1729-1737, 2020 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-32514689

RESUMO

The novel human coronavirus (SARS-CoV-2), the causative agent of COVID-19, has quickly become a threat to the public health and economy worldwide. Despite the severity of some cases, there are no current pathogen-specific antivirals available to treat the disease. Therefore, many studies have focused on the evaluation of the anti-SARS-CoV-2 activity of clinically available drugs. Here, we conducted a systematic review to describe the drug repositioning strategy against SARS-CoV-2 and to discuss the clinical impact of this approach in the current pandemic context. The systematic review was performed on March 23, 2020, using PubMed/MEDLINE, Scopus, Cochrane Library, and Biblioteca Virtual de Saúde (BVS). The data were summarized in tables and critically analyzed. After the database search, 12 relevant studies were identified as eligible for the review. Among the drugs reported in these studies, 57 showed some evidence of antiviral activity. Antivirals, especially antiretrovirals, are the main class of therapeutic agents evaluated against COVID-19. Moreover, studies have reported the anti-SARS-CoV-2 activity of antitumor (16%; 9/57), antimalarial (7%, 4/57), and antibacterial (5%; 3/57) agents. Additionally, seven pharmacological agents (chloroquine, tetrandrine, umifenovir (arbidol), carrimycin, damageprevir, lopinavir/ritonavir) are in phase IV of clinical trials. Due to the evidence of the anti-SARS-CoV-2 activity of various clinically available agents, drug repositioning stands out as a promising strategy for a short-term response in the fight against the novel coronavirus.


Assuntos
Antibacterianos/farmacologia , Antirretrovirais/farmacologia , Antimaláricos/farmacologia , Antineoplásicos/farmacologia , Betacoronavirus/efeitos dos fármacos , Infecções por Coronavirus/tratamento farmacológico , Reposicionamento de Medicamentos , Pneumonia Viral/tratamento farmacológico , Antivirais/farmacologia , Infecções por Coronavirus/prevenção & controle , Humanos , Pandemias/prevenção & controle , Pneumonia Viral/prevenção & controle
7.
PLoS Pathog ; 16(6): e1008381, 2020 06.
Artigo em Inglês | MEDLINE | ID: mdl-32525948

RESUMO

HIV invades the brain during acute infection. Yet, it is unknown whether long-lived infected brain cells release productive virus that can egress from the brain to re-seed peripheral organs. This understanding has significant implication for the brain as a reservoir for HIV and most importantly HIV interplay between the brain and peripheral organs. Given the sheer number of astrocytes in the human brain and their controversial role in HIV infection, we evaluated their infection in vivo and whether HIV infected astrocytes can support HIV egress to peripheral organs. We developed two novel models of chimeric human astrocyte/human peripheral blood mononuclear cells: NOD/scid-IL-2Rgc null (NSG) mice (huAstro/HuPBMCs) whereby we transplanted HIV (non-pseudotyped or VSVg-pseudotyped) infected or uninfected primary human fetal astrocytes (NHAs) or an astrocytoma cell line (U138MG) into the brain of neonate or adult NSG mice and reconstituted the animals with human peripheral blood mononuclear cells (PBMCs). We also transplanted uninfected astrocytes into the brain of NSG mice and reconstituted with infected PBMCs to mimic a biological infection course. As expected, the xenotransplanted astrocytes did not escape/migrate out of the brain and the blood brain barrier (BBB) was intact in this model. We demonstrate that astrocytes support HIV infection in vivo and egress to peripheral organs, at least in part, through trafficking of infected CD4+ T cells out of the brain. Astrocyte-derived HIV egress persists, albeit at low levels, under combination antiretroviral therapy (cART). Egressed HIV evolved with a pattern and rate typical of acute peripheral infection. Lastly, analysis of human cortical or hippocampal brain regions of donors under cART revealed that astrocytes harbor between 0.4-5.2% integrated HIV gag DNA and 2-7% are HIV gag mRNA positive. These studies establish a paradigm shift in the dynamic interaction between the brain and peripheral organs which can inform eradication of HIV reservoirs.


Assuntos
Astrócitos , Barreira Hematoencefálica , Infecções por HIV , HIV-1/metabolismo , Hipocampo , Liberação de Vírus , Animais , Antirretrovirais/farmacologia , Astrócitos/metabolismo , Astrócitos/patologia , Astrócitos/virologia , Barreira Hematoencefálica/metabolismo , Barreira Hematoencefálica/patologia , Barreira Hematoencefálica/virologia , Linhagem Celular Tumoral , Infecções por HIV/genética , Infecções por HIV/metabolismo , Infecções por HIV/patologia , HIV-1/genética , Hipocampo/metabolismo , Hipocampo/patologia , Hipocampo/virologia , Humanos , Camundongos , Camundongos Endogâmicos NOD , Camundongos Knockout , Camundongos SCID
8.
J Virol ; 94(14)2020 07 01.
Artigo em Inglês | MEDLINE | ID: mdl-32350073

RESUMO

Antiretroviral therapy (ART) cannot eradicate human immunodeficiency virus (HIV) and a rapid rebound of virus replication follows analytical treatment interruption (ATI) in the vast majority of HIV-infected individuals. Sustained control of HIV replication without ART has been documented in a subset of individuals, defined as posttreatment controllers (PTCs). The key determinants of post-ART viral control remain largely unclear. Here, we identified 7 SIVmac239-infected rhesus macaques (RMs), defined as PTCs, who started ART 8 weeks postinfection, continued ART for >7 months, and controlled plasma viremia at <104 copies/ml for up to 8 months after ATI and <200 copies/ml at the latest time point. We characterized immunologic and virologic features associated with post-ART SIV control in blood, lymph node (LN), and colorectal (RB) biopsy samples compared to 15 noncontroller (NC) RMs. Before ART initiation, PTCs had higher CD4 T cell counts, lower plasma viremia, and SIV-DNA content in blood and LN compared to NCs, but had similar CD8 T cell function. While levels of intestinal CD4 T cells were similar, PTCs had higher frequencies of Th17 cells. On ART, PTCs had significantly lower levels of residual plasma viremia and SIV-DNA content in blood and tissues. After ATI, SIV-DNA content rapidly increased in NCs, while it remained stable or even decreased in PTCs. Finally, PTCs showed immunologic benefits of viral control after ATI, including higher CD4 T cell levels and reduced immune activation. Overall, lower plasma viremia, reduced cell-associated SIV-DNA, and preserved Th17 homeostasis, including at pre-ART, are the main features associated with sustained viral control after ATI in SIV-infected RMs.IMPORTANCE While effective, antiretroviral therapy is not a cure for HIV infection. Therefore, there is great interest in achieving viral remission in the absence of antiretroviral therapy. Posttreatment controllers represent a small subset of individuals who are able to control HIV after cessation of antiretroviral therapy, but characteristics associated with these individuals have been largely limited to peripheral blood analysis. Here, we identified 7 SIV-infected rhesus macaques that mirrored the human posttreatment controller phenotype and performed immunologic and virologic analysis of blood, lymph node, and colorectal biopsy samples to further understand the characteristics that distinguish them from noncontrollers. Lower viral burden and preservation of immune homeostasis, including intestinal Th17 cells, both before and after ART, were shown to be two major factors associated with the ability to achieve posttreatment control. Overall, these results move the field further toward understanding of important characteristics of viral control in the absence of antiretroviral therapy.


Assuntos
Antirretrovirais/farmacologia , Síndrome de Imunodeficiência Adquirida dos Símios , Vírus da Imunodeficiência Símia , Células Th17 , Animais , Relação CD4-CD8 , Linfócitos T CD8-Positivos/imunologia , Linfócitos T CD8-Positivos/metabolismo , DNA Viral/sangue , DNA Viral/imunologia , Macaca mulatta , Síndrome de Imunodeficiência Adquirida dos Símios/sangue , Síndrome de Imunodeficiência Adquirida dos Símios/tratamento farmacológico , Síndrome de Imunodeficiência Adquirida dos Símios/imunologia , Vírus da Imunodeficiência Símia/imunologia , Vírus da Imunodeficiência Símia/metabolismo , Células Th17/imunologia , Células Th17/metabolismo , Fatores de Tempo
9.
Proc Natl Acad Sci U S A ; 117(18): 9981-9990, 2020 05 05.
Artigo em Inglês | MEDLINE | ID: mdl-32300019

RESUMO

HIV-1 persists in cellular reservoirs that can reignite viremia if antiretroviral therapy (ART) is interrupted. Therefore, insight into the nature of those reservoirs may be revealed from the composition of recrudescing viremia following treatment cessation. A minor population of macrophage-tropic (M-tropic) viruses was identified in a library of recombinant viruses constructed with individual envelope genes that were obtained from plasma of six individuals undergoing analytic treatment interruption (ATI). M-tropic viruses could also be enriched from post-ATI plasma using macrophage-specific (CD14) but not CD4+ T cell-specific (CD3) antibodies, suggesting that M-tropic viruses had a macrophage origin. Molecular clock analysis indicated that the establishment of M-tropic HIV-1 variants predated ATI. Collectively, these data suggest that macrophages are a viral reservoir in HIV-1-infected individuals on effective ART and that M-tropic variants can appear in rebounding viremia when treatment is interrupted. These findings have implications for the design of curative strategies for HIV-1.


Assuntos
Relógios Biológicos/genética , Infecções por HIV/genética , HIV-1/genética , Viremia/genética , Antirretrovirais/farmacologia , Terapia Antirretroviral de Alta Atividade , Linfócitos T CD4-Positivos/patologia , Infecções por HIV/patologia , Infecções por HIV/virologia , Soropositividade para HIV , HIV-1/patogenicidade , Humanos , Macrófagos/imunologia , Macrófagos/patologia , Provírus/genética , Carga Viral/genética , Viremia/patologia , Viremia/virologia
10.
Am J Pathol ; 190(7): 1530-1544, 2020 07.
Artigo em Inglês | MEDLINE | ID: mdl-32246920

RESUMO

HIV-associated sensory neuropathy is a common neurologic comorbidity of HIV infection and prevails in the post-antiretroviral therapy (ART) era. HIV infection drives pathologic changes in the dorsal root ganglia (DRG) through inflammation, altered metabolism, and neuronal dysfunction. Herein, we characterized specific neuronal populations in an SIV-infected macaque model with or without ART. DRG neuronal populations were identified by neurofilament H-chain 200, I-B4 isolectin (IB4), or tropomyosin receptor kinase A expression and assessed for cell body diameter, population size, apoptotic markers, and regeneration signaling. IB4+ and tropomyosin receptor kinase A-positive neurons showed a reduced cell body size (atrophy) and decreased population size (cell death) in the DRG of SIV-infected animals compared with uninfected animals. IB4+ nonpeptidergic neurons were less affected in the presence of ART. DRG neurons showed accumulation of cleaved caspase 3 (apoptosis) and nuclear-localized activating transcription factor 3 (regeneration) in SIV infection, which was significantly lower in uninfected animals and SIV-infected animals receiving ART. Nonpeptidergic neurons predominantly colocalized with cleaved caspase 3 staining. Nonpeptidergic and peptidergic neurons colocalized with nuclear-accumulated activating transcription factor 3, showing active regeneration in sensory neurons. These data suggest that nonpeptidergic and peptidergic neurons are susceptible to pathologic changes from SIV infection, and intervention with ART did not fully ameliorate damage to the DRG, specifically to peptidergic neurons.


Assuntos
Atrofia/patologia , Nociceptores/patologia , Síndrome de Imunodeficiência Adquirida dos Símios/patologia , Animais , Antirretrovirais/farmacologia , Gânglios Espinais/efeitos dos fármacos , Gânglios Espinais/patologia , Lectinas/metabolismo , Macaca mulatta , Masculino , Nociceptores/efeitos dos fármacos , Nociceptores/metabolismo , Polineuropatias/patologia , Polineuropatias/virologia , Receptor trkA/metabolismo , Vírus da Imunodeficiência Símia
11.
Nature ; 578(7793): 160-165, 2020 02.
Artigo em Inglês | MEDLINE | ID: mdl-31969707

RESUMO

Long-lasting, latently infected resting CD4+ T cells are the greatest obstacle to obtaining a cure for HIV infection, as these cells can persist despite decades of treatment with antiretroviral therapy (ART). Estimates indicate that more than 70 years of continuous, fully suppressive ART are needed to eliminate the HIV reservoir1. Alternatively, induction of HIV from its latent state could accelerate the decrease in the reservoir, thus reducing the time to eradication. Previous attempts to reactivate latent HIV in preclinical animal models and in clinical trials have measured HIV induction in the peripheral blood with minimal focus on tissue reservoirs and have had limited effect2-9. Here we show that activation of the non-canonical NF-κB signalling pathway by AZD5582 results in the induction of HIV and SIV RNA expression in the blood and tissues of ART-suppressed bone-marrow-liver-thymus (BLT) humanized mice and rhesus macaques infected with HIV and SIV, respectively. Analysis of resting CD4+ T cells from tissues after AZD5582 treatment revealed increased SIV RNA expression in the lymph nodes of macaques and robust induction of HIV in almost all tissues analysed in humanized mice, including the lymph nodes, thymus, bone marrow, liver and lung. This promising approach to latency reversal-in combination with appropriate tools for systemic clearance of persistent HIV infection-greatly increases opportunities for HIV eradication.


Assuntos
Infecções por HIV/virologia , HIV-1/fisiologia , NF-kappa B/metabolismo , Síndrome de Imunodeficiência Adquirida dos Símios/virologia , Vírus da Imunodeficiência Símia/fisiologia , Latência Viral , Alquinos/farmacologia , Animais , Antirretrovirais/farmacologia , Infecções por HIV/metabolismo , HIV-1/efeitos dos fármacos , Macaca mulatta , Camundongos , Oligopeptídeos/farmacologia , Síndrome de Imunodeficiência Adquirida dos Símios/metabolismo , Vírus da Imunodeficiência Símia/efeitos dos fármacos , Latência Viral/efeitos dos fármacos
12.
Curr Top Med Chem ; 20(3): 227-243, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-31976834

RESUMO

The phenylamino-pyrimidine (PAP) nucleus has been demonstrated to be useful for the development of new drugs and is present in a wide variety of antiretroviral agents and tyrosine kinase inhibitors (TKIs). This review aims to evaluate the application of PAP derivatives in drugs and other bioactive compounds. It was concluded that PAP derivatives are still worth exploring, as they may provide highly competitive ATP TKI's with nano/picomolar activity.


Assuntos
Antirretrovirais/farmacologia , HIV-1/efeitos dos fármacos , Inibidores de Proteínas Quinases/farmacologia , Proteínas Tirosina Quinases/antagonistas & inibidores , Compostos de Anilina , Antirretrovirais/química , Humanos , Estrutura Molecular , Inibidores de Proteínas Quinases/química , Proteínas Tirosina Quinases/metabolismo , Pirimidinas
13.
J Infect Dis ; 221(2): 223-231, 2020 01 02.
Artigo em Inglês | MEDLINE | ID: mdl-31504702

RESUMO

BACKGROUND: Treatment of patients coinfected with hepatitis C and human immunodeficiency viruses (HCV; HIV) requires careful consideration of potential drug-drug interactions between HCV direct-acting antiviral agents (DAA) and HIV antiretrovirals. Glecaprevir/pibrentasvir is a fixed-dose combination of an NS3/4A protease inhibitor and an NS5A inhibitor approved for the treatment of chronic HCV genotype 1-6 infection, including patients with HIV coinfection. METHODS: A series of phase 1 studies was conducted to evaluate potential interactions of glecaprevir and pibrentasvir with elvitegravir/cobicistat/emtricitabine/tenofovir alafenamide, abacavir/dolutegravir/lamivudine, raltegravir, rilpivirine, atazanavir/ritonavir, darunavir/ritonavir, lopinavir/ritonavir, or efavirenz/emtricitabine/tenofovir disoproxil fumarate. Pharmacokinetics of the antiretrovirals and DAAs were characterized when administered alone and in combination to quantify changes in systemic drug exposure. RESULTS: Glecaprevir area under the curve increased >4-fold in the presence of ritonavir-boosted HIV protease inhibitors, while pibrentasvir concentrations were not significantly affected; elevations in alanine transaminase occurred in combination with atazanavir/ritonavir only. Exposures of glecaprevir and pibrentasvir may be significantly decreased by efavirenz. Coadministration with glecaprevir and pibrentasvir did not result in clinically significant changes in the exposure of any antiretroviral agents. CONCLUSIONS: Atazanavir is contraindicated with glecaprevir/pibrentasvir and use of boosted protease inhibitors or efavirenz is not recommended. No clinically significant interactions were observed with other studied antiretrovirals.


Assuntos
Antirretrovirais/farmacologia , Benzimidazóis/farmacologia , Coinfecção/tratamento farmacológico , Interações Medicamentosas , Infecções por HIV/tratamento farmacológico , Hepatite C Crônica/tratamento farmacológico , Pirrolidinas/farmacologia , Quinoxalinas/farmacologia , Sulfonamidas/farmacologia , Adulto , Antirretrovirais/farmacocinética , Antirretrovirais/uso terapêutico , Benzimidazóis/farmacocinética , Benzimidazóis/uso terapêutico , Contraindicações de Medicamentos , Combinação de Medicamentos , Feminino , Hepatite C Crônica/complicações , Humanos , Masculino , Pirrolidinas/farmacocinética , Pirrolidinas/uso terapêutico , Quinoxalinas/farmacocinética , Quinoxalinas/uso terapêutico , Sulfonamidas/farmacocinética , Sulfonamidas/uso terapêutico
14.
Behav Med ; 46(1): 75-85, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-30908162

RESUMO

Consistent antiretroviral adherence is key to viral suppression, but many low-income people of color living with HIV are not optimally adherent due to a wide variety of interrelated social and structural factors. Previous studies have found that HIV medication beliefs are an important facet of adherence. In contrast to the AZT era , currently available antiretroviral therapies are significantly safer and more effective, but research suggests that negative beliefs may persist among racial and ethnic minority people. Twenty-seven semi-structured interviews were conducted with low-income Black and Latinx people living with HIV in New York City that were currently, or had been recently, disengaged from outpatient HIV medical care. This research suggests that socially and economically marginalized people living with HIV, many long-term survivors who lived through the AZT era, recognized that current treatments are very effective in making HIV a chronic, manageable illness and a significant improvement compared to the therapies early in the epidemic. Most importantly, the data suggests that people demonstrate great resilience despite their experiences of social and economic exclusion. Both clinical practice and public health interventions can benefit from these findings. HIV care providers should speak with patients about their beliefs related to HIV medication, and public health interventions should specifically address HIV medication-related beliefs in order to enhance adherence. In order to avoid reifying people's marginalization, public health should endeavor to recognize and support people's resilience.


Assuntos
Infecções por HIV/tratamento farmacológico , Adesão à Medicação/psicologia , Cooperação do Paciente/psicologia , Adulto , Afro-Americanos , Fármacos Anti-HIV/farmacologia , Antirretrovirais/farmacologia , Grupos Étnicos , Feminino , Conhecimentos, Atitudes e Prática em Saúde , Hispano-Americanos , Humanos , Masculino , Pessoa de Meia-Idade , Grupos Minoritários , Cidade de Nova Iorque/epidemiologia , Pobreza
15.
Med Chem ; 16(2): 141-154, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-31161997

RESUMO

BACKGROUND: Styrylquinolines are characteristic fully aromatic compounds with flat, rather lipophilic structures. The first reports on their synthesis and biological activity were published roughly a century ago. However, their low selectivity, unfavorable toxicity and problems with their mechanism of action significantly hampered their development. As a result, they have been abandoned for most of the time since they were discovered. OBJECTIVE: Their renaissance was observed by the antiretroviral activity of several styrylquinoline derivatives that have been reported to be HIV integrase inhibitors. Subsequently, other activities such as their antifungal and anticancer abilities have also been revisited. METHODS: In the present review, the spectrum of the activity of styrylquinolines and their use in drug design is presented and analyzed. RESULTS: New properties and applications that were reported recently have re-established styrylquinolines within medicinal and material chemistry. The considerable increase in the number of published papers regarding their activity spectrum will ensure further discoveries in the field. CONCLUSION: Styrylquinolines have earned a much stronger position in medicinal chemistry due to the discovery of their new activities, profound mechanisms of action and as drug candidates in clinical trials.


Assuntos
Quinolinas/química , Quinolinas/farmacologia , Animais , Anti-Infecciosos/química , Anti-Infecciosos/farmacologia , Antirretrovirais/química , Antirretrovirais/farmacologia , Antineoplásicos/química , Antineoplásicos/farmacologia , Química Farmacêutica , Humanos
16.
Sci Rep ; 9(1): 19946, 2019 12 27.
Artigo em Inglês | MEDLINE | ID: mdl-31882580

RESUMO

Persons infected with HIV are particularly vulnerable to a variety of oral microbial diseases. Although various study designs and detection approaches have been used to compare the oral microbiota of HIV-negative and HIV-positive persons, both with and without highly active antiretroviral therapy (HAART), methods have varied, and results have not been consistent or conclusive. The purpose of the present study was to compare the oral bacterial community composition in HIV-positive persons under HAART to an HIV-negative group using 16S rRNA gene sequence analysis. Extensive clinical data was collected, and efforts were made to balance the groups on clinical variables to minimize confounding. Multivariate analysis was used to assess the independent contribution of HIV status. Eighty-nine HIV-negative participants and 252 HIV-positive participants under HAART were sampled. The independent effect of HIV under HAART on the oral microbiome was statistically significant, but smaller than the effect of gingivitis, periodontal disease, smoking, caries, and other clinical variables. In conclusion, a multivariate comparison of a large sample of persons with HIV under HAART to an HIV-negative control group showed a complex set of clinical features that influenced oral bacterial community composition, including the presence of HIV under HAART.


Assuntos
Cárie Dentária/microbiologia , Infecções por HIV/microbiologia , Microbiota/efeitos dos fármacos , Adulto , Antirretrovirais/farmacologia , Terapia Antirretroviral de Alta Atividade/métodos , Contagem de Linfócito CD4/métodos , Feminino , Infecções por HIV/tratamento farmacológico , HIV-1/efeitos dos fármacos , HIV-1/patogenicidade , Humanos , Masculino , Metagenômica/métodos , Análise Multivariada , RNA Ribossômico 16S/genética
19.
J Med Internet Res ; 21(11): e15681, 2019 11 18.
Artigo em Inglês | MEDLINE | ID: mdl-31738174

RESUMO

BACKGROUND: The use of mobile communication technologies (mHealth: mobile health) in chronic disease management has grown significantly over the years. mHealth interventions have the potential to decentralize access to health care and make it convenient, particularly in resource-constrained settings. It is against this backdrop that we aimed to codevelop (with potential users) a new generation of mobile phone-connected HIV diagnostic tests and Web-based clinical care pathways needed for optimal delivery of decentralized HIV testing, prevention, and care in low- and middle-income countries. OBJECTIVE: The aim of this study was to understand ways in which an mHealth intervention could be developed to overcome barriers to existing HIV testing and care services and promote HIV self-testing and linkage to prevention and care in a poor, HIV hyperendemic community in rural KwaZulu-Natal, South Africa. METHODS: A total of 54 in-depth interviews and 9 focus group discussions were conducted with potential users (including health care providers) in 2 different communities. Theoretically informed by the candidacy framework, themes were identified from the interview transcripts, manually coded, and thematically analyzed. RESULTS: Participants reported barriers, such as fear of HIV identity, stigma, long waiting hours, clinic space, and health care workers' attitudes, as major impediments to effective uptake of HIV testing and care services. People continued to reassess their candidacy for HIV testing and care services on the basis of their experiences and how they or others were treated within the health systems. Despite the few concerns raised about new technology, mobile phone-linked HIV testing was broadly acceptable to potential users (particularly men and young people) and providers because of its privacy (individual control of HIV testing over health provider-initiated testing), convenience (individual time and place of choice for HIV testing versus clinic-based testing), and time saving. CONCLUSIONS: Mobile phone-connected HIV testing and Web-based clinical care and prevention pathways have the potential to support access to HIV prevention and care, particularly for young people and men. Although mHealth provides a way for individuals to test their candidacy for HIV services, the barriers that can make the service unattractive at the clinic level will also need to be addressed if potential demand is to turn into actual demand.


Assuntos
Antirretrovirais/uso terapêutico , Telefone Celular/instrumentação , Infecções por HIV/prevenção & controle , Programas de Rastreamento/métodos , Telemedicina/métodos , Adolescente , Adulto , Antirretrovirais/farmacologia , Feminino , Humanos , Masculino , Pesquisa Qualitativa , População Rural , África do Sul
20.
Cell Rep ; 29(9): 2783-2795.e5, 2019 11 26.
Artigo em Inglês | MEDLINE | ID: mdl-31775045

RESUMO

Latent proviruses persist in central (TCM), transitional (TTM), and effector (TEM) memory cells. We measured the levels of cellular factors involved in HIV gene expression in these subsets. The highest levels of acetylated H4, active nuclear factor κB (NF-κB), and active positive transcription elongation factor b (P-TEFb) were measured in TEM, TCM, and TTM cells, respectively. Vorinostat and romidepsin display opposite abilities to induce H4 acetylation across subsets. Protein kinase C (PKC) agonists are more efficient at inducing NF-κB phosphorylation in TCM cells but more potent at activating PTEF-b in the TEM subset. We selected the most efficient latency-reversing agents (LRAs) and measured their ability to reverse latency in each subset. While ingenol alone has modest activities in the three subsets, its combination with a histone deacetylase inhibitor (HDACi) dramatically increases latency reversal in TCM cells. Altogether, these results indicate that cellular HIV reservoirs are differentially responsive to common LRAs and suggest that combination of compounds will be required to achieve latency reversal in all subsets.


Assuntos
Antirretrovirais/uso terapêutico , Linfócitos T CD4-Positivos/metabolismo , Infecções por HIV/virologia , Antirretrovirais/farmacologia , Humanos
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA
...