Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 82.003
Filtrar
1.
AIDS Res Ther ; 18(1): 58, 2021 09 08.
Artigo em Inglês | MEDLINE | ID: mdl-34496848

RESUMO

OBJECTIVE: The DUALIS study showed that switching to boosted darunavir (bDRV) plus dolutegravir (DTG; 2DR) was non-inferior to continuous bDRV plus 2 nucleoside/nucleotide reverse-transcriptase inhibitors (NRTIs; 3DR) in treatment-experienced virologically suppressed people living with HIV (PLWH). We analyzed virologic outcomes with respect to treatment history and HIV drug resistance. DESIGN: Post hoc analysis of a randomized trial. METHODS: Main inclusion criteria were an HIV RNA level < 50 copies/mL for ≥ 24 weeks and no resistance to integrase strand transfer inhibitors or bDRV. Resistance-associated mutations (RAMs) were interpreted using the Stanford HIVdb mutation list. Outcomes measures were 48-week virologic response (HIV RNA < 50 copies/mL, FDA snapshot) and HIV RNA ≥ 50 copies/mL (including discontinuation due to a lack of efficacy or reasons other than adverse events and HIV RNA ≥ 50 copies/mL, referred to as snapshot non-response). RESULTS: The analysis population included 263 patients (2DR: 131, 3DR: 132): 90.1% males; median age, 48 years; CD4 + T-cell nadir < 200/µl, 47.0%; ≥ 2 treatment changes, 27.4%; NRTI, non-NRTI (NNRTI), and major protease inhibitor (PI) RAMs in 9.5%, 14.4%, and 3.4%, respectively. In patients with RAMs in the 2DR and 3DR groups, virologic response rates were 87.8% and 96.0%, respectively; the corresponding rates in those without RAMs were 85.7% and 81.8%. RAMs were unrelated to virologic non-response in either group. No treatment-emergent RAMs were observed. CONCLUSIONS: DTG + bDRV is an effective treatment option without the risk of treatment-emergent resistance for PLWH on suppressive first- or further-line treatment with or without evidence of pre-existing NRTI, NNRTI, or PI RAMs. TRIAL REGISTRATION: EUDRA-CT Number 2015-000360-34; registered 07 April 2015; https://www.clinicaltrialsregister.eu/ctr-search/trial/2015-000360-34/DE .


Assuntos
Fármacos Anti-HIV , Infecções por HIV , HIV-1 , Fármacos Anti-HIV/uso terapêutico , Darunavir/uso terapêutico , Resistência a Medicamentos , Feminino , Infecções por HIV/tratamento farmacológico , HIV-1/genética , Compostos Heterocíclicos com 3 Anéis , Humanos , Masculino , Pessoa de Meia-Idade , Oxazinas , Piperazinas , Piridonas
2.
J Pak Med Assoc ; 71(Suppl 4)(8): S26-S29, 2021 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-34469425

RESUMO

OBJECTIVE: To estimate the probability of human immunodeficiency virus (HIV)-1 transmission from different key HIV population groups using probabilistic modelling. Methods: This study was conducted in December 2020. A probabilistic model was used to estimate the probability of HIV-1 transmission from different key HIV population groups in Larkana. Our model was run on three probabilistic assumptions: 1) each replication gave two conceivable results: 'true' or 'false'; 2) the chance of giving a 'true' result is the same for each replication; and 3) the replications are independent - 'true' in one will not impact the likelihood of 'true' in another. RESULTS: The results estimated the probability of HIV transmission in key HIV population groups in Larkana to range between 0.42-0.54 per trial, where the highest probability of transmission was predicted for men who have sex with men (MSM; 0.54 per trial), followed by transgender (TG; 0.46 per trial) and people who inject drugs (PWID; 0.457 per trial). CONCLUSIONS: Our results suggest that there is a high likelihood of HIV transmission by key population groups in Larkana, such as MSM, TG, and PWID. Mathematic models, such as one proposed in our study can aid the HIV and acquired immunodeficiency syndrome (AIDS) control programmes in evaluating and optimising the strategies in controlling transmission of HIV from the key population groups.


Assuntos
Infecções por HIV , HIV-1 , Minorias Sexuais e de Gênero , Abuso de Substâncias por Via Intravenosa , Infecções por HIV/epidemiologia , Homossexualidade Masculina , Humanos , Masculino , Paquistão/epidemiologia , Grupos Populacionais
3.
AIDS Res Ther ; 18(1): 57, 2021 09 06.
Artigo em Inglês | MEDLINE | ID: mdl-34488812

RESUMO

INTRODUCTION: Although individual antiretroviral drugs have been shown to be associated with elevated cardiovascular disease (CVD) risk, data are limited on the role of antiretroviral drug combinations. Therefore, we sought to investigate CVD risk associated with antiretroviral drug combinations. METHODS: Using an administrative health-plan dataset, risk of acute myocardial infarction (AMI) associated with current exposure to antiretroviral drug combinations was assessed among persons living with HIV receiving antiretroviral therapy (ART) across the U.S. from October 2009 through December 2014. To account for confounding-by-indication and for factors simultaneously acting as causal mediators and confounders, we applied inverse probability of treatment weighted marginal structural models to longitudinal data of patients. RESULTS: Over 114,417 person-years (n = 73,071 persons) of ART exposure, 602 cases of AMI occurred at an event rate of 5.26 (95% CI: 4.86, 5.70)/1000 person-years. Of the 14 antiretroviral drug combinations studied, persons taking abacavir-lamivudine-darunavir had the highest incidence rate (IR: 11/1000; 95% CI: 7.4-16.0) of AMI. Risk (HR; 95% CI) of AMI was elevated for current exposure to abacavir-lamivudine-darunavir (1.91; 1.27-2.88), abacavir-lamivudine-atazanavir (1.58; 1.08-2.31), and tenofovir-emtricitabine-raltegravir (1.35; 1.07-1.71). Tenofovir-emtricitabine-efavirenz was associated with reduced risk (0.65; 0.54-0.78). Abacavir-lamivudine-darunavir was associated with increased risk of AMI beyond that expected of abacavir alone, likely attributable to darunavir co-administration. We did not find an elevated risk of AMI when abacavir-lamivudine was combined with efavirenz or raltegravir. CONCLUSION: The antiretroviral drug combinations abacavir-lamivudine-darunavir, abacavir-lamivudine-atazanavir and tenofovir-emtricitabine-raltegravir were found to be associated with elevated risk of AMI, while tenofovir-emtricitabine-efavirenz was associated with a lower risk. The AMI risk associated with abacavir-lamivudine-darunavir was greater than what was previously described for abacavir, which could suggest an added risk from darunavir. The results should be confirmed in additional studies.


Assuntos
Fármacos Anti-HIV , Infecções por HIV , HIV-1 , Infarto do Miocárdio , Fármacos Anti-HIV/efeitos adversos , Didesoxinucleosídeos/efeitos adversos , Combinação de Medicamentos , Infecções por HIV/tratamento farmacológico , Infecções por HIV/epidemiologia , Humanos , Lamivudina/uso terapêutico , Infarto do Miocárdio/induzido quimicamente , Infarto do Miocárdio/tratamento farmacológico , Infarto do Miocárdio/epidemiologia , Tenofovir/efeitos adversos , Estados Unidos/epidemiologia
4.
Nat Commun ; 12(1): 4817, 2021 08 10.
Artigo em Inglês | MEDLINE | ID: mdl-34376662

RESUMO

Engineered ectodomain trimer immunogens based on BG505 envelope glycoprotein are widely utilized as components of HIV vaccine development platforms. In this study, we used rhesus macaques to evaluate the immunogenicity of several stabilized BG505 SOSIP constructs both as free trimers and presented on a nanoparticle. We applied a cryoEM-based method for high-resolution mapping of polyclonal antibody responses elicited in immunized animals (cryoEMPEM). Mutational analysis coupled with neutralization assays were used to probe the neutralization potential at each epitope. We demonstrate that cryoEMPEM data can be used for rapid, high-resolution analysis of polyclonal antibody responses without the need for monoclonal antibody isolation. This approach allowed to resolve structurally distinct classes of antibodies that bind overlapping sites. In addition to comprehensive mapping of commonly targeted neutralizing and non-neutralizing epitopes in BG505 SOSIP immunogens, our analysis revealed that epitopes comprising engineered stabilizing mutations and of partially occupied glycosylation sites can be immunogenic.


Assuntos
Vacinas contra a AIDS/imunologia , Anticorpos Monoclonais/imunologia , Anticorpos Neutralizantes/imunologia , Formação de Anticorpos/imunologia , Anticorpos Anti-HIV/imunologia , Produtos do Gene env do Vírus da Imunodeficiência Humana/imunologia , Animais , Anticorpos Monoclonais/química , Anticorpos Monoclonais/ultraestrutura , Anticorpos Neutralizantes/química , Anticorpos Neutralizantes/ultraestrutura , Microscopia Crioeletrônica/métodos , Epitopos/química , Epitopos/imunologia , Epitopos/metabolismo , Glicosilação , Anticorpos Anti-HIV/química , Anticorpos Anti-HIV/ultraestrutura , Infecções por HIV/imunologia , Infecções por HIV/prevenção & controle , Infecções por HIV/virologia , HIV-1/genética , HIV-1/imunologia , HIV-1/metabolismo , Humanos , Macaca mulatta , Modelos Moleculares , Conformação Proteica , Produtos do Gene env do Vírus da Imunodeficiência Humana/ultraestrutura
5.
J Immunol ; 207(5): 1239-1249, 2021 09 01.
Artigo em Inglês | MEDLINE | ID: mdl-34389623

RESUMO

HIV-1 infection substantially increases the risk of developing tuberculosis (TB). Mechanisms such as defects in the Th1 response to Mycobacterium tuberculosis in HIV-infected persons have been widely reported. However, Th1-independent mechanisms also contribute to protection against TB. To identify a broader spectrum of defects in TB immunity during HIV infection, we examined IL-17A and IL-22 production in response to mycobacterial Ags in peripheral blood of persons with latent TB infection and HIV coinfection. Upon stimulating with mycobacterial Ags, we observed a distinct CD4+ Th lineage producing IL-22 in the absence of IL-17A and IFN-γ. Mycobacteria-specific Th22 cells were present at high frequencies in blood and contributed up to 50% to the CD4+ T cell response to mycobacteria, comparable in magnitude to the IFN-γ Th1 response (median 0.91% and 0.55%, respectively). Phenotypic characterization of Th22 cells revealed that their memory differentiation was similar to M. tuberculosis-specific Th1 cells (i.e., predominantly early differentiated CD45RO+CD27+ phenotype). Moreover, CCR6 and CXCR3 expression profiles of Th22 cells were similar to Th17 cells, whereas their CCR4 and CCR10 expression patterns displayed an intermediate phenotype between Th1 and Th17 cells. Strikingly, mycobacterial IL-22 responses were 3-fold lower in HIV-infected persons compared with uninfected persons, and the magnitude of responses correlated inversely with HIV viral load. These data provide important insights into mycobacteria-specific Th subsets in humans and suggest a potential role for IL-22 in protection against TB during HIV infection. Further studies are needed to fully elucidate the role of IL-22 in protective TB immunity.


Assuntos
Linfócitos T CD4-Positivos/imunologia , Infecções por HIV/imunologia , HIV-1/fisiologia , Interleucinas/metabolismo , Tuberculose Latente/imunologia , Mycobacterium tuberculosis/fisiologia , Subpopulações de Linfócitos T/imunologia , Adulto , Células Cultivadas , Coinfecção , Feminino , Soropositividade para HIV , Humanos , Interleucina-17/metabolismo , Masculino , África do Sul , Carga Viral , Adulto Jovem
6.
Int J Mol Sci ; 22(16)2021 Aug 04.
Artigo em Inglês | MEDLINE | ID: mdl-34445073

RESUMO

Human immunodeficiency virus (HIV-1) is still a major problem, not only in developing countries but is also re-emerging in several developed countries, thus the development of new compounds able to inhibit the virus, either for prophylaxis or treatment, is still needed. Nanotechnology has provided the science community with several new tools for biomedical applications. G2-S16 is a polyanionic carbosilane dendrimer capable of inhibiting HIV-1 in vitro and in vivo by interacting directly with viral particles. One of the main barriers for HIV-1 eradication is the reservoirs created in primoinfection. These reservoirs, mainly in T cells, are untargetable by actual drugs or immune system. Thus, one approach is inhibiting HIV-1 from reaching these reservoir cells. In this context, macrophages play a main role as they can deliver viral particles to T cells establishing reservoirs. We showed that G2-S16 dendrimer is capable of inhibiting the infection from infected macrophages to healthy T CD4/CD8 lymphocytes by eliminating HIV-1 infectivity inside macrophages, so they are not able to carry infectious particles to other body locations, thus preventing the reservoirs from forming.


Assuntos
Alcanossulfonatos/farmacologia , Fármacos Anti-HIV/farmacologia , Dendrímeros/farmacologia , Infecções por HIV/tratamento farmacológico , HIV-1/efeitos dos fármacos , Macrófagos/efeitos dos fármacos , Compostos de Organossilício/farmacologia , Silanos/farmacologia , Linhagem Celular , Células Cultivadas , Infecções por HIV/transmissão , Humanos , Macrófagos/virologia , Polieletrólitos/farmacologia
7.
Sci Transl Med ; 13(607)2021 08 18.
Artigo em Inglês | MEDLINE | ID: mdl-34408080

RESUMO

Anti-HIV broadly neutralizing antibodies (bNAbs) may favor development of antiviral immunity by engaging the immune system during immunotherapy. Targeting integrin α4ß7 with an anti-α4ß7 monoclonal antibody (Rh-α4ß7) affects immune responses in SIV/SHIV-infected macaques. To explore the therapeutic potential of combining bNAbs with α4ß7 integrin blockade, SHIVSF162P3-infected, viremic rhesus macaques were treated with bNAbs only (VRC07-523LS and PGT128 anti-HIV antibodies) or a combination of bNAbs and Rh-α4ß7 or were left untreated as a control. Treatment with bNAbs alone decreased viremia below 200 copies/ml in all macaques, but seven of eight macaques (87.5%) in the bNAbs-only group rebounded within a median of 3 weeks (95% CI: 2 to 9). In contrast, three of six macaques treated with a combination of Rh-α4ß7 and bNAbs (50%) maintained a viremia below 200 copies/ml until the end of the follow-up period; viremia in the other three macaques rebounded within a median of 6 weeks (95% CI: 5 to 11). Thus, there was a modest delay in viral rebound in the macaques treated with the combination antibody therapy compared to bNAbs alone. Our study suggests that α4ß7 integrin blockade may prolong virologic control by bNAbs in SHIVSF162P3-infected macaques.


Assuntos
Infecções por HIV , HIV-1 , Síndrome de Imunodeficiência Adquirida dos Símios , Vírus da Imunodeficiência Símia , Animais , Anticorpos Neutralizantes , Anticorpos Antivirais , Anticorpos Amplamente Neutralizantes , Anticorpos Anti-HIV , Infecções por HIV/tratamento farmacológico , Integrinas , Macaca mulatta , Síndrome de Imunodeficiência Adquirida dos Símios/tratamento farmacológico
8.
Science ; 373(6555): 621-622, 2021 08 06.
Artigo em Inglês | MEDLINE | ID: mdl-34353938
9.
Ann Palliat Med ; 10(7): 7775-7785, 2021 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-34353064

RESUMO

BACKGROUND: It is largely unknown how frequently minor HIV drug-resistant variants at levels under limit of detection of conventional genotyping are present in patients experiencing virological failure (VF). Further, the clinical implications of minor drug-resistant variants at time of virologic failure are unknown. METHODS: Fifteen patients experiencing VF on a first-line regimen were evaluated by high-throughput sequencing and compared with the conventional Sanger genotype drug resistance detection method. RESULTS: NRTI drug resistant mutations (DRMs) were detected in a high proportion of subjects, with the most common being M184V and TAMs. Minor resistant mutations accounted for 19.27% of the total drug-resistant mutations in patients with VF. A mean of 1.7 additional mutations per subject were detected by high-throughput sequencing, the difference was statistically significant, and those additional low-abundance drug-resistant mutations increased the genotypic resistance scores in 10 of 11 subjects (90.9%). Among persons experiencing VF, minor variants possessing major PI (protease inhibitor) DRMs were present in a minority of cases, which was also the case in ARV-naive subjects, and suggests PIs may be effective in subjects experiencing VF on subsequent second-line PI-based antiretroviral regimen. The high-throughput sequencing results of mutations between ART failure subjects and treatment naïve subjects were also compared. Three novel mutations were then screened with higher frequencies in the ART failure subjects. CONCLUSIONS: It is important to guide the replacement of treatment programs and screening for new drug-resistant mutation sites, and the use of high-throughput sequencing methods can more comprehensively study the characteristics of drug-resistant viral variants of patients experiencing VF on a first-line regimen.


Assuntos
Fármacos Anti-HIV , Infecções por HIV , HIV-1 , Preparações Farmacêuticas , Fármacos Anti-HIV/uso terapêutico , Farmacorresistência Viral/genética , Infecções por HIV/tratamento farmacológico , HIV-1/genética , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Carga Viral
10.
Science ; 373(6555): 700-704, 2021 08 06.
Artigo em Inglês | MEDLINE | ID: mdl-34353956

RESUMO

Gag, the primary structural protein of HIV-1, is recruited to the plasma membrane for virus assembly by its matrix (MA) domain. Gag is subsequently cleaved into its component domains, causing structural maturation to repurpose the virion for cell entry. We determined the structure and arrangement of MA within immature and mature HIV-1 through cryo-electron tomography. We found that MA rearranges between two different hexameric lattices upon maturation. In mature HIV-1, a lipid extends out of the membrane to bind with a pocket in MA. Our data suggest that proteolytic maturation of HIV-1 not only assembles the viral capsid surrounding the genome but also repurposes the membrane-bound MA lattice for an entry or postentry function and results in the partial removal of up to 2500 lipids from the viral membrane.


Assuntos
Antígenos HIV/química , Antígenos HIV/metabolismo , HIV-1/química , HIV-1/fisiologia , Envelope Viral/metabolismo , Produtos do Gene gag do Vírus da Imunodeficiência Humana/química , Produtos do Gene gag do Vírus da Imunodeficiência Humana/metabolismo , Capsídeo/química , Capsídeo/fisiologia , Tomografia com Microscopia Eletrônica , HIV-1/ultraestrutura , Bicamadas Lipídicas , Lipídeos de Membrana/metabolismo , Modelos Moleculares , Conformação Proteica , Domínios Proteicos , Estrutura Secundária de Proteína , Envelope Viral/química , Envelope Viral/ultraestrutura , Vírion/química , Vírion/fisiologia , Vírion/ultraestrutura , Montagem de Vírus , Produtos do Gene env do Vírus da Imunodeficiência Humana/química , Produtos do Gene env do Vírus da Imunodeficiência Humana/metabolismo
11.
Health Qual Life Outcomes ; 19(1): 201, 2021 Aug 23.
Artigo em Inglês | MEDLINE | ID: mdl-34425825

RESUMO

BACKGROUND: There is limited evidence regarding oral health related quality of life of HIV positive populations in sub-Saharan Africa. Focusing HIV positive- and HIV negative Ugandan mothers, this study assessed the influence of HIV status on oral health related quality of life in terms of oral impacts on daily performances, whilst adjusting for clinical- and socio-behavioural factors. We also examined whether any association of clinical and socio-behavioural factors with oral impacts on daily performances vary according to mothers' HIV status. METHODS: This cross-sectional study used data from a trial (n = 164) and a comparison group (n = 181). The trial comprised of mothers with HIV-1 participating in the ANRS 121741-PROMISE-PEP-trial (NCT00640263) conducted between 2009 and 2013 and from the ANRS 12341-PROMISE-PEP-M&S follow-up study conducted in 2017. The comparison group comprised of HIV negative mothers recruited in 2017. Interviews and clinical oral examinations were performed. The oral health related quality of life was assessed using the oral impacts on daily performances frequency scale. Caries experience and gingival bleeding were assessed using the World Health Organization's Decayed, Missed and Filled teeth indices and community periodontal index. Logistic and negative binomial regression analyses were performed. RESULTS: 29% of HIV-1 positive and 32% among the comparison reported any oral impact on daily performance. In adjusted logistic regression analysis, HIV status was not significantly associated with oral impacts on daily performances. Mother's self-reported oral health, caries experience, gingival bleeding and oral health related quality of life of their children were independently associated with oral impacts on daily performances. Corresponding prevalence ratios and 95% confidence intervals were: 0.3 (0.2-0.6), 1.8 (1.0-3.2), 1.1 (1.0-1.1), and 2.1 (1.1-4.3). No significant interaction between HIV status and covariates were observed. CONCLUSIONS: Oral health related quality of life was substantially impaired in Ugandan mothers but did not discriminate between HIV positive and negative participants. Mothers with impaired oral health related quality of life were more likely to have dental caries and children with impaired oral health related quality of life. HIV positive and negative mothers in Uganda deserve special attention regarding their oral disease and quality of life status.


Assuntos
Cárie Dentária/psicologia , Infecções por HIV/psicologia , Mães/psicologia , Saúde Bucal , Qualidade de Vida/psicologia , Criança , Estudos Transversais , Assistência Odontológica/estatística & dados numéricos , Cárie Dentária/epidemiologia , Feminino , Seguimentos , HIV-1 , Humanos , Mães/estatística & dados numéricos , Higiene Bucal/estatística & dados numéricos , Prevalência , Uganda/epidemiologia
12.
Top Antivir Med ; 29(3): 355-360, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34370417

RESUMO

The Conference on Retroviruses and Opportunistic Infections (CROI) serves as one of the most highly visible platforms upon which researchers gather to share the most recent findings on HIV/AIDS and, recently, on SARS-CoV-2 research. Research presentations on the novel coronavirus SARS-CoV-2 have become an increasing fixture at the conference since it was first covered at last year's conference. Although CROI 2021 was virtual, the organizers coordinated a seamless platform for presentations and poster sessions that effectively engaged the audience. CROI 2021 had a strong showing in terms of basic science presentations on HIV-1 and on SARS-CoV-2. Highlights included new insights into some of the more elusive steps in the viral replication cycle as well as new findings on immune escape strategies employed by SARS-CoV-2. The new investigator workshop has become a valuable resource that can be used by early stage and established investigators alike to receive state-of-the-art updates on research areas that might be outside their immediate areas of research. The new investigator workshop featured engaging presentations on novel aspects of HIV-1 and SARS-CoV-2 replication, impact of host immunity on HIV-1 and SARS-CoV-2, and approaches to assessing viral reservoir dynamics and strategies for viral reservoir elimination.


Assuntos
Pesquisa Biomédica , Congressos como Assunto , HIV-1/imunologia , SARS-CoV-2/imunologia , HIV-1/fisiologia , Humanos , SARS-CoV-2/fisiologia , Latência Viral
14.
Molecules ; 26(16)2021 Aug 06.
Artigo em Inglês | MEDLINE | ID: mdl-34443358

RESUMO

Plants are the everlasting source of a wide spectrum of specialized metabolites, characterized by wide variability in term of chemical structures and different biological properties such antiviral activity. In the search for novel antiviral agents against Human Immunodeficiency Virus type 1 (HIV-1) from plants, the phytochemical investigation of Scrophularia trifoliata L. led us to isolate and characterize four flavonols glycosides along with nine iridoid glycosides, two of them, 5 and 13, described for the first time. In the present study, we investigated, for the first time, the contents of a methanol extract of S. trifoliata leaves, in order to explore the potential antiviral activity against HIV-1. The antiviral activity was evaluated in biochemical assays for the inhibition of HIV-1Reverse Transcriptase (RT)-associated Ribonuclease H (RNase H) activity and HIV-1 Integrase (IN). Three isolated flavonoids, rutin, kaempferol-7-O-rhamnosyl-3-O-glucopyranoside, and kaempferol-3-O-glucopyranoside, 8-10, inhibited specifically the HIV-1 IN activity at submicromolar concentration, with the latter being the most potent, showing an IC50 value of 24 nM.


Assuntos
Flavonóis/química , Flavonóis/farmacologia , HIV-1/efeitos dos fármacos , Iridoides/química , Iridoides/farmacologia , Scrophularia/química , Fármacos Anti-HIV/química , Fármacos Anti-HIV/farmacologia , Concentração Inibidora 50 , Folhas de Planta/química
15.
Nat Commun ; 12(1): 4996, 2021 08 17.
Artigo em Inglês | MEDLINE | ID: mdl-34404793

RESUMO

Between 10 and 20 million people worldwide are infected with the human T-cell lymphotropic virus type 1 (HTLV-1). Despite causing life-threatening pathologies there is no therapeutic regimen for this deltaretrovirus. Here, we screened a library of integrase strand transfer inhibitor (INSTI) candidates built around several chemical scaffolds to determine their effectiveness in limiting HTLV-1 infection. Naphthyridines with substituents in position 6 emerged as the most potent compounds against HTLV-1, with XZ450 having highest efficacy in vitro. Using single-particle cryo-electron microscopy we visualised XZ450 as well as the clinical HIV-1 INSTIs raltegravir and bictegravir bound to the active site of the deltaretroviral intasome. The structures reveal subtle differences in the coordination environment of the Mg2+ ion pair involved in the interaction with the INSTIs. Our results elucidate the binding of INSTIs to the HTLV-1 intasome and support their use for pre-exposure prophylaxis and possibly future treatment of HTLV-1 infection.


Assuntos
Antivirais/química , Antivirais/farmacologia , Microscopia Crioeletrônica , Infecções por HTLV-I/tratamento farmacológico , Vírus Linfotrópico T Tipo 1 Humano/efeitos dos fármacos , Amidas , Domínio Catalítico , Deltaretrovirus , Farmacorresistência Viral/efeitos dos fármacos , Integrase de HIV/efeitos dos fármacos , HIV-1 , Compostos Heterocíclicos com 3 Anéis , Vírus Linfotrópico T Tipo 1 Humano/genética , Humanos , Naftiridinas/farmacologia , Piperazinas , Piridonas , Proteínas Recombinantes
16.
Mikrobiyol Bul ; 55(3): 426-434, 2021 Jul.
Artigo em Turco | MEDLINE | ID: mdl-34416807

RESUMO

Human T-lymphotropic virus-I/II (HTLV-I/II) and human immun viruses (HIVs), that have similar genomic characteristics also share the same transmission routes and infect T lymphocytes. Regarding this epidemiological similarity, HIV and HTLV infections can be seen together. HIV and HTLV-I/II coinfection occurs with variable frequencies in different populations and geographic regions. There are not any population-based studies carried out defining the number of individuals coinfected with HIV and HTLV-I/II in Turkey. The aim of this study was to determine the seropositivity rates of HTLV-I/II in patients whose HIV viral load was monitored in Gazi University Faculty of Medicine Medical Virology Laboratory Forty-seven HIV positive cases followed-up in Medical Virology Laboratory for HIV viral load monitoring between May 2017-January 2019 were included in the study. HIV seropositivity of the samples was confirmed by the chemiluminescence microparticle immunoassay method. HIV viral load values of the samples were evaluated by real-time reverse transcriptase polymerase chain reaction. The samples were screened for antibodies against HTLV-I/II using chemiluminescent microparticle immunoassay. The study population range was between 19 to 60 years of age. Among the study population, 39 (83%) patients were male and 8 (17%) patients were female. Of 47 samples, 18 samples (38.3%) had viral load of <1000 copies/ml, 10 samples (21.3%) had viral load of 1000-10000 copies/ml, 19 samples (40.4%) had viral load of ≥10000 copies/ml. HTLV serology was negative in all samples included in the study. CD4+ results were available for 42 patients and the CD4+ results of five patients could not be studied. Co-infection with different retroviruses is a well-known fact which should be thoroughly examined. HTLV-I co-infection leads to faster progression of the disease in HIV-1 positive patients. Although it is known that the co-infection has a significant effect on the progression of the disease, there are very few centers in the world and in our country that routinely perform HTLV testing in HIV-positive patients. We think that in order to evaluate the clinical and microbiological importance of the coinfection of retroviruses with each other and to determine the frequency of these infections together, there is a need for studies involving a larger number of patients, including detailed clinical backgrounds of individuals, and that the importance of this issue should be realized at the same time.


Assuntos
Infecções por HIV , HIV-1 , Vírus Linfotrópico T Tipo 1 Humano , Feminino , Infecções por HIV/complicações , Infecções por HIV/epidemiologia , HIV-1/genética , Vírus Linfotrópico T Tipo 1 Humano/genética , Vírus Linfotrópico T Tipo 2 Humano/genética , Humanos , Masculino , Reação em Cadeia da Polimerase Via Transcriptase Reversa
17.
Curr Opin HIV AIDS ; 16(5): 241-242, 2021 09 01.
Artigo em Inglês | MEDLINE | ID: mdl-34334613
18.
Int J Mol Sci ; 22(15)2021 Jul 29.
Artigo em Inglês | MEDLINE | ID: mdl-34360891

RESUMO

Globally, HIV/AIDS and cancer are increasingly public health problems and continue to exist as comorbidities. The sub-Saharan African region has the largest number of HIV infections. Malignancies previously associated with HIV/AIDS, also known as the AIDS-defining cancers (ADCs) have been documented to decrease, while the non-AIDS defining cancer (NADCs) are on the rise. On the other hand, cancer is a highly heterogeneous disease and precision oncology as the most effective cancer therapy is gaining attraction. Among HIV-infected individuals, the increased risk for developing cancer is due to the immune system of the patient being suppressed, frequent coinfection with oncogenic viruses and an increase in risky behavior such as poor lifestyle. The core of personalised medicine for cancer depends on the discovery and the development of biomarkers. Biomarkers are specific and highly sensitive markers that reveal information that aid in leading to the diagnosis, prognosis and therapy of the disease. This review focuses mainly on the risk assessment, diagnostic, prognostic and therapeutic role of various cancer biomarkers in HIV-positive patients. A careful selection of sensitive and specific HIV-associated cancer biomarkers is required to identify patients at most risk of tumour development, thus improving the diagnosis and prognosis of the disease.


Assuntos
Síndrome de Imunodeficiência Adquirida/diagnóstico , Síndrome de Imunodeficiência Adquirida/epidemiologia , HIV-1 , Neoplasias/diagnóstico , Neoplasias/epidemiologia , Síndrome de Imunodeficiência Adquirida/tratamento farmacológico , Síndrome de Imunodeficiência Adquirida/virologia , Terapia Antirretroviral de Alta Atividade/métodos , Biomarcadores Tumorais/classificação , Biomarcadores Tumorais/genética , Biomarcadores Tumorais/metabolismo , Comorbidade , Detecção Precoce de Câncer , Feminino , Humanos , Masculino , Neoplasias/genética , Neoplasias/metabolismo , Vírus Oncogênicos , Medicina de Precisão/métodos , Prevalência , Prognóstico , Medição de Risco , Fatores de Risco , Resultado do Tratamento
19.
Arch Virol ; 166(10): 2853-2857, 2021 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-34373969

RESUMO

Strains of the HIV-1 circulating recombinant forms (CRFs) 06_cpx and 56_cpx were identified for the first time in Guangzhou, China. The nearly full-length genome (NFLG) sequence was amplified, and the PCR products were sequenced by the Sanger method. The CRF06_cpx and CRF56_cpx strains were identified using the Basic Local Alignment Search Tool (BLAST) and confirmed by neighbour-joining (NJ) phylogenetic analysis. Additionally, these strains were found to contain transmitted drug resistance mutations that have little effect on first-line efavirenz (EFV)-based treatment. Genetic analysis of the detailed sequence data will provide more information on the HIV-1 epidemic in China.


Assuntos
Infecções por HIV/virologia , HIV-1/genética , Adulto , China/epidemiologia , Cidades/epidemiologia , Farmacorresistência Viral/genética , Feminino , Genoma Viral/genética , Genótipo , Infecções por HIV/epidemiologia , HIV-1/classificação , HIV-1/isolamento & purificação , Humanos , Masculino , Mutação , Filogenia , Recombinação Genética , Produtos do Gene pol do Vírus da Imunodeficiência Humana/genética
20.
Acc Chem Res ; 54(17): 3349-3361, 2021 09 07.
Artigo em Inglês | MEDLINE | ID: mdl-34403258

RESUMO

Treatment of HIV-1 has largely involved targeting viral enzymes using a cocktail of inhibitors. However, resistance to these inhibitors and toxicity in the long term have pushed the field to identify new therapeutic targets. To that end, -1 programmed ribosomal frameshifting (-1 PRF) has gained attention as a potential node for therapeutic intervention. In this process, a ribosome moves one nucleotide backward in the course of translating a mRNA, revealing a new reading frame for protein synthesis. In HIV-1, -1 PRF allows the virus to regulate the ratios of enzymatic and structural proteins as needed for correct viral particle assembly. Two RNA structural elements are central to -1 PRF in HIV: a slippery sequence and a highly conserved stable hairpin called the HIV-1 frameshifting stimulatory signal (FSS). Dysregulation of -1 PRF is deleterious for the virus. Thus, -1 PRF is an attractive target for new antiviral development. It is important to note that HIV-1 is not the only virus exploiting -1 PRF for regulating production of its proteins. Coronaviruses, including the COVID-19 pandemic virus SARS-CoV-2, also rely on -1 PRF. In SARS-CoV-2 and other coronaviruses, -1 PRF is required for synthesis of RNA-dependent RNA polymerase and several other nonstructural proteins. Coronaviruses employ a more complex RNA structural element for regulating -1 PRF called a pseudoknot. The purpose of this Account is primarily to review the development of molecules targeting HIV-1 -1 PRF. These approaches are case studies illustrating how the entire pipeline from screening to the generation of high-affinity leads might be implemented. We consider both target-based and function-based screening, with a particular focus on our group's approach beginning with a resin-bound dynamic combinatorial library (RBDCL) screen. We then used rational design approaches to optimize binding affinity, selectivity, and cellular bioavailability. Our tactic is, to the best of our knowledge, the only study resulting in compounds that bind specifically to the HIV-1 FSS RNA and reduce infectivity of laboratory and drug-resistant strains of HIV-1 in human cells. Lessons learned from strategies targeting -1 PRF HIV-1 might provide solutions in the development of antivirals in areas of unmet medical need. This includes the development of new frameshift-altering therapies for SARS-CoV-2, approaches to which are very recently beginning to appear.


Assuntos
Antivirais/farmacologia , HIV-1/efeitos dos fármacos , SARS-CoV-2/efeitos dos fármacos , Antivirais/química , Técnicas de Química Combinatória , Mudança da Fase de Leitura do Gene Ribossômico/efeitos dos fármacos , Humanos , Testes de Sensibilidade Microbiana
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA
...