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1.
AAPS PharmSciTech ; 22(5): 171, 2021 Jun 07.
Artigo em Inglês | MEDLINE | ID: mdl-34100170

RESUMO

Macrophages act as a cellular reservoir in HIV infection. Elimination of HIV from macrophages has been an unfulfilled dream due to the failure of drugs to reach them. To address this, we developed CD44 receptor-targeted, novel hyaluronic acid (HA)-coated nanostructured lipid carriers (NLCs) of efavirenz via washless layer-by-layer (LbL) assembly of HA and polyallylamine hydrochloride (PAH). NLCs were subjected to TEM analysis, size and zeta potential, in vitro release and encapsulation efficiency studies. The uptake of NLCs in THP-1 cells was studied using fluorescence microscopy and flow cytometry. The anti-HIV efficacy was evaluated using p24 antigen inhibition assay. NLCs were found to be spherical in shape with anionic zeta potential (-23.66 ± 0.87 mV) and 241.83 ± 5.38 nm particle size. NLCs exhibited prolonged release of efavirenz during in vitro drug release studies. Flow cytometry revealed 1.73-fold higher uptake of HA-coated NLCs in THP-1 cells. Cytotoxicity studies showed no significant change in cell viability in presence of NLCs as compared with the control. HA-coated NLCs distributed throughout the cell including cytoplasm, plasma membrane and nucleus, as observed during fluorescence microscopy. HA-coated NLCs demonstrated consistent and significantly higher inhibition (81.26 ± 1.70%) of p24 antigen which was 2.08-fold higher than plain NLCs. The obtained results suggested preferential uptake of HA-coated NLCs via CD44-mediated uptake. The present finding demonstrates that HA-based CD44 receptor targeting in HIV infection is an attractive strategy for maximising the drug delivery to macrophages and achieve effective viral inhibition.


Assuntos
Portadores de Fármacos/administração & dosagem , HIV-1/efeitos dos fármacos , Receptores de Hialuronatos , Macrófagos/efeitos dos fármacos , Nanoestruturas/administração & dosagem , Inibidores da Transcriptase Reversa/administração & dosagem , Alcinos/administração & dosagem , Alcinos/síntese química , Alcinos/metabolismo , Benzoxazinas/administração & dosagem , Benzoxazinas/síntese química , Benzoxazinas/metabolismo , Sobrevivência Celular/efeitos dos fármacos , Sobrevivência Celular/fisiologia , Ciclopropanos/administração & dosagem , Ciclopropanos/síntese química , Ciclopropanos/metabolismo , Relação Dose-Resposta a Droga , Portadores de Fármacos/síntese química , Portadores de Fármacos/metabolismo , Sistemas de Liberação de Medicamentos/métodos , Células HEK293 , Infecções por HIV/tratamento farmacológico , Infecções por HIV/metabolismo , HIV-1/fisiologia , Humanos , Receptores de Hialuronatos/metabolismo , Lipídeos/administração & dosagem , Lipídeos/síntese química , Macrófagos/metabolismo , Nanoestruturas/química , Inibidores da Transcriptase Reversa/síntese química , Inibidores da Transcriptase Reversa/metabolismo , Células THP-1
2.
Nat Commun ; 12(1): 2500, 2021 05 04.
Artigo em Inglês | MEDLINE | ID: mdl-33947853

RESUMO

Reverse transcription of the HIV-1 viral RNA genome (vRNA) is an integral step in virus replication. Upon viral entry, HIV-1 reverse transcriptase (RT) initiates from a host tRNALys3 primer bound to the vRNA genome and is the target of key antivirals, such as non-nucleoside reverse transcriptase inhibitors (NNRTIs). Initiation proceeds slowly with discrete pausing events along the vRNA template. Despite prior medium-resolution structural characterization of reverse transcriptase initiation complexes (RTICs), higher-resolution structures of the RTIC are needed to understand the molecular mechanisms that underlie initiation. Here we report cryo-EM structures of the core RTIC, RTIC-nevirapine, and RTIC-efavirenz complexes at 2.8, 3.1, and 2.9 Å, respectively. In combination with biochemical studies, these data suggest a basis for rapid dissociation kinetics of RT from the vRNA-tRNALys3 initiation complex and reveal a specific structural mechanism of nucleic acid conformational stabilization during initiation. Finally, our results show that NNRTIs inhibit the RTIC and exacerbate discrete pausing during early reverse transcription.


Assuntos
Transcriptase Reversa do HIV/química , HIV-1/efeitos dos fármacos , RNA de Transferência de Lisina/química , RNA Viral/química , Inibidores da Transcriptase Reversa/química , Alcinos/química , Alcinos/farmacologia , Benzoxazinas/química , Benzoxazinas/farmacologia , Domínio Catalítico , Microscopia Crioeletrônica , Ciclopropanos/química , Ciclopropanos/farmacologia , Transcriptase Reversa do HIV/genética , Transcriptase Reversa do HIV/metabolismo , HIV-1/enzimologia , HIV-1/genética , HIV-1/metabolismo , Modelos Moleculares , Nevirapina/química , Nevirapina/farmacologia , Conformação de Ácido Nucleico/efeitos dos fármacos , RNA de Transferência de Lisina/genética , RNA Viral/genética , Inibidores da Transcriptase Reversa/farmacologia
3.
Mutat Res ; 865: 503336, 2021 05.
Artigo em Inglês | MEDLINE | ID: mdl-33865542

RESUMO

The increased life expectancy of people living with HIV (PLWH) receiving antiretroviral treatment (ART) has transformed HIV infection into a chronic disease. However, patients may be at risk of accelerated aging and the accumulation of cellular damage, which may trigger the development of cancer. We evaluated genomic instability in HIV-positive individuals with different viral loads receiving antiretroviral treatment (ART) and in HIV ART-naïve individuals. We included 67 participants divided into four groups: group 1 (n = 24) HIV patients receiving reverse-transcriptase inhibitors (tenofovir/ emtricitabine/ efavirenz and abacavir/ lamivudine/ efavirenz), group 2 (n = 22) HIV patients receiving protease inhibitors combined with other antiretroviral drugs (tenofovir/ emtricitabine with ritonavir/ atazanavir or lopinavir/ ritonavir, and darunavir/ ritonavir/ raltegravir), group 3 (n = 13) HIV ART-naïve patients, and group 4 (n = 8) healthy individuals (controls). Nuclear abnormalities in buccal mucosal samples (micronuclei, binucleated cells, nuclear buds, karyorrhexis, karyolysis, and pyknosis) were quantified. Simultaneously, blood samples were taken to quantify CD4+, CD8+, and HIV viral load. There was a significant age difference between HIV ART-naïve patients and receiving ART groups. Infection time was longer in HIV patients with ART than in ART-naïve patients. There were no differences in sex, smoking, alcohol consumption, or number of micronucleated cells between the study groups. We found higher frequencies of binucleated cells and nuclear buds in HIV patients, HIV ART-naïve, and HIV ART patients compared to the control group. We found a positive correlation between nuclear buds and CD4/CD8 ratio in the HIV ART-naïve group. In conclusion, PLWH showed increased genomic instability. The CD4/CD8 ratio affects the numbers of nuclear buds and binucleated cells. These findings are pertinent to mechanisms of damage and possible strategies to mitigate carcinogenesis in PLWH.


Assuntos
Instabilidade Genômica , Infecções por HIV/genética , Adulto , Fármacos Anti-HIV/efeitos adversos , Fármacos Anti-HIV/uso terapêutico , Contagem de Linfócito CD4 , Relação CD4-CD8 , Feminino , Instabilidade Genômica/efeitos dos fármacos , HIV/efeitos dos fármacos , HIV/fisiologia , Infecções por HIV/tratamento farmacológico , Infecções por HIV/imunologia , Infecções por HIV/patologia , Humanos , Masculino , Pessoa de Meia-Idade , Inibidores da Transcriptase Reversa/efeitos adversos , Inibidores da Transcriptase Reversa/uso terapêutico , Carga Viral/efeitos dos fármacos , Carga Viral/fisiologia , Adulto Jovem
4.
Lancet HIV ; 8(4): e185-e196, 2021 04.
Artigo em Inglês | MEDLINE | ID: mdl-33794181

RESUMO

BACKGROUND: There is a need for more convenient, less frequent treatment to help address challenges associated with daily oral HIV treatment in people living with HIV, including stigma, pill burden, drug-food interactions, and adherence. The phase 3 ATLAS and FLAIR studies showed non-inferiority of long-acting cabotegravir and rilpivirine dosed every 4 weeks compared with standard oral therapy for the maintenance of virological suppression in adults with HIV-1 over 48 weeks. We present the 96-week findings. METHODS: FLAIR is a randomised, phase 3, open-label, multicentre study done in 11 countries investigating whether switching to long-acting cabotegravir and rilpivirine is non-inferior to daily dolutegravir, abacavir, and lamivudine in virologically suppressed adults living with HIV-1. Antiretroviral therapy (ART)-naive participants received induction therapy with daily oral dolutegravir (50 mg), abacavir (600 mg), and lamivudine (300 mg) for 20 weeks. After 16 weeks, participants with less than 50 HIV-1 RNA copies per mL were randomly assigned (1:1) to continue the standard of care regimen (standard care group) or switch to receive daily oral cabotegravir 30 mg and rilpivirine 25 mg for at least 4 weeks followed by long-acting cabotegravir 400 mg and rilpivirine 600 mg, administered as two 2 mL intramuscular injections, every 4 weeks for at least 96 weeks (long-acting group). Randomisation was stratified by baseline (preinduction) HIV-1 RNA (<100 000 or ≥100 000 copies per mL) and sex at birth and used GlaxoSmithKline-verified randomisation software (RandAll NG, version 1.3.3) for treatment assignment. The primary endpoint was the proportion of participants with plasma HIV-1 RNA of 50 copies per mL or more assessed as per the US Food and Drug Administration (FDA) Snapshot algorithm at week 48, which has been reported previously. Here, we report the proportion of participants with 50 or more HIV-1 RNA copies per mL using the FDA Snapshot algorithm at week 96 (intention-to-treat population; non-inferiority margin 6%). The trial is registered with ClinicalTrials.gov, NCT02938520. FINDINGS: Between Oct 27, 2016, and March 24, 2017, 809 participants were screened. 631 (78%) participants entered the induction phase and 566 (70%) were randomly assigned to either the standard care group (283 [50%] participants) or the long-acting group (283 [50%]). Median age was 34 years (IQR 29 to 43), 62 (11%) were 50 years or older, 127 (22%) were women (sex at birth), and 419 (74%) were white. At week 96, nine (3%) participants in each arm had 50 or more HIV-1 RNA copies per mL, with an adjusted difference of 0·0 (95% CI -2·9 to 2·9), consistent with non-inferiority established at week 48. Across both treatment groups, adverse events leading to withdrawal were infrequent (14 [5%] participants in the long-acting group and four [1%] in the standard care group). Injection site reactions were the most common adverse event, reported by 245 (88%) participants in the long-acting group; their frequency decreased over time. Median injection site reaction duration was 3 days (IQR 2 to 4), and 3082 (99%) of 3100 reactions were grade 1 or 2. No deaths occurred during the maintenance phase. INTERPRETATION: The 96-week results reaffirm the 48-week results, showing long-acting cabotegravir and rilpivirine continued to be non-inferior compared with continuing a standard care regimen in adults with HIV-1 for the maintenance of viral suppression. These results support the durability of long-acting cabotegravir and rilpivirine, over an almost 2-year-long period, as a therapeutic option for virally suppressed adults with HIV-1. FUNDING: ViiV Healthcare and Janssen Research and Development.


Assuntos
Fármacos Anti-HIV/administração & dosagem , Infecções por HIV/tratamento farmacológico , HIV-1/efeitos dos fármacos , Piridonas/administração & dosagem , Rilpivirina/administração & dosagem , Adulto , Fármacos Anti-HIV/efeitos adversos , Esquema de Medicação , Quimioterapia Combinada , Feminino , Infecções por HIV/virologia , Inibidores de Integrase de HIV/administração & dosagem , Inibidores de Integrase de HIV/efeitos adversos , Humanos , Injeções Intramusculares , Masculino , Pessoa de Meia-Idade , Piridonas/efeitos adversos , RNA Viral/sangue , Inibidores da Transcriptase Reversa/administração & dosagem , Inibidores da Transcriptase Reversa/efeitos adversos , Rilpivirina/efeitos adversos , Resultado do Tratamento , Carga Viral/efeitos dos fármacos
5.
J Med Chem ; 64(8): 5067-5081, 2021 04 22.
Artigo em Inglês | MEDLINE | ID: mdl-33851529

RESUMO

Considering the nonideal metabolic stability of the difluoro-biphenyl-diarylpyrimidine lead compound 4, a series of novel alkylated difluoro-biphenyl-diarylpyrimidines were designed and synthesized based on their structure. Introducing alkyl or substituted alkyl groups on the linker region to block the potential metabolic sensitive sites generated 22 derivatives. Among them, compound 12a with an N-methyl group displayed excellent anti-HIV-1 activity and selectivity. The methyl group was hopped to the central pyrimidine to occupy the small linker region and maintain the water-mediated hydrogen bond observed in the binding of compound 4 with RT. The resulting compound 16y exhibited an improved anti-HIV-1 activity, much lower cytotoxicity, and nanomolar activity toward multiple mutants. In addition, 16y has a better stability in human liver microsomes than 4. Moreover, no apparent in vivo acute toxicity was observed in 16y-treated female, especially pregnant mice. This series of alkylated compounds with highly potency and safety represent a promising lead template for future discovery.


Assuntos
Compostos de Bifenilo/química , Desenho de Fármacos , Transcriptase Reversa do HIV/antagonistas & inibidores , Pirimidinas/química , Inibidores da Transcriptase Reversa/química , Alquilação , Animais , Sítios de Ligação , Linhagem Celular , Sobrevivência Celular/efeitos dos fármacos , Estabilidade de Medicamentos , Feminino , Transcriptase Reversa do HIV/genética , Transcriptase Reversa do HIV/metabolismo , Meia-Vida , Humanos , Interações Hidrofóbicas e Hidrofílicas , Camundongos , Microssomos Hepáticos/metabolismo , Simulação de Acoplamento Molecular , Mutação , Pirimidinas/metabolismo , Pirimidinas/farmacologia , Inibidores da Transcriptase Reversa/metabolismo , Inibidores da Transcriptase Reversa/farmacologia , Relação Estrutura-Atividade
6.
J Med Chem ; 64(7): 4239-4256, 2021 04 08.
Artigo em Inglês | MEDLINE | ID: mdl-33734714

RESUMO

There is an urgent unmet medical need for novel human immunodeficiency virus type 1 (HIV-1) inhibitors that are effective against a variety of NNRTI-resistance mutations. We report our research efforts aimed at discovering a novel chemotype of anti-HIV-1 agents with improved potency against a variety of NNRTI-resistance mutations in this paper. Structural modifications of the lead K-5a2 led to the identification of a potent inhibitor 16c. 16c yielded highly potent anti-HIV-1 activities and improved resistance profiles compared with the approved drug etravirine. The co-crystal structure revealed the key role of the water networks surrounding the NNIBP for binding and for resilience against resistance mutations, while suggesting further extension of 16c toward the NNRTI-adjacent site as a lead development strategy. Furthermore, 16c demonstrated favorable pharmacokinetic and safety properties, suggesting the potential of 16c as a promising anti-HIV-1 drug candidate.


Assuntos
Fármacos Anti-HIV/farmacologia , Transcriptase Reversa do HIV/antagonistas & inibidores , HIV-1/efeitos dos fármacos , Pirimidinas/farmacologia , Inibidores da Transcriptase Reversa/farmacologia , Animais , Fármacos Anti-HIV/síntese química , Fármacos Anti-HIV/metabolismo , Cristalografia por Raios X , Desenho de Fármacos , Células HEK293 , Transcriptase Reversa do HIV/metabolismo , HIV-1/genética , Humanos , Camundongos , Testes de Sensibilidade Microbiana , Estrutura Molecular , Mutação , Ligação Proteica , Pirimidinas/síntese química , Pirimidinas/metabolismo , Ratos Sprague-Dawley , Inibidores da Transcriptase Reversa/síntese química , Inibidores da Transcriptase Reversa/metabolismo , Relação Estrutura-Atividade
7.
Eur J Med Chem ; 214: 113204, 2021 Mar 15.
Artigo em Inglês | MEDLINE | ID: mdl-33567378

RESUMO

With our previously identified potent NNRTIs 25a and HBS-11c as leads, series of novel thiophene[3,2-d]pyrimidine and thiophene[2,3-d]pyrimidine derivatives were designed via molecular hybridization strategy. All the target compounds were evaluated for their anti-HIV-1 activity and cytotoxicity in MT-4 cells. Compounds 16a1 and 16b1 turned out to be the most potent inhibitors against WT and mutant HIV-1 strains (L100I, K103N, and E138K), with EC50 values ranging from 0.007 µM to 0.043 µM. Gratifyingly, 16b1 exhibited significantly reduced cytotoxicity (CC50 > 217.5 µM) and improved water solubility (S = 49.3 µg/mL at pH 7.0) compared to the lead 25a (S < 1 µg/mL at pH 7.0, CC50 = 2.30 µM). Moreover, molecular docking was also conducted to rationalize the structure-activity relationships of these novel derivatives and to understand their key interactions with the binding pocket.


Assuntos
Fármacos Anti-HIV/farmacologia , Transcriptase Reversa do HIV/antagonistas & inibidores , HIV-1/efeitos dos fármacos , Pirimidinas/farmacologia , Inibidores da Transcriptase Reversa/farmacologia , Tiofenos/farmacologia , Fármacos Anti-HIV/síntese química , Fármacos Anti-HIV/química , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Relação Dose-Resposta a Droga , Transcriptase Reversa do HIV/metabolismo , Humanos , Testes de Sensibilidade Microbiana , Modelos Moleculares , Estrutura Molecular , Pirimidinas/síntese química , Pirimidinas/química , Inibidores da Transcriptase Reversa/síntese química , Inibidores da Transcriptase Reversa/química , Relação Estrutura-Atividade , Tiofenos/síntese química , Tiofenos/química
8.
Science ; 371(6535)2021 03 19.
Artigo em Inglês | MEDLINE | ID: mdl-33542150

RESUMO

HIV-1 has high mutation rates and exists as mutant swarms within the host. Rapid evolution of HIV-1 allows the virus to outpace the host immune system, leading to viral persistence. Approaches to targeting immutable components are needed to clear HIV-1 infection. Here, we report that the caspase recruitment domain-containing protein 8 (CARD8) inflammasome senses HIV-1 protease activity. HIV-1 can evade CARD8 sensing because its protease remains inactive in infected cells before viral budding. Premature intracellular activation of the viral protease triggered CARD8 inflammasome-mediated pyroptosis of HIV-1-infected cells. This strategy led to the clearance of latent HIV-1 in patient CD4+ T cells after viral reactivation. Thus, our study identifies CARD8 as an inflammasome sensor of HIV-1, which holds promise as a strategy for the clearance of persistent HIV-1 infection.


Assuntos
Proteínas Adaptadoras de Sinalização CARD/metabolismo , Infecções por HIV/virologia , Protease de HIV/metabolismo , HIV-1/fisiologia , Inflamassomos/metabolismo , Proteínas de Neoplasias/metabolismo , Piroptose , Alcinos/farmacologia , Fármacos Anti-HIV/farmacologia , Benzoxazinas/farmacologia , Proteínas Adaptadoras de Sinalização CARD/química , Linfócitos T CD4-Positivos/fisiologia , Linfócitos T CD4-Positivos/virologia , Caspase 1/metabolismo , Ciclopropanos/farmacologia , Ativação Enzimática , Infecções por HIV/tratamento farmacológico , HIV-1/efeitos dos fármacos , Humanos , Macrófagos/fisiologia , Macrófagos/virologia , Proteínas de Neoplasias/química , Inibidores da Transcriptase Reversa/farmacologia , Rilpivirina/farmacologia , Células THP-1 , Latência Viral
9.
BMC Infect Dis ; 21(1): 112, 2021 Jan 23.
Artigo em Inglês | MEDLINE | ID: mdl-33485301

RESUMO

BACKGROUND: The plasma concentration of patients treated with efavirenz (EFV) 600 mg was found to exceed the upper limit of the proposed therapeutic window in most Chinese HIV-infected individuals; thus, dosage reduction of EFV to 400 mg daily warranted consideration. This study aimed to assess the pharmacodynamics of EFV 400 mg for HIV-1-infected patients in China. METHOD: Twenty cART-naïve individuals were enrolled in this study. EFV 400 mg combined with tenofovir (TDF) and lamivudine (3TC) as an initial antiretroviral regimen was administered for 48 weeks. EFV concentration and T cell subsets as well as HIV RNA load were evaluated at baseline and at 4, 12, 24, and 48 weeks. Moreover, neuropsychiatric adverse effects were also assessed by the Hamilton depression (HAMD) scale and Pittsburgh sleep quality index (PSQI). RESULTS: Eighteen males and two females whose median age was 26 (interquartile range [IQR]: 23-32) years completed 48 weeks of follow-up. The median EFV concentrations were 1.88 (IQR: 1.54-2.42), 1.74 (IQR: 1.36-1.93), 1.93 (IQR: 1.66-2.22), and 1.85 (IQR: 1.54-2.14) mg/L at weeks 4, 12, 24, and 48, respectively. The viral load was 4.59 (IQR: 4.10-5.19) log10 copies/mL at baseline, and it decreased by 4.6 (IQR: 3.98-5.18) log10 copies/mL from baseline to week 48. Three of 20 (15%), 10 of 20 (50.0%), 17 of 20 (85%), and 18 of 19 (95%) participants had a plasma viral load less than 50 copies/mL at weeks 4, 12, 24, and 48, respectively. The median CD4 cell count was 330 (IQR: 237-410) cells/µL at baseline, and it increased to 473 (IQR: 344-574) cells/µL at 48 weeks. The HAMD score was 5 (IQR: 3-9.8) and 3 (IQR: 2.25-4) at baseline and 48 weeks, respectively. The PSQI score was 4 (IQR: 2-5.8) and 3 (IQR: 2-4) at baseline and 48 weeks, respectively. Dizziness was the most common event, occurring in 70% of patients within the first 2 weeks of treatment. CONCLUSION: Patients prescribed with EFV 400 mg-containing agents demonstrated favourable virological and immunological responses. And the plasma EFV concentration was within the recommended therapeutic range, with fewer adverse reactions than with EFV 600 mg. EFV 400 mg was effective and safe in Chinese HIV-infected patients. TRIAL REGISTRATION: NCT04596488 ; Registered 21 October, 2020; Retrospectively registered.


Assuntos
Alcinos/farmacocinética , Fármacos Anti-HIV/farmacocinética , Benzoxazinas/farmacocinética , Ciclopropanos/farmacocinética , Infecções por HIV/tratamento farmacológico , HIV-1/efeitos dos fármacos , Inibidores da Transcriptase Reversa/farmacocinética , Adulto , Alcinos/administração & dosagem , Alcinos/efeitos adversos , Fármacos Anti-HIV/administração & dosagem , Fármacos Anti-HIV/efeitos adversos , Benzoxazinas/administração & dosagem , Benzoxazinas/efeitos adversos , Contagem de Linfócito CD4 , China , Ciclopropanos/administração & dosagem , Ciclopropanos/efeitos adversos , Quimioterapia Combinada , Feminino , Infecções por HIV/imunologia , Infecções por HIV/virologia , Humanos , Masculino , Estudos Prospectivos , Inibidores da Transcriptase Reversa/administração & dosagem , Inibidores da Transcriptase Reversa/efeitos adversos , Resultado do Tratamento , Carga Viral/efeitos dos fármacos
10.
Viruses ; 13(1)2021 Jan 18.
Artigo em Inglês | MEDLINE | ID: mdl-33477685

RESUMO

HIV reverse transcriptases (RTs) convert viral genomic RNA into double-stranded DNA. During reverse transcription, polypurine tracts (PPTs) resilient to RNase H cleavage are used as primers for plus-strand DNA synthesis. Nonnucleoside RT inhibitors (NNRTIs) can interfere with the initiation of plus-strand DNA synthesis by enhancing PPT removal, while HIV RT connection subdomain mutations N348I and N348I/T369I mitigate this effect by altering RNase H cleavage specificity. Now, we demonstrate that among approved nonnucleoside RT inhibitors (NNRTIs), nevirapine and doravirine show the largest effects. The combination N348I/T369I in HIV-1BH10 RT has a dominant effect on the RNase H cleavage specificity at the PPT/U3 site. Biochemical studies showed that wild-type HIV-1 and HIV-2 RTs were able to process efficiently and accurately all tested HIV PPT sequences. However, the cleavage accuracy at the PPT/U3 junction shown by the HIV-2EHO RT was further improved after substituting the sequence YQEPFKNLKT of HIV-1BH10 RT (positions 342-351) for the equivalent residues of the HIV-2 enzyme (HQGDKILKV). Our results highlight the role of ß-sheets 17 and 18 and their connecting loop (residues 342-350) in the connection subdomain of the large subunit, in determining the RNase H cleavage window of HIV RTs.


Assuntos
Genoma Viral , Infecções por HIV/virologia , Repetição Terminal Longa de HIV , HIV-1/fisiologia , RNA Viral , Ribonuclease H do Vírus da Imunodeficiência Humana/metabolismo , Sequência de Bases , Infecções por HIV/tratamento farmacológico , HIV-1/efeitos dos fármacos , Humanos , Modelos Moleculares , Conformação Molecular , Mutagênese , Ligação Proteica , Proteólise , RNA Viral/química , Inibidores da Transcriptase Reversa/farmacologia , Inibidores da Transcriptase Reversa/uso terapêutico , Ribonuclease H do Vírus da Imunodeficiência Humana/química
12.
ChemMedChem ; 16(9): 1403-1419, 2021 05 06.
Artigo em Inglês | MEDLINE | ID: mdl-33427377

RESUMO

Nucleoside and nucleotide analogues are structurally similar antimetabolites and are promising small-molecule chemotherapeutic agents against various infectious DNA and RNA viruses. To date, these analogues have not been documented in-depth as anti-human immunodeficiency virus (HIV) and anti-hepatitis virus agents, these are at various stages of testing ranging from pre-clinical, to those withdrawn from trials, or those that are approved as drugs. Hence, in this review, the importance of these analogues in tackling HIV and hepatitis virus infections is discussed with a focus on the viral genome and the mechanism of action of these analogues, both in a mutually exclusive manner and their role in HIV/hepatitis coinfection. This review encompasses nucleoside and nucleotide analogues from 1987 onwards, starting with the first nucleoside analogue, zidovudine, and going on to those in current clinical trials and even the drugs that have been withdrawn. This review also sheds light on the prospects of these nucleoside analogues in clinical trials as a treatment option for the COVID-19 pandemic.


Assuntos
Fármacos Anti-HIV/uso terapêutico , Infecções por HIV/tratamento farmacológico , Hepatite Viral Humana/tratamento farmacológico , Nucleosídeos/uso terapêutico , Nucleotídeos/uso terapêutico , /tratamento farmacológico , Ensaios Clínicos como Assunto , Reposicionamento de Medicamentos , HIV/efeitos dos fármacos , HIV/enzimologia , Transcriptase Reversa do HIV/antagonistas & inibidores , Vírus de Hepatite/efeitos dos fármacos , Vírus de Hepatite/enzimologia , Humanos , Pandemias , Inibidores da Transcriptase Reversa/uso terapêutico , /efeitos dos fármacos
13.
AIDS ; 35(6): 869-882, 2021 05 01.
Artigo em Inglês | MEDLINE | ID: mdl-33443370

RESUMO

OBJECTIVE: To compare the incidence of dyslipidemia in people with HIV receiving integrase inhibitors (INSTI) versus boosted protease inhibitors (PI/b) and nonnucleoside reverse transcriptase inhibitors (NNRTI) within RESPOND consortium of prospective cohorts. METHODS: Participants were eligible if they were at least 18 years, without dyslipidemia and initiated or switched to a three-drug antiretroviral therapy (ART)-regimen consisting of either INSTI, NNRTI, or PI/b for the first time, between 1 January 2012 and 31 December 2018. Dyslipidemia was defined as random total cholesterol more than 240 mg/dl, HDL less than 35 mg/dl, triglyceride more than 200 mg/dl, or initiation of lipid-lowering therapy. Poisson regression was used to determine the adjusted incidence rate ratios. Follow-up was censored after 3 years or upon ART-regimen discontinuation or last lipid measurement or 31 December 2019, whichever occurred first. RESULTS: Overall, 4577 people with HIV were eligible (INSTI = 66.9%, PI/b = 12.5%, and NNRTI = 20.6%), 1938 (42.3%) of whom were ART-naive. During 1.7 (interquartile range, 0.6-3.0) median years of follow-up, 1460 participants developed dyslipidemia [incidence rate: 191.6 per 1000 person-years, 95% confidence interval (CI) 182.0-201.7]. Participants taking INSTI had a lower incidence of dyslipidemia compared with those on PI/b (adjusted incidence rate ratio 0.71; CI 0.59-0.85), but higher rate compared with those on NNRTI (1.35; CI 1.15-1.58). Compared with dolutegravir, the incidence of dyslipidemia was higher with elvitegravir/cobicistat (1.20; CI 1.00-1.43) and raltegravir (1.24; CI 1.02-1.51), but lower with rilpivirine (0.77; CI 0.63-0.94). CONCLUSION: In this large consortium of heterogeneous cohorts, dyslipidemia was less common with INSTI than with PI/b. Compared with dolutegravir, dyslipidemia was more common with elvitegravir/cobicistat and raltegravir, but less common with rilpivirine.


Assuntos
Fármacos Anti-HIV , Dislipidemias , Infecções por HIV , Inibidores de Integrase de HIV , Fármacos Anti-HIV/uso terapêutico , Antirretrovirais/efeitos adversos , Dislipidemias/induzido quimicamente , Dislipidemias/tratamento farmacológico , Dislipidemias/epidemiologia , Infecções por HIV/complicações , Infecções por HIV/tratamento farmacológico , Inibidores de Integrase de HIV/efeitos adversos , Humanos , Incidência , Estudos Prospectivos , Inibidores da Transcriptase Reversa/uso terapêutico
15.
PLoS One ; 15(12): e0243650, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33347449

RESUMO

Human immunodeficiency virus-1 (HIV-1) exhibits high diversity and complexity in China, challenging the disease surveillance and antiretroviral therapy. Between July 1, 2014 and January 30, 2017, we investigated the profiles of HIV-1 infection stages, genotype distribution and drug resistance mutations (DRMs) using plasma samples from HIV Western blot (WB) confirmed blood donors from five Chinese blood centers (Chongqing, Guangxi, Luoyang, Mianyang, and Urumqi). HIV pol regions consisted of whole protease and partial reverse transcriptase were genotyped and analyzed for DRMs. Lag-Avidity testing was performed to identify the infection stages. Of the 356 HIV-1 WB positive samples tested by Lag-avidity assay, 19.1% (68/356) were recent infections. Genotyping on 356 amplified sequences presented the subtype distributions as following: CRF07_BC (65.7%), CRF08_BC (7.3%), CRF01_AE (19.1%), B (4.2%), CRF55_01B (3.1%), CRF59_01B (0.3%) and CRF68_01B (0.3%). No significant difference in genotype distribution was observed between recent and long-term infections. 48 DRMs were identified from 43 samples, indicating a drug resistance prevalence of 12.1% (43/356), which include seven protease inhibitors (PIs) accessory DRMs (Q58E, L23I and I84M), two PIs major DRMs (M46I, M46L), seven nucleoside RT inhibitors DRMs (D67N, K70Q, K219R and M184L), and 32 non-nucleoside RT inhibitors DRMs (K103N, V179E, K238N, V179D, E138G, G190E, A98G, Y188D and E138A). In addition, we had also identified CRFs from the 01B subtype including CRF55_01B (3.1%), CRF59_01B (0.3%) and CRF68_01B (0.3%). As an important part of the continuous monitoring of HIV-1 circulating strains among blood donors, our findings were expected to contribute to the comprehensive AIDS control and development of proper diagnostics for HIV-1 in China.


Assuntos
Doadores de Sangue/estatística & dados numéricos , Farmacorresistência Viral/genética , Infecções por HIV/epidemiologia , HIV-1/genética , Adulto , Fármacos Anti-HIV/farmacologia , Fármacos Anti-HIV/uso terapêutico , China/epidemiologia , Genótipo , Técnicas de Genotipagem , Infecções por HIV/tratamento farmacológico , Infecções por HIV/virologia , Protease de HIV/genética , HIV-1/isolamento & purificação , Humanos , Mutação , Filogenia , RNA Viral/genética , RNA Viral/isolamento & purificação , Inibidores da Transcriptase Reversa/farmacologia , Inibidores da Transcriptase Reversa/uso terapêutico , Estudos Soroepidemiológicos , Adulto Jovem
16.
PLoS One ; 15(12): e0243625, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33382756

RESUMO

OBJECTIVES: To compare virologic and immunologic outcomes of integrase inhibitor (INSTI)-containing, contemporary boosted protease inhibitor (PI/b)-containing and non-nucleotide reverse transcriptase inhibitor (NNRTI)-containing regimens in a real-life setting. METHODS: Using logistic regression, virologic and immunologic outcomes of INSTI use were compared to outcomes of PI/b or NNRTI treatment 12 months after treatment start or switch, for participants in the RESPOND cohort consortium. A composite treatment outcome (cTO) was used, defining success as viral load (VL) <200 copies/mL and failure as at least one of: VL ≥200 copies/mL, unknown VL in the time window, any changes of antiretroviral therapy (ART) regimen, AIDS, or death. In addition, on-treatment analysis including only individuals with known VL and no regimen changes was performed. Favorable immunologic response was defined as a 25% increase in CD4 count or as reaching ≥750 CD4 cells/µL. RESULTS: Between January 2012 and January 2019, 13,703 (33.0% ART-naïve) individuals were included, of whom 7,147 started/switched to a regimen with an INSTI, 3,102 to a PI/b and 3,454 to an NNRTI-containing regimen. The main reason for cTO failure in all treatment groups were changes in ART regimen. Compared to INSTIs, the adjusted odds ratio (aOR) of cTO success was significantly lower for PI/b (0.74 [95% confidence interval, CI 0.67-0.82], p <0.001), but similar for NNRTIs (1.07 [CI 0.97-1.17], p = 0.11). On-treatment analysis and sensitivity analyses using a VL cut-off of 50 copies/mL were consistent. Compared to INSTIs, the aORs of a 25% increase in CD4 count were lower for NNRTIs (0.80 [CI 0.71-0.91], p<0.001) and PI/b (0.87 [CI 0.76-0.99], p = 0.04). CONCLUSION: In this large analysis of a real-world population, cTO and on-treatment success were similar between INSTIs and NNRTIs, but lower for PI/b, though residual confounding cannot be fully excluded. Obtaining favorable immunologic outcomes were more likely for INSTIs than the other drug classes.


Assuntos
Infecções por HIV/tratamento farmacológico , Inibidores de Integrase de HIV/uso terapêutico , Inibidores da Protease de HIV/uso terapêutico , Inibidores da Transcriptase Reversa/uso terapêutico , Adulto , Contagem de Linfócito CD4 , Estudos de Coortes , Feminino , HIV/efeitos dos fármacos , HIV/imunologia , Infecções por HIV/imunologia , Infecções por HIV/virologia , Humanos , Masculino , Pessoa de Meia-Idade , Resultado do Tratamento , Carga Viral/efeitos dos fármacos , Carga Viral/imunologia
17.
Molecules ; 25(24)2020 Dec 13.
Artigo em Inglês | MEDLINE | ID: mdl-33322154

RESUMO

The ongoing development of drug resistance in HIV continues to push for the need of alternative drug targets in inhibiting HIV. One such target is the Reverse transcriptase (RT) enzyme which is unique and critical in the viral life cycle-a rational target that is likely to have less off-target effects in humans. Serendipitously, we found two chemical scaffolds from the National Cancer Institute (NCI) Diversity Set V that inhibited HIV-1 RT catalytic activity. Computational structural analyses and subsequent experimental testing demonstrated that one of the two chemical scaffolds binds to a novel location in the HIV-1 RT p51 subunit, interacting with residue Y183, which has no known association with previously reported drug resistance. This finding supports the possibility of a novel druggable site on p51 for a new class of non-nucleoside RT inhibitors that may inhibit HIV-1 RT allosterically. Although inhibitory activity was shown experimentally to only be in the micromolar range, the scaffolds serve as a proof-of-concept of targeting the HIV RT p51 subunit, with the possibility of medical chemistry methods being applied to improve inhibitory activity towards more effective drugs.


Assuntos
Transcriptase Reversa do HIV/antagonistas & inibidores , Transcriptase Reversa do HIV/química , HIV-1/efeitos dos fármacos , Inibidores da Transcriptase Reversa/química , Inibidores da Transcriptase Reversa/farmacologia , Sequência de Aminoácidos , Antivirais/química , Antivirais/farmacologia , Sítios de Ligação , Relação Dose-Resposta a Droga , Ativação Enzimática/efeitos dos fármacos , Infecções por HIV/tratamento farmacológico , Infecções por HIV/virologia , HIV-1/enzimologia , Humanos , Conformação Molecular , Simulação de Acoplamento Molecular , Simulação de Dinâmica Molecular , Estrutura Molecular , Terapia de Alvo Molecular , Ligação Proteica , Relação Estrutura-Atividade
18.
J Int AIDS Soc ; 23(12): e25656, 2020 12.
Artigo em Inglês | MEDLINE | ID: mdl-33369131

RESUMO

INTRODUCTION: WHO's 2019 report on HIV drug resistance (HIVDR) documents a high prevalence of pretreatment drug resistance (PDR) among populations initiating first-line antiretroviral therapy (ART) in low- and middle-income countries (LMIC). However, systematic evidence on the prevalence of PDR among key populations remains limited. We performed a systematic review to characterize levels of PDR in key population groups and compared them to levels of PDR in the "general population" across different geographical regions. METHODS: Ten electronic databases were searched for papers published until February 2019 that included predefined search terms. We included studies that reported the number of successfully tested genotypes and the number of genotypes with drug resistance mutations among antiretroviral therapy treatment naïve people, recently infected people, or people initiating first-line ART from key populations. To assess the prevalence of PDR for each key population, we pooled estimates using random-effects meta-analysis of proportions. Where possible, we computed the differences in the odds of PDR (any, and by drug class) present in each key population compared to the "general population". The I2 statistic (a measure of heterogeneity between studies) is reported. RESULTS AND DISCUSSION: A total of 332 datasets (from 218 studies) and 63,111 people with successful HIVDR genotyping were included in the analysis. The pooled prevalence estimate of any PDR was high among men who have sex with men (13.0%, 95% CI 11.0 to 14.0%, I2  = 93.19), sex workers (17.0%, 95% CI 6.0 - 32.0, I2  = 87.31%) and people in prisons (18.0%, 95% CI 11.0 to 25.0, I2  = 70.18%), but less so among people who inject drugs (7.0%, 95% CI 5.0 to 10.0, I2  = 90.23). Overall, men who have sex with men were more likely to carry any PDR compared to the "general population," a finding which was statistically significant (odds ratio (OR) 1.28, 95% CI 1.13 - 1.46, I2 48.9%). CONCLUSIONS: High prevalence of PDR found in key populations highlights the need to increase access to effective first-line HIV treatment. The low prevalence of nucleotide reverse transcriptase inhibitor (NRTI) PDR suggests that current WHO recommendations for pre-exposure prophylaxis (PrEP) regimens will remain effective and can be scaled up to prevent new HIV infections in high-risk groups.


Assuntos
Fármacos Anti-HIV/uso terapêutico , Infecções por HIV/tratamento farmacológico , Farmacorresistência Viral , Feminino , Homossexualidade Masculina , Humanos , Masculino , Prevalência , Inibidores da Transcriptase Reversa/uso terapêutico , Profissionais do Sexo
19.
BMC Infect Dis ; 20(1): 660, 2020 Sep 07.
Artigo em Inglês | MEDLINE | ID: mdl-32894102

RESUMO

INTRODUCTION: Although women comprise 33% of the HIV-1-carriers in Israel, they have not previously been considered a risk group requiring special attention. Immigration waves from countries in Africa and in East Europe may have changed the local landscape of women diagnosed with HIV-1. Here, we aimed to assess viral and demographic characteristics of HIV-1-positive women identified in Israel between 2010 and 2018. METHODS: All > 16 year-old, HIV-1-infected women, diagnosed in Israel in 2010-2018, (n = 763) registered in the National HIV reference laboratory were included in this cross-sectional study. Demographic and clinical characteristics were extracted from the database. Viral subtypes and transmitted drug resistance mutations (TDRM) were determined in 337 (44.2%) randomly selected samples collected from treatment-naive women. RESULTS: Median age at diagnosis was 38 years. Most (73.3%) women were immigrants from the former Soviet Union (FSU) (41.2%, 314) or sub-Saharan Africa (SSA) (32.2%, 246) and carried subtype A (79.7%) or C (90.3%), respectively. Only 11.4% (87) were Israeli-born women. Over the years, the prevalence of women from SSA decreased while that of women from FSU increased significantly (p < 0.001). The median CD4+ cell count was 263 cells/mm3, and higher (391 cells/mm3) in Israeli-born women. TDRM were identified in 10.4% of the tested samples; 1.8, 3 and 7.1% had protease inhibitors (PI), nucleotide reverse transcriptase inhibitors (NRTI) and non-nucleoside reverse transcriptase inhibitors (NNRTI) TDRM, respectively. The prevalence of women with NNRTI TDRM significantly increased from 4.9% in 2010-2012 to 13.3% in 2016-2018. Israeli-born women had the highest prevalence (16.3%) of NNRTI TDRM (p = 0.014). NRTI A62 (5.6%), NNRTI E138 and K103 (5.6 and 4.2%, respectively) were the most prominent mutated sites. CONCLUSIONS: Most HIV-1-positive women diagnosed in Israel in 2010-2018 were immigrants, with the relative ratio of FSU immigrants increasing in recent years. The high proportion of women diagnosed with resistance mutations, particularly, the yearly increase in the frequency of NNRTI mutations, support the national policy of resistance testing at baseline.


Assuntos
Infecções por HIV/diagnóstico , Infecções por HIV/epidemiologia , HIV-1/genética , Adulto , Antivirais/uso terapêutico , Contagem de Linfócito CD4 , Estudos de Coortes , Estudos Transversais , Farmacorresistência Viral/genética , Emigrantes e Imigrantes , Feminino , Infecções por HIV/tratamento farmacológico , Humanos , Israel/epidemiologia , Pessoa de Meia-Idade , Mutação , Prevalência , Inibidores da Transcriptase Reversa/uso terapêutico
20.
Nat Commun ; 11(1): 4737, 2020 09 23.
Artigo em Inglês | MEDLINE | ID: mdl-32968070

RESUMO

Innate immune signaling through the NLRP3 inflammasome is activated by multiple diabetes-related stressors, but whether targeting the inflammasome is beneficial for diabetes is still unclear. Nucleoside reverse-transcriptase inhibitors (NRTI), drugs approved to treat HIV-1 and hepatitis B infections, also block inflammasome activation. Here, we show, by analyzing five health insurance databases, that the adjusted risk of incident diabetes is 33% lower in patients with NRTI exposure among 128,861 patients with HIV-1 or hepatitis B (adjusted hazard ratio for NRTI exposure, 0.673; 95% confidence interval, 0.638 to 0.710; P < 0.0001; 95% prediction interval, 0.618 to 0.734). Meanwhile, an NRTI, lamivudine, improves insulin sensitivity and reduces inflammasome activation in diabetic and insulin resistance-induced human cells, as well as in mice fed with high-fat chow; mechanistically, inflammasome-activating short interspersed nuclear element (SINE) transcripts are elevated, whereas SINE-catabolizing DICER1 is reduced, in diabetic cells and mice. These data suggest the possibility of repurposing an approved class of drugs for prevention of diabetes.


Assuntos
Diabetes Mellitus Tipo 2/tratamento farmacológico , Reposicionamento de Medicamentos , Inflamassomos/efeitos dos fármacos , Resistência à Insulina , Inibidores da Transcriptase Reversa/farmacologia , Adipócitos/metabolismo , Animais , Sobrevivência Celular , RNA Helicases DEAD-box/metabolismo , Diabetes Mellitus Tipo 2/prevenção & controle , Dieta Hiperlipídica/efeitos adversos , HIV-1/efeitos dos fármacos , Hepatite B , Humanos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Células Musculares/metabolismo , Ribonuclease III/metabolismo
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