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1.
Lancet HIV ; 7(10): e666-e676, 2020 10.
Artigo em Inglês | MEDLINE | ID: mdl-33010240

RESUMO

BACKGROUND: ADVANCE compared the efficacy and safety of two antiretroviral first-line combinations (dolutegravir combined with emtricitabine and either tenofovir disoproxil fumarate or tenofovir alafenamide), with a third regimen (efavirenz combined with emtricitabine and tenofovir disoproxil fumarate) previously recommended by WHO. Here, we report the 96-week data for the study. METHODS: This randomised, open-label, non-inferiority phase 3 trial, was done at two research sites in Johannesburg, South Africa, after participant recruitment from 11 public health clinics also in Johannesburg. Eligible participants were aged 12 years or older with HIV-1 infection, who weighed at least 40 kg, had no antiretroviral exposure in the previous 6 months, with a creatinine clearance of more than 60 mL/min (>80 mL per min in individuals aged <19 years), and a plasma HIV-1 RNA concentration of 500 copies per mL or higher. Individuals who were pregnant or had tuberculosis were excluded. Participants were randomly assigned (1:1:1) by study staff using a computerised randomisation system. Randomisation was stratified by age (12 and <19 years and ≥19 years). Participants were randomly assigned to once-daily oral fixed-dose combination tenofovir alafenamide 25 mg and emtricitabine 200 mg, and once-daily oral dolutegravir 50 mg; once-daily oral fixed-dose combination tenofovir disoproxil fumarate 300 mg and emtricitabine 200 mg, and once-daily oral dolutegravir 50 mg; or once-daily oral fixed-dose combination of tenofovir disoproxil fumarate 300 mg, emtricitabine 200 mg, and efavirenz 600 mg. The primary efficacy endpoint was the proportion of participants who had a plasma HIV-1 RNA concentration of less than 50 copies per mL at week 48, which has been reported previously. Here, we report the key secondary efficacy endpoint of the proportion of participants who had a plasma HIV-1 RNA concentration of less than 50 copies per mL at the week 96 visit, assessed in all participants who received at least one dose of any study drug, with a prespecified non-inferiority margin of -10%. Safety data, including clinical, dual-energy X-ray absorptiometry and laboratory data, are also reported. This study was registered with ClinicalTrials.gov, NCT03122262. FINDINGS: Between Jan 17, 2017, and May 14, 2018, we screened 1453 individuals, of whom 1053 were enrolled: 351 participants were randomly assigned to the tenofovir alafenamide, emtricitabine, and dolutegravir group, 351 to the tenofovir disoproxil fumarate, emtricitabine, and dolutegravir group, and 351 to the tenofovir disoproxil fumarate, emtricitabine, and efavirenz group. All participants received at least one dose of study medication and were included in the primary analysis. At week 96, 276 (79%) of 351 participants in the tenofovir alafenamide, emtricitabine, and dolutegravir group, 275 (78%) of 351 participants in the tenofovir disoproxil fumarate, emtricitabine, and dolutegravir group, and 258 (74%) of 351 participants in the tenofovir disoproxil fumarate, emtricitabine, and efavirenz group had achieved a plasma HIV-1 RNA concentration of less than 50 copies per mL. Non-inferiority was established in all three comparisons. The proportion of patients with protocol-defined virological failure at week 96 was low in all treatment groups. Participants in the tenofovir alafenamide, emtricitabine, and dolutegravir group had fewer changes in bone density than the two other treatment groups. Mean weight gain was substantial (7·1 kg [SD 7·4] in the tenofovir alafenamide, emtricitabine, and dolutegravir group; 4·3 kg [6·7] in the tenofovir disoproxil fumarate, emtricitabine, and dolutegravir group, and 2·3 kg [7·0] in the tenofovir disoproxil fumarate, emtricitabine, and efavirenz group), and was greater among women than men. Ten (3%) of 351 participants in the tenofovir disoproxil fumarate, emtricitabine, and efavirenz group discontinued due to treatment-related adverse events, of which liver dysfunction (n=4) and rash (n=4) were most common. INTERPRETATION: Medium-term and long-term metabolic and clinical consequences of the considerable increase in bodyweight observed in participants given these antiretroviral regimens and the trajectory of this weight gain over time, especially among women, require further study. FUNDING: USAID, Unitaid, South African Medical Research Council, ViiV Healthcare.


Assuntos
Fármacos Anti-HIV/uso terapêutico , Terapia Antirretroviral de Alta Atividade , Infecções por HIV/tratamento farmacológico , Infecções por HIV/virologia , HIV-1/efeitos dos fármacos , Adenina/administração & dosagem , Adenina/análogos & derivados , Adolescente , Adulto , Fármacos Anti-HIV/administração & dosagem , Fármacos Anti-HIV/efeitos adversos , Benzoxazinas/administração & dosagem , Composição Corporal , Peso Corporal , Duração da Terapia , Emtricitabina/administração & dosagem , Feminino , Compostos Heterocíclicos com 3 Anéis/administração & dosagem , Humanos , Masculino , Pessoa de Meia-Idade , Tenofovir/administração & dosagem , Resultado do Tratamento , Carga Viral , Adulto Jovem
2.
Lancet HIV ; 7(10): e677-e687, 2020 10.
Artigo em Inglês | MEDLINE | ID: mdl-33010241

RESUMO

BACKGROUND: Updated WHO guidelines recommend a dolutegravir-based regimen as the preferred first-line treatment for HIV infection and low-dose efavirenz (400 mg) as an alternative. We aimed to report the non-inferior efficacy of dolutegravir compared with efavirenz 400 mg at week 96. METHODS: We did a multicentre, randomised, open label, phase 3 trial in in three hospitals in Yaoundé, Cameroon, in HIV-1 infected antiretroviral-naive adults with an HIV RNA viral load of greater than 1000 copies per mL to compare dolutegravir 50 mg with efavirenz 400 mg (reference treatment), both combined with lamivudine and tenofovir disoproxil fumarate. The primary endpoint was the proportion with a viral load of less than 50 copies per mL at week 48 (10% non-inferiority margin). The study is registered with ClinicalTrials.gov, NCT02777229 and is ongoing. FINDINGS: Between July, 2016, and August, 2019, of 820 patients assessed, 613 were randomly assigned to receive at least one dose of study medication, with 310 in the dolutegravir group and 303 in the efavirenz 400 mg group. At week 96 in the intention-to-treat analysis, 229 (74%) of 310 patients receiving dolutegravir and 219 (72%) of 303 patients receiving efavirenz, achieved plasma HIV-1 RNA less than 50 copies per mL (difference 1·6%, 95% CI -5·4 to 8·6; p=0.66). Viral load suppression was reached significantly more rapidly in the dolutegravir group (p<0·001). Virological failure (>1000 copies per mL) was observed in 27 patients (eight in the dolutegravir group, among which, three women switched to efavirenz 600 mg because of the dolutegravir teratogeneicity signal, and 19 in the efavirenz 400 mg group). No acquired resistance mutations to dolutegravir were observed against 17 mutations to efavirenz with or without mutations to lamivudine and tenofovir disoproxil fumarate among the 19 efavirenz 400 mg participants with virological failure. Weight gain was greater in the dolutegravir group (median weight gain, 5·0 kg in the dolutegravir group and 3·0 kg in the efavirenz 400 mg group, p<0·001, and incidence of obesity, 22% in the dolutegravir group and 16% in the efavirenz 400 mg group, p=0·043). The incidence of new WHO HIV-related stage 3 and 4 events was similar in each group (12 [4%] in each group). The two groups had similar rates of serious adverse events (28 [9%] of 310 in the dolutegravir group and 21 [7%] of 303 in the efavirenz 400 mg group). 18 deaths were observed during the 96-week follow-up (eight in the dolutegravir group and ten in the efavirenz 400 mg group). INTERPRETATION: The non-inferior efficacy of the dolutegravir-based regimen and non-emergence of dolutegravir resistance at 96 weeks supports its use as a first-line regimen for antiretroviral-naive adults with HIV-1 infection. Viral load suppression was reached more quickly in the dolutegravir group and weight gain was significantly higher. FUNDING: UNITAID and the French National Agency for AIDS Research.


Assuntos
Fármacos Anti-HIV/uso terapêutico , Terapia Antirretroviral de Alta Atividade , Infecções por HIV/tratamento farmacológico , Infecções por HIV/virologia , HIV-1/efeitos dos fármacos , Adulto , Fármacos Anti-HIV/administração & dosagem , Fármacos Anti-HIV/efeitos adversos , Terapia Antirretroviral de Alta Atividade/efeitos adversos , Terapia Antirretroviral de Alta Atividade/métodos , Benzoxazinas/administração & dosagem , Contagem de Linfócito CD4 , Duração da Terapia , Feminino , Compostos Heterocíclicos com 3 Anéis/administração & dosagem , Humanos , Pessoa de Meia-Idade , Resultado do Tratamento , Carga Viral , Adulto Jovem
3.
Lancet HIV ; 7(10): e688-e698, 2020 10.
Artigo em Inglês | MEDLINE | ID: mdl-33010242

RESUMO

BACKGROUND: Bioinformatically designed mosaic antigens increase the breadth of HIV vaccine-elicited immunity. This study compared the safety, tolerability, and immunogenicity of a newly developed, tetravalent Ad26 vaccine with the previously tested trivalent formulation. METHODS: This randomised, parallel-group, placebo-controlled, double-blind, phase 1/2a study (TRAVERSE) was done at 11 centres in the USA and one centre in Rwanda. Eligible participants were adults aged 18 to 50 years, who were HIV-uninfected, healthy at screening based on their medical history and a physical examination including laboratory assessment and vital sign measurements, and at low risk of HIV infection in the opinion of study staff, who applied a uniform definition of low-risk guidelines that was aligned across sites. Enrolled participants were randomly assigned at a 2:1 ratio to tetravalent and trivalent groups. Participants in tetravalent and trivalent groups were then further randomly assigned at a 5:1 ratio to adenovirus 26 (Ad26)-vectored vaccine and placebo subgroups. Randomisation was stratified by region (USA and Rwanda) and based on a computer-generated schedule using randomly permuted blocks prepared under the sponsor's supervision. We masked participants and investigators to treatment allocation throughout the study. On day 0, participants received a first injection of tetravalent vaccine (Ad26.Mos4.HIV or placebo) or trivalent vaccine (Ad26.Mos.HIV or placebo), and those injections were repeated 12 weeks later. At week 24, vaccine groups received a third dose of tetravalent or trivalent together with clade C gp140, and this was repeated at week 48, with placebos again administered to the placebo group. All study vaccines and placebo were administered by intramuscular injection in the deltoid muscle. We assessed adverse events in all participants who received at least one study injection (full analysis set) and Env-specific binding antibodies in all participants who received at least the first three vaccinations according to the protocol-specified vaccination schedule, had at least one measured post-dose blood sample collected, and were not diagnosed with HIV during the study (per-protocol set). This study is registered with Clinicaltrials.gov, NCT02788045. FINDINGS: Of 201 participants who were enrolled and randomly assigned, 198 received the first vaccination: 110 were in the tetravalent group, 55 in the trivalent group, and 33 in the placebo group. Overall, 185 (93%) completed two scheduled vaccinations per protocol, 180 (91%) completed three, and 164 (83%) completed four. Solicited, self-limiting local, systemic reactogenicity and unsolicited adverse events were similar in vaccine groups and higher than in placebo groups. All participants in the per-protocol set developed clade C Env binding antibodies after the second vaccination, with higher total IgG titres after the tetravalent vaccine than after the trivalent vaccine (10 413 EU/mL, 95% CI 7284-14 886 in the tetravalent group compared with 5494 EU/mL, 3759-8029 in the trivalent group). Titres further increased after the third and fourth vaccinations, persisting at least through week 72. Other immune responses were also higher with the tetravalent vaccine, including the magnitude and breadth of binding antibodies against a cross-clade panel of Env antigens, and the magnitude of IFNγ ELISPOT responses (median 521 SFU/106 peripheral blood mononuclear cells [PBMCs] in the tetravalent group and median 282 SFU/106 PBMCs in the trivalent group after the fourth vaccination) and Env-specific CD4+ T-cell response rates after the third and fourth vaccinations. No interference by pre-existing Ad26 immunity was identified. INTERPRETATION: The tetravalent vaccine regimen was generally safe, well-tolerated, and found to elicit higher immune responses than the trivalent regimen. Regimens that use this tetravalent vaccine component are being advanced into field trials to assess efficacy against HIV-1 infection. FUNDING: National Institutes of Health, Henry M Jackson Foundation for Advancement of Military Medicine and the US Department of Defense, Ragon Institute of MGH, MIT, & Harvard, Bill & Melinda Gates Foundation, and Janssen Vaccines & Prevention.


Assuntos
Vacinas contra a AIDS/imunologia , Infecções por HIV/imunologia , HIV-1/imunologia , Imunogenicidade da Vacina , Vacinas contra a AIDS/administração & dosagem , Vacinas contra a AIDS/efeitos adversos , Adulto , Feminino , Anticorpos Anti-HIV/imunologia , Infecções por HIV/prevenção & controle , Voluntários Saudáveis , Humanos , Esquemas de Imunização , Masculino , Pessoa de Meia-Idade , Resultado do Tratamento , Vacinação , Adulto Jovem
4.
BMC Infect Dis ; 20(1): 727, 2020 Oct 06.
Artigo em Inglês | MEDLINE | ID: mdl-33023498

RESUMO

BACKGROUND: Viral load (VL) testing is the gold-standard approach for monitoring human immunodeficiency virus (HIV) treatment success and virologic failure, but uptake is suboptimal in resource-limited and rural settings. We conducted a cross-sectional study of risk factors for non-uptake of VL testing in rural Uganda. METHODS: We conducted a cross-sectional analysis of uptake of VL testing among randomly selected people with HIV (PWH) receiving anti-retroviral treatment (ART) for at least 6 months at all eight primary health centers in Gomba district, rural Uganda. Socio-demographic and clinical data were extracted from medical records for the period January to December 2017. VL testing was routinely performed 6 months after ART initiation and 12 months thereafter for PWH stable on ART. We used descriptive statistics and multivariable logistic regression to evaluate factors associated with non-uptake of VL testing (the primary outcome). RESULTS: Of 414 PWH, 60% were female, and the median age was 40 years (interquartile range [IQR] 31-48). Most (62.3%) had been on ART > 2 years, and the median duration of treatment was 34 months (IQR 14-55). Thirty three percent did not receive VL testing: 36% of women and 30% of men. Shorter duration of ART (≤2 years) (adjusted odds ratio [AOR] 2.38; 95% CI:1.37-4.12; p = 0.002), younger age 16-30 years (AOR 2.74; 95% CI:1.44-5.24; p = 0.002) and 31-45 years (AOR 1.92; 95% CI 1.12-3.27; p = 0.017), and receipt of ART at Health Center IV (AOR 2.85; 95% CI: 1.78-4.56; p < 0.001) were significantly associated with non-uptake of VL testing. CONCLUSIONS: One-in-three PWH on ART missed VL testing in rural Uganda. Strategies to improve coverage of VL testing, such as VL focal persons to flag missed tests, patient education and demand creation for VL testing are needed, particularly for recent ART initiates and younger persons on treatment, in order to attain the third Joint United Nations Program on HIV/AIDS (UNAIDS) 95-95-95 target - virologic suppression for 95% of PWH on ART.


Assuntos
Antirretrovirais/uso terapêutico , Infecções por HIV/tratamento farmacológico , Infecções por HIV/epidemiologia , HIV-1/imunologia , População Rural , Carga Viral/efeitos dos fármacos , Adolescente , Adulto , Criança , Pré-Escolar , Estudos Transversais , Feminino , Infecções por HIV/virologia , Humanos , Lactente , Modelos Logísticos , Masculino , Pessoa de Meia-Idade , Razão de Chances , Fatores de Risco , Testes Sorológicos , Resposta Viral Sustentada , Uganda/epidemiologia , Adulto Jovem
5.
BMC Infect Dis ; 20(1): 742, 2020 Oct 09.
Artigo em Inglês | MEDLINE | ID: mdl-33036558

RESUMO

BACKGROUND: The surge of methamphetamine use has been a complicating factor compounding the steeply increasing number of drug overdose deaths in the U.S. Infection from blood-borne viruses including hepatitis B virus (HBV), hepatitis C virus (HCV) and HIV, related to methamphetamine use continue to grow. This study aims to examine the risk factors associated with HBV, HCV and HIV among people who used methamphetamine. METHODS: People who ever used methamphetamine were identified from five National Health and Nutrition Examination Survey (NHANES) cohorts, 2007 to 2016. The outcome was either positive or negative for blood-borne viruses as identified from laboratory tests. Weighted statistics for the combined ten years of data were calculated by multiplying the weighted variable for laboratory measurements by 0.2. We examined the association of sexual activities (sexual partners, sexual identity), drug use behaviors (poly-drug use, injection drug use, frequency of drug use, age started using methamphetamine), demographics, and socio-economic status with blood-borne viruses using bivariate and multivariable logistic regression models. RESULTS: There were 1132 participants representing approximately 11,996,319 persons who ever used methamphetamine in the U.S. Blood-borne viruses' positive rate was 13.0 per 100,000. Multivariable logistic regression analyses showed significant associations of blood-borne infections with age 40-49 years (vs. age 20-29 years, adjusted odds ratio 4.77, 95% CI 1.11-20.55), age 50-59 years (vs. age 20-29 years, 10.25, 2.40-43.82), living within poverty index 1-1.9 (vs. poverty index > = 2, 2.55; 1.19-5.49), living below the poverty threshold (vs. poverty index > = 2, 2.55; 1.11-5.86), having lower than high school education (vs. equal or higher than high school education, 3.13; 1.51-6.46), sexual identity as other than heterosexual (vs. heterosexual, 5.60; 1.72-18.28), using methamphetamine and heroin and cocaine (vs. using methamphetamine alone, 4.24; 1.06-16.92), injection drug use (vs. no injection drug use, 3.15; 1.61-6.16), and started using methamphetamine at age above 25 (vs. started using methamphetamine at age between 10 and 17, 2.09; 1.01-4.35). CONCLUSIONS: Among people who use methamphetamine, those who use polysubstance, or who inject substances, are in urgent need for vaccination and interventions to avoid further harm from blood borne infections.


Assuntos
Infecções por HIV/epidemiologia , HIV-1/imunologia , HIV-2/imunologia , Hepacivirus/imunologia , Vírus da Hepatite B/imunologia , Hepatite B/epidemiologia , Hepatite C/epidemiologia , Metanfetamina , Abuso de Substâncias por Via Intravenosa , Adulto , Estudos de Coortes , Estudos Transversais , Feminino , Infecções por HIV/virologia , Hepatite B/virologia , Hepatite C/virologia , Humanos , Modelos Logísticos , Masculino , Pessoa de Meia-Idade , Inquéritos Nutricionais , Razão de Chances , Fatores de Risco , Assunção de Riscos , Testes Sorológicos , Comportamento Sexual , Parceiros Sexuais , Adulto Jovem
6.
Phys Rev Lett ; 125(12): 128101, 2020 Sep 18.
Artigo em Inglês | MEDLINE | ID: mdl-33016741

RESUMO

The efficiency of a virus to establish its infection in host cells varies broadly among viruses. It remains unclear if there is a key step in this process that controls viral infectivity. To address this question, we use single-particle tracking and Brownian dynamics simulation to examine human immunodeficiency virus type 1 (HIV-1) infection in cell culture. We find that the frequency of viral-cell encounters is consistent with diffusion-limited interactions. However, even under the most favorable conditions, only 1% of the viruses can become immobilized on cell surface and subsequently enter the cell. This is a result of weak interaction between viral surface gp120 and CD4 receptor, which is insufficient to form a stable complex the majority of the time. We provide the first direct quantitation for efficiencies of these events relevant to measured HIV-1 infectivity and demonstrate that immobilization on host cell surface post-virion-diffusion is the key step in viral infection. Variation of its probability controls the efficiency of a virus to infect its host cells. These results explain the low infectivity of cell-free HIV-1 in vitro and offer a potential rationale for the pervasive high efficiency of cell-to-cell transmission of animal viruses.


Assuntos
HIV-1/patogenicidade , Antígenos CD4/metabolismo , Linhagem Celular , Proteína gp120 do Envelope de HIV/metabolismo , HIV-1/metabolismo , Humanos , Imagem Óptica , Imagem com Lapso de Tempo , Vírion/metabolismo , Vírion/patogenicidade
7.
Medicine (Baltimore) ; 99(41): e22606, 2020 Oct 09.
Artigo em Inglês | MEDLINE | ID: mdl-33031315

RESUMO

To determine effects of cryptococcal meningitis (CM) on human immunodeficiency virus (HIV)-1C cerebrospinal fluid (CSF) viral escape, CSF/plasma viral discordance, and drug resistance mutation (DRM) discordance between CSF and plasma compartments, we compared CSF and plasma viral load (VL) and DRMs in individuals with HIV-associated CM in Botswana.This cross-sectional study utilized 45 paired CSF/plasma samples from participants in a CM treatment trial (2014-2016). HIV-1 VL was determined and HIV-1 protease and reverse transcriptase genotyping performed. DRMs were determined using the Stanford HIV database. CSF viral escape was defined as HIV-1 ribonucleic acid ≥0.5 log10 higher in CSF than plasma and VL discordance as CSF VL > plasma VL.HIV-1 VL was successfully measured in 39/45 pairs, with insufficient sample volume in 6; 34/39 (87.2%) participants had detectable HIV-1 in plasma and CSF, median 5.1 (interquartile range: 4.7-5.7) and 4.6 (interquartile range:3.7-4.9) log10 copies/mL, respectively (P≤.001). CSF viral escape was present in 1/34 (2.9%) and VL discordance in 6/34 (17.6%). Discordance was not associated with CD4 count, antiretroviral status, fungal burden, CSF lymphocyte percentage nor mental status. Twenty-six of 45 (57.8%) CSF/plasma pairs were successfully sequenced. HIV-1 DRM discordance was found in 3/26 (11.5%); 1 had I84IT and another had M46MI in CSF only. The third had K101E in plasma and V106 M in CSF.Our findings suggest that HIV-1 escape and DRM discordance may occur at lower rates in participants with advanced HIV-disease and CM compared to those with HIV associated neurocognitive impairment.


Assuntos
Farmacorresistência Viral/genética , Infecções por HIV/sangue , Infecções por HIV/líquido cefalorraquidiano , HIV-1/genética , Meningite Criptocócica/virologia , Adulto , Estudos Transversais , Feminino , Genes pol , Infecções por HIV/virologia , Humanos , Masculino , Meningite Criptocócica/sangue , Meningite Criptocócica/líquido cefalorraquidiano , Mutação , Estudos Retrospectivos , Carga Viral
8.
Cells ; 9(9)2020 09 15.
Artigo em Inglês | MEDLINE | ID: mdl-32942671

RESUMO

The small molecule macrocyclic lactone ivermectin, approved by the US Food and Drug Administration for parasitic infections, has received renewed attention in the last eight years due to its apparent exciting potential as an antiviral. It was identified in a high-throughput chemical screen as inhibiting recognition of the nuclear localizing Human Immunodeficiency Virus-1 (HIV-1) integrase protein by the host heterodimeric importin (IMP) α/ß1 complex, and has since been shown to bind directly to IMPα to induce conformational changes that prevent its normal function in mediating nuclear import of key viral and host proteins. Excitingly, cell culture experiments show robust antiviral action towards HIV-1, dengue virus (DENV), Zika virus, West Nile virus, Venezuelan equine encephalitis virus, Chikungunya virus, Pseudorabies virus, adenovirus, and SARS-CoV-2 (COVID-19). Phase III human clinical trials have been completed for DENV, with >50 trials currently in progress worldwide for SARS-CoV-2. This mini-review discusses the case for ivermectin as a host-directed broad-spectrum antiviral agent for a range of viruses, including SARS-CoV-2.


Assuntos
Antivirais/farmacologia , Betacoronavirus/efeitos dos fármacos , Infecções por Coronavirus/tratamento farmacológico , HIV-1/efeitos dos fármacos , Ivermectina/farmacologia , Pneumonia Viral/tratamento farmacológico , Animais , Linhagem Celular , Chlorocebus aethiops , Dengue/tratamento farmacológico , Vírus da Dengue/efeitos dos fármacos , Infecções por HIV/tratamento farmacológico , Integrase de HIV/efeitos dos fármacos , Inibidores de Integrase de HIV/farmacologia , Humanos , Pandemias , Células Vero , Zika virus/efeitos dos fármacos , Infecção por Zika virus/tratamento farmacológico
9.
PLoS Pathog ; 16(8): e1008753, 2020 08.
Artigo em Inglês | MEDLINE | ID: mdl-32866207

RESUMO

The induction of broad and potent immunity by vaccines is the key focus of research efforts aimed at protecting against HIV-1 infection. Soluble native-like HIV-1 envelope glycoproteins have shown promise as vaccine candidates as they can induce potent autologous neutralizing responses in rabbits and non-human primates. In this study, monoclonal antibodies were isolated and characterized from rhesus macaques immunized with the BG505 SOSIP.664 trimer to better understand vaccine-induced antibody responses. Our studies reveal a diverse landscape of antibodies recognizing immunodominant strain-specific epitopes and non-neutralizing neo-epitopes. Additionally, we isolated a subset of mAbs against an epitope cluster at the gp120-gp41 interface that recognize the highly conserved fusion peptide and the glycan at position 88 and have characteristics akin to several human-derived broadly neutralizing antibodies.


Assuntos
Vacinas contra a AIDS/imunologia , Mapeamento de Epitopos , Epitopos/imunologia , Anticorpos Anti-HIV/imunologia , Proteína gp120 do Envelope de HIV/imunologia , Proteína gp41 do Envelope de HIV/imunologia , HIV-1/imunologia , Vacinas contra a AIDS/genética , Animais , Anticorpos Monoclonais Murinos/imunologia , Epitopos/genética , Anticorpos Anti-HIV/genética , Proteína gp41 do Envelope de HIV/genética , HIV-1/genética , Macaca mulatta , Multimerização Proteica/genética , Multimerização Proteica/imunologia
10.
PLoS Comput Biol ; 16(9): e1008122, 2020 09.
Artigo em Inglês | MEDLINE | ID: mdl-32881984

RESUMO

Spread of HIV typically involves uneven transmission patterns where some individuals spread to a large number of individuals while others to only a few or none. Such transmission heterogeneity can impact how fast and how much an epidemic spreads. Further, more efficient interventions may be achieved by taking such transmission heterogeneity into account. To address these issues, we developed two phylogenetic methods based on virus sequence data: 1) to generally detect if significant transmission heterogeneity is present, and 2) to pinpoint where in a phylogeny high-level spread is occurring. We derive inference procedures to estimate model parameters, including the amount of transmission heterogeneity, in a sampled epidemic. We show that it is possible to detect transmission heterogeneity under a wide range of simulated situations, including incomplete sampling, varying levels of heterogeneity, and including within-host genetic diversity. When evaluating real HIV-1 data from different epidemic scenarios, we found a lower level of transmission heterogeneity in slowly spreading situations and a higher level of heterogeneity in data that included a rapid outbreak, while R0 and Sackin's index (overall tree shape statistic) were similar in the two scenarios, suggesting that our new method is able to detect transmission heterogeneity in real data. We then show by simulations that targeted prevention, where we pinpoint high-level spread using a coalescence measurement, is efficient when sequence data are collected in an ongoing surveillance system. Such phylogeny-guided prevention is efficient under both single-step contact tracing as well as iterative contact tracing as compared to random intervention.


Assuntos
Infecções por HIV/prevenção & controle , Infecções por HIV/transmissão , HIV-1/classificação , HIV-1/genética , Algoritmos , Biologia Computacional , Simulação por Computador , Infecções por HIV/epidemiologia , Infecções por HIV/virologia , Humanos , Filogenia
11.
PLoS Pathog ; 16(9): e1008853, 2020 09.
Artigo em Inglês | MEDLINE | ID: mdl-32886726

RESUMO

HIV-1 transmission is associated with a severe bottleneck in which a limited number of variants from a pool of genetically diverse quasispecies establishes infection. The IAVI protocol C cohort of discordant couples, female sex workers, other heterosexuals and men who have sex with men (MSM) present varying risks of HIV infection, diverse HIV-1 subtypes and represent a unique opportunity to characterize transmitted/founder viruses (TF) where disease outcome is known. To identify the TF, the HIV-1 repertoire of 38 MSM participants' samples was sequenced close to transmission (median 21 days post infection, IQR 18-41) and assessment of multivariant infection done. Patient derived gag genes were cloned into an NL4.3 provirus to generate chimeric viruses which were characterized for replicative capacity (RC). Finally, an evaluation of how the TF virus predicted disease progression and modified the immune response at both acute and chronic HIV-1 infection was done. There was higher prevalence of multivariant infection compared with previously described heterosexual cohorts. A link was identified between multivariant infection and replicative capacity conferred by gag, whereby TF gag tended to be of lower replicative capacity in multivariant infection (p = 0.02) suggesting an overall lowering of fitness requirements during infection with multiple variants. Notwithstanding, multivariant infection was associated with rapid CD4+ T cell decline and perturbances in the CD4+ T cell and B cell compartments compared to single variant infection, which were reversible upon control of viremia. Strategies aimed at identifying and mitigating multivariant infection could contribute toward improving HIV-1 prognosis and this may involve strategies that tighten the stringency of the transmission bottleneck such as treatment of STI. Furthermore, the sequences and chimeric viruses help with TF based experimental vaccine immunogen design and can be used in functional assays to probe effective immune responses against TF.


Assuntos
Linfócitos T CD4-Positivos/imunologia , Efeito Fundador , Infecções por HIV , HIV-1/fisiologia , Replicação Viral , Produtos do Gene gag do Vírus da Imunodeficiência Humana , Doença Aguda , Adolescente , Adulto , Linfócitos B/imunologia , Linfócitos B/patologia , Linfócitos T CD4-Positivos/patologia , Linfócitos T CD4-Positivos/virologia , Feminino , Infecções por HIV/genética , Infecções por HIV/imunologia , Infecções por HIV/patologia , Humanos , Masculino , Pessoa de Meia-Idade , Viremia/genética , Viremia/imunologia , Viremia/patologia , Replicação Viral/genética , Replicação Viral/imunologia , Produtos do Gene gag do Vírus da Imunodeficiência Humana/genética , Produtos do Gene gag do Vírus da Imunodeficiência Humana/imunologia
12.
PLoS Pathog ; 16(9): e1008821, 2020 09.
Artigo em Inglês | MEDLINE | ID: mdl-32941545

RESUMO

MHC-I-restricted, virus-specific cytotoxic CD8+ T cells (CTLs) may control human immunodeficiency virus (HIV) and simian immunodeficiency virus (SIV) replication via the recognition and killing of productively infected CD4+ T cells. Several studies in SIV-infected macaques suggest that CD8+ T cells may also decrease virus production by suppressing viral transcription. Here, we show that non-HIV-specific, TCR-activated non-cytolytic CD8+ T cells suppress HIV transcription via a virus- and MHC-independent immunoregulatory mechanism that modulates CD4+ T cell proliferation and activation. We also demonstrate that this CD8+ T cell-mediated effect promotes the survival of infected CD4+ T cells harboring integrated, inducible virus. Finally, we used RNA sequencing and secretome analyses to identify candidate cellular pathways that are involved in the virus-silencing mediated by these CD8+ T cells. This study characterizes a previously undescribed mechanism of immune-mediated HIV silencing that may be involved in the establishment and maintenance of the reservoir under antiretroviral therapy and therefore represent a major obstacle to HIV eradication.


Assuntos
Linfócitos T CD8-Positivos/imunologia , HIV-1/fisiologia , Antígenos de Histocompatibilidade Classe I/imunologia , Imunidade Inata , Transcrição Genética/imunologia , Replicação Viral/imunologia , Animais , Linfócitos T CD4-Positivos/imunologia , Linfócitos T CD8-Positivos/patologia , Proliferação de Células , Humanos , Macaca
13.
PLoS Pathog ; 16(9): e1008834, 2020 09.
Artigo em Inglês | MEDLINE | ID: mdl-32956422

RESUMO

Despite the widespread use of anti-retroviral therapy, human immunodeficiency virus (HIV) still persists in an infected cell reservoir that harbors transcriptionally silent yet replication-competent proviruses. While significant progress has been made in understanding how the HIV reservoir is established, transcription repression mechanisms that are enforced on the integrated viral promoter have not been fully revealed. In this study, we performed a whole-genome CRISPR knockout screen in HIV infected T cells to identify host genes that potentially promote HIV latency. Of several top candidates, the KRAB-containing zinc finger protein, ZNF304, was identified as the top hit. ZNF304 silences HIV gene transcription through associating with TRIM28 and recruiting to the viral promoter heterochromatin-inducing methyltransferases, including the polycomb repression complex (PRC) and SETB1. Depletion of ZNF304 expression reduced levels of H3K9me3, H3K27me3 and H2AK119ub repressive histone marks on the HIV promoter as well as SETB1 and TRIM28, ultimately enhancing HIV gene transcription. Significantly, ZNF304 also promoted HIV latency, as its depletion delayed the entry of HIV infected cells into latency. In primary CD4+ cells, ectopic expression of ZNF304 silenced viral transcription. We conclude that by associating with TRIM28 and recruiting host transcriptional repressive complexes, SETB1 and PRC, to the HIV promoter, ZNF304 silences HIV gene transcription and promotes viral latency.


Assuntos
Linfócitos T CD4-Positivos/metabolismo , Regulação Viral da Expressão Gênica , Inativação Gênica , HIV-1/fisiologia , Proteínas Repressoras , Fatores de Transcrição , Transcrição Genética , Latência Viral , Linfócitos T CD4-Positivos/virologia , Sistemas CRISPR-Cas , Técnicas de Inativação de Genes , Estudo de Associação Genômica Ampla , Humanos , Células Jurkat , Regiões Promotoras Genéticas , Proteínas Repressoras/genética , Proteínas Repressoras/metabolismo , Fatores de Transcrição/genética , Fatores de Transcrição/metabolismo , Proteína 28 com Motivo Tripartido/genética , Proteína 28 com Motivo Tripartido/metabolismo
14.
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
16.
Zhonghua Liu Xing Bing Xue Za Zhi ; 41(8): 1335-1340, 2020 Aug 10.
Artigo em Chinês | MEDLINE | ID: mdl-32867446

RESUMO

Objective: To understand the characteristics of HIV-1 genotypes and drug resistance among men who have sex with men in Kunming in 2018. Methods: A total of 193 plasma samples were collected from the newly reported HIV-1 infected MSM in Kunming from January to December 2018. Viral RNA was extracted, and the gag, pol, env gene segments were amplified by nested PCR. HIV-1 genotypes and drug resistance were also analyzed. Subsequently, the evolutionary characteristics of CRF55_01B and CRF68_01B among MSM in Kunming were analyzed by Bayesian Markov Chain Monte Carlo method. Results: Multiple HIV-1 genotypes were identified among these 193 samples, including CRF07_BC (39.4%, 76/193), CRF01_AE (34.2%, 66/193), unique recombinant forms (URFs) (20.2%, 39/193), CRF08_BC (3.1%, 6/193), CRF55_01B (1.6%, 3/193), subtype B (1.0%, 2/193) and CRF68_01B (0.5%, 1/193). Results from the Bayesian evolutionary analysis showed that CRF55_01B started to spread locally after being imported from other provinces, while CRF68_01B was likely to have been brought in from the eastern provinces of China. Prevalence of HIV-1 drug resistant strains was 2.6%(5/190) before antiviral treatment, with mutation rates resistant to non-nucleoside reverse transcriptase inhibitors being the highest (2.1%, 4/190) among MSM in Kunming, 2018. Conclusion: The diversity of HIV-1 was increasing among MSM in Kunming. Although the resistance rate on pretreatment drug was relatively low, the emergence of multiple resistant strains to first-line antiviral drugs posed a challenge to antiretroviral therapy, in Kunming.


Assuntos
Farmacorresistência Viral/genética , Infecções por HIV/virologia , HIV-1/genética , Homossexualidade Masculina , Teorema de Bayes , China/epidemiologia , Genótipo , Infecções por HIV/epidemiologia , Humanos , Masculino
17.
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
18.
Sci Adv ; 6(35): eaba7910, 2020 08.
Artigo em Inglês | MEDLINE | ID: mdl-32923629

RESUMO

Targeting a universal host protein exploited by most viruses would be a game-changing strategy that offers broad-spectrum solution and rapid pandemic control including the current COVID-19. Here, we found a common YxxØ-motif of multiple viruses that exploits host AP2M1 for intracellular trafficking. A library chemical, N-(p-amylcinnamoyl)anthranilic acid (ACA), was identified to interrupt AP2M1-virus interaction and exhibit potent antiviral efficacy against a number of viruses in vitro and in vivo, including the influenza A viruses (IAVs), Zika virus (ZIKV), human immunodeficiency virus, and coronaviruses including MERS-CoV and SARS-CoV-2. YxxØ mutation, AP2M1 depletion, or disruption by ACA causes incorrect localization of viral proteins, which is exemplified by the failure of nuclear import of IAV nucleoprotein and diminished endoplasmic reticulum localization of ZIKV-NS3 and enterovirus-A71-2C proteins, thereby suppressing viral replication. Our study reveals an evolutionarily conserved mechanism of protein-protein interaction between host and virus that can serve as a broad-spectrum antiviral target.


Assuntos
Proteínas Adaptadoras de Transporte Vesicular/metabolismo , Antivirais/farmacologia , Cinamatos/farmacologia , Infecções por Coronavirus/tratamento farmacológico , Infecções por HIV/tratamento farmacológico , Influenza Humana/tratamento farmacológico , Pneumonia Viral/tratamento farmacológico , ortoaminobenzoatos/farmacologia , Células A549 , Animais , Betacoronavirus/efeitos dos fármacos , Sítios de Ligação/genética , Linhagem Celular Tumoral , Chlorocebus aethiops , Infecções por Coronavirus/patologia , Cães , Células HEK293 , Infecções por HIV/patologia , HIV-1/efeitos dos fármacos , Interações Hospedeiro-Patógeno/efeitos dos fármacos , Humanos , Vírus da Influenza A/efeitos dos fármacos , Influenza Humana/patologia , Células Madin Darby de Rim Canino , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Camundongos Knockout , Coronavírus da Síndrome Respiratória do Oriente Médio/efeitos dos fármacos , Pandemias , Pneumonia Viral/patologia , Ligação Proteica/genética , Transporte Proteico/efeitos dos fármacos , RNA Viral/genética , Receptor de Interferon alfa e beta/genética , Fator de Crescimento Transformador beta1/metabolismo , Células Vero , Replicação Viral/efeitos dos fármacos , Zika virus/efeitos dos fármacos , Infecção por Zika virus/patologia
19.
Lancet HIV ; 7(9): e620-e628, 2020 09.
Artigo em Inglês | MEDLINE | ID: mdl-32890497

RESUMO

BACKGROUND: Antiretroviral therapy (ART) scale-up in sub-Saharan Africa combined with weak routine virological monitoring has driven increasing HIV drug resistance. We investigated ART failure, drug resistance, and early mortality among patients with HIV admitted to hospital in Malawi. METHODS: This observational cohort study was nested within the rapid urine-based screening for tuberculosis to reduce AIDS-related mortality in hospitalised patients in Africa (STAMP) trial, which recruited unselected (ie, irrespective of clinical presentation) adult (aged ≥18 years) patients with HIV-1 at admission to medical wards. Patients were included in our observational cohort study if they were enrolled at the Malawi site (Zomba Central Hospital) and were taking ART for at least 6 months at admission. Patients who met inclusion criteria had frozen plasma samples tested for HIV-1 viral load. Those with HIV-1 RNA of at least 1000 copies per mL had drug resistance testing by ultra-deep sequencing, with drug resistance defined as intermediate or high-level resistance using the Stanford HIVDR program. Mortality risk was calculated 56 days from enrolment. Patients were censored at death, at 56 days, or at last contact if lost to follow-up. The modelling strategy addressed the causal association between HIV multidrug resistance and mortality, excluding factors on the causal pathway (most notably, CD4 cell count, clinical signs of advanced HIV, and poor functional and nutritional status). FINDINGS: Of 1316 patients with HIV enrolled in the STAMP trial at the Malawi site between Oct 26, 2015, and Sept 19, 2017, 786 had taken ART for at least 6 months. 252 (32%) of 786 patients had virological failure (viral load ≥1000 copies per mL). Mean age was 41·5 years (SD 11·4) and 528 (67%) of 786 were women. Of 237 patients with HIV drug resistance results available, 195 (82%) had resistance to lamivudine, 128 (54%) to tenofovir, and 219 (92%) to efavirenz. Resistance to at least two drugs was common (196, 83%), and this was associated with increased mortality (adjusted hazard ratio 1·7, 95% CI 1·2-2·4; p=0·0042). INTERPRETATION: Interventions are urgently needed and should target ART clinic, hospital, and post-hospital care, including differentiated care focusing on patients with advanced HIV, rapid viral load testing, and routine access to drug resistance testing. Prompt diagnosis and switching to alternative ART could reduce early mortality among inpatients with HIV. FUNDING: Joint Global Health Trials Scheme of the Medical Research Council, UK Department for International Development, and Wellcome Trust.


Assuntos
Farmacorresistência Viral , Infecções por HIV/epidemiologia , Infecções por HIV/virologia , HIV-1/efeitos dos fármacos , Carga Viral , Adulto , Terapia Antirretroviral de Alta Atividade , Duração da Terapia , Feminino , Infecções por HIV/tratamento farmacológico , Infecções por HIV/mortalidade , HIV-1/genética , Hospitalização , Humanos , Malaui/epidemiologia , Masculino , Mortalidade , RNA Viral , Falha de Tratamento
20.
Nan Fang Yi Ke Da Xue Xue Bao ; 40(4): 519-524, 2020 Apr 30.
Artigo em Chinês | MEDLINE | ID: mdl-32895127

RESUMO

OBJECTIVE: To construct a HIV-1 gp120 transgenic mice (gp120 Tg) with vimentin (VIM) gene knockout. METHODS: Female HIV-1 gp120 Tg mice were mated to VIM heterozygote mice (F0). All the offspring mice were derived from these original founders so that both genotypes had the same mixed genetic background. The F1 mice were bred to generate of VIM+/+, VIM-/-, VIM+/+/gp120 Tg and VIM-/-/gp120 Tg mice. PCR was performed for genotyping of the mice, and the expressions of VIM and gp120 in the brain tissues were examined using immunoblotting. RESULTS: The results of PCR showed the presence of the target bands in VIM+/+, VIM-/-, VIM+/+/gp120 Tg and VIM-/-/gp120 Tg mice. In VIM-/-/gp120 Tg mice, gp120 expression was detected throughout the brain regions while no VIM expression was detected. CONCLUSIONS: We generated gp120 transgenic mouse models with VIM gene knockout, which facilitate the exploration of the role of VIM in gp120-induced neurotoxicity.


Assuntos
HIV-1 , Animais , Encéfalo , Modelos Animais de Doenças , Feminino , Proteína gp120 do Envelope de HIV , Camundongos , Camundongos Knockout , Camundongos Transgênicos , Vimentina
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