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1.
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
2.
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
3.
PLoS One ; 15(9): e0237469, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32870911

RESUMO

BACKGROUND: It is estimated that approximately half of new HIV diagnoses among heterosexual migrants in Victoria, Australia, were acquired post-migration. We investigated the characteristics of phylogenetic clusters in notified cases of HIV among heterosexual migrants. METHODS: Partial HIV pol sequences obtained from routine clinical genotype tests were linked to Victorian HIV notifications with the following exposures listed on the notification form: heterosexual sexual contact, injecting drug use, bisexual sexual contact, male-to male sexual contact or heterosexual sexual contact in combination with injecting drug use, unknown exposure. Those with heterosexual sexual contact as the only exposure were the focus of this study, with the other exposures included to better understand transmission networks. Additional reference sequences were extracted from the Los Alamos database. Maximum likelihood methods were used to infer the phylogeny and the robustness of the resulting tree was assessed using bootstrap analysis. Phylogenetic clusters were defined on the basis of bootstrap and genetic distance. RESULTS: HIV pol sequences were available for 332 of 445 HIV notifications attributed to only heterosexual sexual contact in Victoria from 2005-2014. Forty-three phylogenetic clusters containing at least one heterosexual migrant were detected, 30 (70%) of which were pairs. The characteristics of these phylogenetic clusters varied considerably by cluster size. Pairs were more likely to be composed of people living with HIV from a single country of birth (p = 0.032). Larger clusters (n≥3) were more likely to contain people born in Australian/New Zealand (p = 0.002), migrants from more than one country of birth (p = 0.013) and viral subtype-B, the most common subtype in Australia (p = 0.006). Pairs were significantly more likely to contain females (p = 0.037) and less likely to include HIV diagnoses with male-to-male sexual contact reported as a possible exposure (p<0.001) compared to larger clusters (n≥3). CONCLUSION: Migrants appear to be at elevated risk of HIV acquisition, in part due to intimate relationships between migrants from the same country of origin, and in part due to risks associated with the broader Australian HIV epidemic. However, there was no evidence of large transmission clusters driven by heterosexual transmission between migrants. A multipronged approach to prevention of HIV among migrants is warranted.


Assuntos
Infecções por HIV/epidemiologia , HIV/genética , Filogenia , Adulto , Austrália/epidemiologia , Análise por Conglomerados , Feminino , HIV/isolamento & purificação , Infecções por HIV/diagnóstico , HIV-1/genética , HIV-1/isolamento & purificação , Heterossexualidade , Humanos , Masculino , Pessoa de Meia-Idade , Migrantes , Produtos do Gene pol do Vírus da Imunodeficiência Humana/genética
4.
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
5.
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
6.
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
7.
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
8.
PLoS One ; 15(9): e0237770, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32966293

RESUMO

OBJECTIVES: The aim of this proof-of-concept study is to test feasibility and efficacy of NVP plus Lamivudine (3TC) as novel simplified HIV maintenance dual therapy (DT) strategy. METHODS: Patients under combined antiretroviral treatment (cART) with fully suppressed HIV plasma viral load (pVL) >24 months-whereof >6 months on an NVP- containing regimen-were switched to oral NVP plus 3TC for 24 weeks. Patients could then decide whether to continue DT or return to the previous cART. HIV pVL was monitored monthly until week 144. The primary outcome was confirmed viral failure (RNA >100 copies/ml). Low-level detection of HIV-RNA in plasma was compared in each patient with pre-study viral load measurements. RESULTS: Twenty patients were included, switched to DT and all completed week 24. One patient decided thereafter to discontinue study participation for personal reasons. After a total of 144 observation weeks, none of the patients failed. The frequency of low- level HIV-RNA detection was not different from the period before randomization. CONCLUSIONS: Our findings are surprising but given the nature of a proof-of-concept study, the results do not support the use of this dual regimen. However, as this dual HIV maintenance strategy was feasible and effective, over a period of 144 weeks, we suggest NVP plus 3TC warrants further evaluation as potential maintenance option in patients tolerating nevirapine. A properly sized multicentre non-inferiority trial is ongoing to further evaluate the value of this DT maintenance strategy.


Assuntos
Fármacos Anti-HIV/uso terapêutico , Infecções por HIV/tratamento farmacológico , Infecções por HIV/virologia , HIV-1/fisiologia , Lamivudina/uso terapêutico , Estudo de Prova de Conceito , Fármacos Anti-HIV/farmacologia , Feminino , Infecções por HIV/sangue , HIV-1/efeitos dos fármacos , HIV-1/genética , Humanos , Lamivudina/farmacologia , Masculino , Pessoa de Meia-Idade , Nevirapina/uso terapêutico , RNA Viral/sangue
9.
Virology ; 548: 152-159, 2020 09.
Artigo em Inglês | MEDLINE | ID: mdl-32838936

RESUMO

Despite anti-retroviral therapy (ART) interventions for HIV+ pregnant mothers, over 43,000 perinatal infections occur yearly. Understanding risk factors that lead to mother-to-child transmission (MTCT) of HIV are critical. We evaluated maternal and infant plasma binding and neutralizing antibody responses in a drug-naïve, CRF01_AE infected MTCT cohort from Thailand to determine associations with transmission risk. Env V3-specific IgG and neutralizing antibody responses were significantly higher in HIV- infants, as compared to HIV+ infants. In fact, infant plasma neutralizing antibodies significantly associated with non-transmission. Conversely, increased maternal Env V3-specific IgG and neutralizing antibody responses were significantly associated with increased transmission risk, after controlling for maternal viral load. Our results highlight the importance of evaluating both maternal and infant humoral immune responses to better understand mechanisms of protection, as selective placental antibody transport may have a role in MTCT. This study further emphasizes the complex role of Env-specific antibodies in MTCT of CRF01_AE HIV.


Assuntos
Anticorpos Neutralizantes/imunologia , Anticorpos Anti-HIV/imunologia , Infecções por HIV/imunologia , Infecções por HIV/transmissão , HIV-1/imunologia , Adulto , Estudos de Coortes , Feminino , Infecções por HIV/virologia , HIV-1/genética , Humanos , Lactente , Recém-Nascido , Transmissão Vertical de Doença Infecciosa/estatística & dados numéricos , Masculino , Gravidez , Complicações Infecciosas na Gravidez , Tailândia/epidemiologia , Adulto Jovem
10.
Virology ; 548: 73-81, 2020 09.
Artigo em Inglês | MEDLINE | ID: mdl-32838948

RESUMO

The host protein SERINC5 inhibits the infectivity of HIV-1 virions in an Env-dependent manner and is counteracted by Nef. The conformation of the Env trimer reportedly correlates with sensitivity to SERINC5. Here, we tested the hypothesis that the "open" conformation of the Env trimer revealed by sensitivity to the V3-loop specific antibody 447-52D directly correlates with sensitivity to SERINC5. Of five Envs tested, SF162 was the most sensitive to neutralization by 447-52D, but it was not the most sensitive to SERINC5; instead the Env of LAI was substantially more sensitive to SERINC5 than all the other Envs. Mutational opening of the trimer by substitution of two tyrosines that mediate interaction between the V2 and V3 loops sensitized the Envs of JRFL and LAI to 447-52D as previously reported, but only BaL was sensitized to SERINC5. These data suggest that trimer "openness" is not sufficient for sensitivity to SERINC5.


Assuntos
Anticorpos Monoclonais/imunologia , Anticorpos Anti-HIV/imunologia , Infecções por HIV/imunologia , HIV-1/imunologia , Proteínas de Membrana/imunologia , Produtos do Gene env do Vírus da Imunodeficiência Humana/química , Produtos do Gene env do Vírus da Imunodeficiência Humana/imunologia , Anticorpos Neutralizantes/imunologia , Infecções por HIV/genética , Infecções por HIV/virologia , HIV-1/química , HIV-1/genética , HIV-1/fisiologia , Humanos , Proteínas de Membrana/química , Proteínas de Membrana/genética , Mutação , Produtos do Gene env do Vírus da Imunodeficiência Humana/genética
11.
PLoS One ; 15(8): e0236156, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32804970

RESUMO

BACKGROUND: HIV drug resistance (HIVDR) poses a threat to the HIV epidemic control in Zambia especially in sub-populations such as the 15-24 years where there is poor virological suppression. Understanding the prevalence and patterns of HIVDR in this population (15-24 years) will contribute to defining effective antiretroviral therapy (ART) regimens, improving clinical decision making, and supporting behavioral change interventions needed to achieve HIV epidemic control. METHODS: A cross-sectional analysis of study enrollment data from the Project YES! Youth Engaging for Success randomized controlled trial was conducted. Participants were 15 to 24 years old, who knew their HIV status, and had been on ART for at least 6 months. All participants completed a survey and underwent viral load (VL) testing. Participants with viral failure (VL ≥1,000 copies/mL) underwent HIVDR testing which included analysis of mutations in the protease and reverse transcriptase genes. RESULTS: A total of 99 out of 273 analyzed participants receiving ART had VL failure, of whom 77 had successful HIVDR amplification and analysis. Out of the 77, 75% (58) had at least one drug resistant mutation, among which 83% (48/58) required a drug change. Among the 58 with HIVDR mutations, the prevalence of at least one HIVDR mutation to nucleoside reverse transcriptase inhibitors (NRTIs), non-nucleoside reverse transcriptase inhibitors (NNRTIs) and protease inhibitors (PIs) were 81%, 65.5% and 1.7%. The mutation M184V which confers resistance to NRTI drugs of lamivudine (3TC) and emtricitabine (FTC) was the most common (81%) among NRTI associated mutations followed by K65R (34.5%) which is associated with both tenofovir disoproxil fumarate (TDF) and tenofovir alafenamide fumarate (TAF) resistance. Thymidine analogue mutations (TAMs) which confer resistance primarily to zidovudine (AZT), stavudine (d4T) and other NRTIs were observed at 32.8%. Common TAMs were K70RTQNE (32.8%), K219QE (22.4%), D67N (17.2%) and T215IT (15.5%). The most common NNRTI associated mutation was the K103N (65.5%) which confers resistance to both efavirenz (EFV) and nevirapine (NVP). There was a relatively high occurrence of other NNRTI mutations V106A (36.2%), as well as Y188C (36.2%) and Y181C (36.2%) which confer resistance to etravirine. CONCLUSIONS: There is a high prevalence of HIVDR including TAMs despite majority of these patients (90.48%) being on AZT or d4T sparing first line ART among the youth. Emergence of these mutations including the NNRTI associated mutations (Y181C and Y188C) may compromise future second- and third-line regimens in the absence of routine HIVDR testing. HIVDR monitoring at start of ART or at first-line failure can better inform clinical decision making and ART programing.


Assuntos
Fármacos Anti-HIV/farmacologia , Farmacorresistência Viral/genética , Infecções por HIV/tratamento farmacológico , HIV-1/isolamento & purificação , Adolescente , Fármacos Anti-HIV/uso terapêutico , Tomada de Decisão Clínica , Estudos Transversais , Feminino , Infecções por HIV/epidemiologia , HIV-1/genética , Humanos , Masculino , Mutação , Prevalência , RNA Viral/genética , RNA Viral/isolamento & purificação , Ensaios Clínicos Controlados Aleatórios como Assunto , Timidina/genética , Carga Viral/efeitos dos fármacos , Adulto Jovem , Zâmbia
12.
PLoS Pathog ; 16(8): e1008752, 2020 08.
Artigo em Inglês | MEDLINE | ID: mdl-32760121

RESUMO

Members of the family of pyrin and HIN domain containing (PYHIN) proteins play an emerging role in innate immunity. While absent in melanoma 2 (AIM2) acts a cytosolic sensor of non-self DNA and plays a key role in inflammasome assembly, the γ-interferon-inducible protein 16 (IFI16) restricts retroviral gene expression by sequestering the transcription factor Sp1. Here, we show that the remaining two human PYHIN proteins, i.e. myeloid cell nuclear differentiation antigen (MNDA) and pyrin and HIN domain family member 1 (PYHIN1 or IFIX) share this antiretroviral function of IFI16. On average, knock-down of each of these three nuclear PYHIN proteins increased infectious HIV-1 yield from human macrophages by more than an order of magnitude. Similarly, knock-down of IFI16 strongly increased virus transcription and production in primary CD4+ T cells. The N-terminal pyrin domain (PYD) plus linker region containing a nuclear localization signal (NLS) were generally required and sufficient for Sp1 sequestration and anti-HIV-1 activity of IFI16, MNDA and PYHIN1. Replacement of the linker region of AIM2 by the NLS-containing linker of IFI16 resulted in a predominantly nuclear localization and conferred direct antiviral activity to AIM2 while attenuating its ability to form inflammasomes. The reverse change caused nuclear-to-cytoplasmic relocalization of IFI16 and impaired its antiretroviral activity but did not result in inflammasome assembly. We further show that the Zn-finger domain of Sp1 is critical for the interaction with IFI16 supporting that pyrin domains compete with DNA for Sp1 binding. Finally, we found that human PYHIN proteins also inhibit Hepatitis B virus and simian vacuolating virus 40 as well as the LINE-1 retrotransposon. Altogether, our data show that IFI16, PYHIN1 and MNDA restrict HIV-1 and other viral pathogens by interfering with Sp1-dependent gene expression and support an important role of nuclear PYHIN proteins in innate antiviral immunity.


Assuntos
Linfócitos T CD4-Positivos/imunologia , Núcleo Celular/metabolismo , Infecções por HIV/prevenção & controle , HIV-1/imunologia , Macrófagos/imunologia , Proteínas Nucleares/metabolismo , Fator de Transcrição Sp1/metabolismo , Linfócitos T CD4-Positivos/metabolismo , Linfócitos T CD4-Positivos/virologia , Núcleo Celular/genética , DNA Viral/genética , Células HEK293 , Infecções por HIV/imunologia , Infecções por HIV/patologia , Infecções por HIV/virologia , HIV-1/genética , HIV-1/isolamento & purificação , Células Hep G2 , Humanos , Imunidade Inata/imunologia , Inflamassomos/genética , Inflamassomos/imunologia , Macrófagos/metabolismo , Macrófagos/virologia , Proteínas Nucleares/genética , Fator de Transcrição Sp1/genética , Replicação Viral
14.
Nature ; 585(7824): 261-267, 2020 09.
Artigo em Inglês | MEDLINE | ID: mdl-32848246

RESUMO

Sustained, drug-free control of HIV-1 replication is naturally achieved in less than 0.5% of infected individuals (here termed 'elite controllers'), despite the presence of a replication-competent viral reservoir1. Inducing such an ability to spontaneously maintain undetectable plasma viraemia is a major objective of HIV-1 cure research, but the characteristics of proviral reservoirs in elite controllers remain to be determined. Here, using next-generation sequencing of near-full-length single HIV-1 genomes and corresponding chromosomal integration sites, we show that the proviral reservoirs of elite controllers frequently consist of oligoclonal to near-monoclonal clusters of intact proviral sequences. In contrast to individuals treated with long-term antiretroviral therapy, intact proviral sequences from elite controllers were integrated at highly distinct sites in the human genome and were preferentially located in centromeric satellite DNA or in Krüppel-associated box domain-containing zinc finger genes on chromosome 19, both of which are associated with heterochromatin features. Moreover, the integration sites of intact proviral sequences from elite controllers showed an increased distance to transcriptional start sites and accessible chromatin of the host genome and were enriched in repressive chromatin marks. These data suggest that a distinct configuration of the proviral reservoir represents a structural correlate of natural viral control, and that the quality, rather than the quantity, of viral reservoirs can be an important distinguishing feature for a functional cure of HIV-1 infection. Moreover, in one elite controller, we were unable to detect intact proviral sequences despite analysing more than 1.5 billion peripheral blood mononuclear cells, which raises the possibility that a sterilizing cure of HIV-1 infection, which has previously been observed only following allogeneic haematopoietic stem cell transplantation2,3, may be feasible in rare instances.


Assuntos
Inativação Gênica , Infecções por HIV/genética , Infecções por HIV/virologia , HIV-1/genética , Heterocromatina/genética , Provírus/genética , Integração Viral/genética , Latência Viral/genética , Adulto , Idoso , Centrômero/genética , Cromossomos Humanos Par 19/genética , DNA Satélite/genética , Feminino , Genoma Viral/genética , Infecções por HIV/sangue , HIV-1/isolamento & purificação , Heterocromatina/metabolismo , Humanos , Masculino , Pessoa de Meia-Idade , Provírus/isolamento & purificação , Proteínas Repressoras/genética , Sítio de Iniciação de Transcrição
15.
Nat Commun ; 11(1): 4089, 2020 08 14.
Artigo em Inglês | MEDLINE | ID: mdl-32796830

RESUMO

Clonal expansions occur in the persistent HIV reservoir as shown by the duplication of proviral integration sites. However, the source of the proliferation of HIV-infected cells remains unclear. Here, we analyze the TCR repertoire of single HIV-infected cells harboring translation-competent proviruses in longitudinal samples from eight individuals on antiretroviral therapy (ART). When compared to uninfected cells, the TCR repertoire of reservoir cells is heavily biased: expanded clonotypes are present in all individuals, account for the majority of reservoir cells and are often maintained over time on ART. Infected T cell clones are detected at low frequencies in the long-lived central memory compartment and overrepresented in the most differentiated memory subsets. Our results indicate that clonal expansions highly contribute to the persistence of the HIV reservoir and suggest that reservoir cells displaying a differentiated phenotype are the progeny of infected central memory cells undergoing antigen-driven clonal expansion during ART.


Assuntos
Antirretrovirais/uso terapêutico , Infecções por HIV/genética , Receptores de Antígenos de Linfócitos T alfa-beta/metabolismo , Adulto , Células Cultivadas , Feminino , Citometria de Fluxo , Infecções por HIV/tratamento farmacológico , HIV-1/efeitos dos fármacos , HIV-1/genética , HIV-1/patogenicidade , Humanos , Masculino , Receptores de Antígenos de Linfócitos T alfa-beta/genética , Carga Viral , Replicação Viral/efeitos dos fármacos , Replicação Viral/genética
16.
J Assoc Physicians India ; 68(8): 47-51, 2020 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-32738841

RESUMO

The central nervous system is believed to be a safe sanctuary site which is established very early in the course of HIV infection where the virus can escape antiretroviral therapy. HIV associated neurocognitive disorder (HAND) is seen to occur even in patients on successful systemic ART. HIV RNA can be at higher levels in CSF than plasma termed as CSF / plasma discordance or CSF escape. We aimed to study the prevalence, risk factors and outcomes in HIV patients who develop neurocognitive dysfunction on otherwise successful (suppressive) ART. We reported 6 cases of HAND in patients on regular successful ART over a 3 year period. Neurological examination , CSF analysis , plasma CD4 T cell count and neuroimaging were done.. Plasma HIV RNA and CSF HIV RNA was also estimated. Most of the patients' (5/6) were male, median age was 38.5 years and median time since HIV diagnosis was 3 years. All patients' were on Tenofovir plus Boosted Protease inhibitors when neurocognitive symptoms were manifest. 4/6 patients had an acute onset of clinical presentation. CSF showed elevated protein and mild pleocytosis in all patients. Median nadir CD4 T cell count was 222 cells / µl and at presentation of HAND with CSF escape was 374 cells / µl. CSF / Plasma HIV RNA discordance was present in all patients' at time of diagnosis. Outcome is good if diagnosed and treated early.


Assuntos
Infecções por HIV , HIV-1/genética , Adulto , Contagem de Linfócito CD4 , Humanos , Índia , Masculino , RNA Viral , Carga Viral
17.
Zhonghua Liu Xing Bing Xue Za Zhi ; 41(7): 1121-1125, 2020 Jul 10.
Artigo em Chinês | MEDLINE | ID: mdl-32741182

RESUMO

Objective: To analyze the characteristics of HIV-1 molecular network in men who have sex with men (MSM) from 2016 to 2018 in Kunming, Yunnan province, explore the risk factors associated with HIV-1 transmission network and provide evidence for the effective implementation of intervention. Methods: A total of 540 samples of newly reported HIV-1 positive MSM were consecutively collected in Kunming from 2016 to 2018, the pol gene fragments were amplified by nested polymerase chain reaction (PCR). HIV-1 molecular networks were constructed according to the bootstrap value of the maximum likelihood evolutionary tree over 95% and the genetic distance less than 3%. The factors associated with the subjects entering network and network growth were further analyzed. Results: Among 459 successfully sequenced samples, seven genotypes were found, in which CRF07_BC (49.2%, 226/459) and CRF01_AE (40.3%, 185/459 ) were predominant. Other genotypes included URFs (4.8%, 22/459), CRF08_BC (3.1%, 14/459), CRF55_01B (1.7%, 8/459), B (0.7%, 3/459) and CRF68_01B (0.2%, 1/459). A total of 163 sequences entered the network, with an entry rate of 35.5%(163/459), forming 56 clusters with the number of individuals in the cluster was between 2 and 13. The analysis of the factors associated with entering network showed that the MSM who married and had multiple homosexual partners were more likely to be found in HIV-1 molecular networks. Multivariate logistic regression analysis showed that the number of sexual partners was the factor for the growth of HIV-1 molecular network. According to the criteria for the emergence of three or more newly reported cases in every year, six transmission clusters were judged as active transmission clusters, in which MSM who were not Kunming natives, had sexually transmitted diseases (STD), were divorced and students were the key targets of intervention. Conclusions: HIV-1 genotypes in MSM in Kunming were becoming complex, the risk factors associated with transmission networks in MSM in Kunming included being married and having multiple partners, the intervention targets in active transmission clusters included MSM who were not Kunming natives, had STD, were divorced and students. This study provided the basis for applying HIV-1 molecular networks to real-time intervention in this population.


Assuntos
Infecções por HIV/virologia , HIV-1/genética , Homossexualidade Masculina/estatística & dados numéricos , China/epidemiologia , Genótipo , Infecções por HIV/epidemiologia , HIV-1/isolamento & purificação , Humanos , Masculino
18.
BMC Infect Dis ; 20(1): 569, 2020 Aug 04.
Artigo em Inglês | MEDLINE | ID: mdl-32753067

RESUMO

BACKGROUND: HIV-1 produces defective mutants in the process of reproduction. The significance of the mutants has not been well investigated. METHODS: The plasmids of wild type (HIV-1NL4-3) and Env-defective (HIV-1SG3ΔEnv) HIV-1 were co-transfected into HEK293T cells. The progeny virus was collected to infect MT4 cells. The env gene and near-full-length genome (NFLG) of HIV-1 were amplified and sequenced. The phylogenetic diversity, recombinant patterns and hotspots, and the functionality of HIV-1 Env were determined. RESULTS: A total of 42 env genes and 8 NFLGs were successfully amplified and sequenced. Five types of recombinant patterns of env were identified and the same recombinant sites were detected in different patterns. The recombination hotspots were found distributing mainly in conservative regions of env. The recombination between genes of HIV-1NL4-3 and HIV-1SG3Δenv increased the variety of viral quasispecies and resulted in progeny viruses with relative lower infectious ability than that of HIVNL4-3. The defective env genes as well as NFLG could be detected after 20 passages. CONCLUSION: The existence of the defective HIV-1 promotes the phylogenetic evolution of the virus, thus increasing the diversity of virus population. The role of defective genes may be converted from junk genes to useful materials and cannot be neglected in the study of HIV-1 reservoir.


Assuntos
Evolução Molecular , Infecções por HIV/patologia , HIV-1/fisiologia , Produtos do Gene env do Vírus da Imunodeficiência Humana/genética , Células HEK293 , Infecções por HIV/virologia , HIV-1/classificação , HIV-1/genética , Humanos , Filogenia , Plasmídeos/genética , Plasmídeos/metabolismo , Recombinação Genética , Produtos do Gene env do Vírus da Imunodeficiência Humana/química , Produtos do Gene env do Vírus da Imunodeficiência Humana/metabolismo
19.
PLoS Pathog ; 16(8): e1008678, 2020 08.
Artigo em Inglês | MEDLINE | ID: mdl-32760119

RESUMO

GWAS, immune analyses and biomarker screenings have identified host factors associated with in vivo HIV-1 control. However, there is a gap in the knowledge about the mechanisms that regulate the expression of such host factors. Here, we aimed to assess DNA methylation impact on host genome in natural HIV-1 control. To this end, whole DNA methylome in 70 untreated HIV-1 infected individuals with either high (>50,000 HIV-1-RNA copies/ml, n = 29) or low (<10,000 HIV-1-RNA copies/ml, n = 41) plasma viral load (pVL) levels were compared and identified 2,649 differentially methylated positions (DMPs). Of these, a classification random forest model selected 55 DMPs that correlated with virologic (pVL and proviral levels) and HIV-1 specific adaptive immunity parameters (IFNg-T cell responses and neutralizing antibodies capacity). Then, cluster and functional analyses identified two DMP clusters: cluster 1 contained hypo-methylated genes involved in antiviral and interferon response (e.g. PARP9, MX1, and USP18) in individuals with high viral loads while in cluster 2, genes related to T follicular helper cell (Tfh) commitment (e.g. CXCR5 and TCF7) were hyper-methylated in the same group of individuals with uncontrolled infection. For selected genes, mRNA levels negatively correlated with DNA methylation, confirming an epigenetic regulation of gene expression. Further, these gene expression signatures were also confirmed in early and chronic stages of infection, including untreated, cART treated and elite controllers HIV-1 infected individuals (n = 37). These data provide the first evidence that host genes critically involved in immune control of the virus are under methylation regulation in HIV-1 infection. These insights may offer new opportunities to identify novel mechanisms of in vivo virus control and may prove crucial for the development of future therapeutic interventions aimed at HIV-1 cure.


Assuntos
Biomarcadores/metabolismo , Linfócitos T CD4-Positivos/imunologia , Metilação de DNA , Infecções por HIV/imunologia , HIV-1/imunologia , Fatores Reguladores de Interferon/genética , Carga Viral , Antivirais/uso terapêutico , Epigênese Genética , Feminino , Infecções por HIV/tratamento farmacológico , Infecções por HIV/genética , Infecções por HIV/virologia , HIV-1/genética , Interações Hospedeiro-Patógeno , Humanos , Fatores Reguladores de Interferon/metabolismo , Interferons/metabolismo , Masculino , Linfócitos T Auxiliares-Indutores/imunologia , Replicação Viral
20.
BMC Infect Dis ; 20(1): 631, 2020 Aug 26.
Artigo em Inglês | MEDLINE | ID: mdl-32842977

RESUMO

BACKGROUND: The drug resistance and the virologic failure of antiretroviral therapy (ART) are quite severe in Liangshan. A better understanding of the virologic failure of ART and the HIV-1 transmission network dynamics is essential for the surveillance and prevention of HIV. Here, we analyzed the HIV-1 CRF07_BC strain genetic transmission networks and their associated factors among people living with HIV-1 (PLWH) who had virologic failure of ART by using close genetic links. METHODS: The drug-resistant mutations were determined using the Stanford University HIV Drug Resistance Database. HIV-1 pol genes sequences were used for phylogenetic and genotypic drug resistance analysis. The genetic transmission networks were performed by comparing sequences, constructing the phylogenetic tree, calculating the pairwise distance, and visualizing the network. RESULTS: A total of 1050 PLWH with CRF07_BC pol sequences were finally identified and included in the genetic transmission network analysis from 2016 to 2017. Of the 1050 CRF07_BC pol sequences, 346 (32.95%) fell into clusters at a genetic distance of 0.006, resulting in 137 clusters ranging in size from 2 to 40 individuals. Subjects who were widowed or divorced were less likely to form a genetic transmission network (adjusted OR: 0.50), while subjects who had shared a needle ≥ five times were more likely to form a network (adjusted OR: 1.88). CONCLUSIONS: The genetic transmission networks revealed the complex transmission pattern, highlighting the urgent need for transmission monitoring of virologic failure of ART and selection of more effective therapeutic regimens to promote viral suppression.


Assuntos
Fármacos Anti-HIV/efeitos adversos , Fármacos Anti-HIV/uso terapêutico , Farmacorresistência Viral/genética , Infecções por HIV/tratamento farmacológico , Infecções por HIV/transmissão , HIV-1/genética , Grupos Minoritários , Adolescente , Adulto , China/epidemiologia , Estudos Transversais , Feminino , Genes pol , Infecções por HIV/virologia , Humanos , Masculino , Mutação , Filogenia , Falha de Tratamento , Adulto Jovem
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