RESUMEN
BACKGROUND: Cocaine-one of the most frequently abused illicit drugs among persons living with HIV [people living with HIV (PLWH)]-slows the decline of viral production after antiretroviral therapy and is associated with higher HIV viral load, more rapid HIV progression, and increased mortality. SETTING: We examined the impact of cocaine use on the CD4+ T-cell HIV latent reservoir (HLR) in virally suppressed PLWH participating in a national, longitudinal cohort study of the natural and treated history of HIV in the United States. METHODS: CD4+ T-cell genomic DNA from 434 women of diverse ancestry (ie, 75% Black, 14% Hispanic, 12% White) who self-reported cocaine use (ie, 160 cocaine users, 59 prior users, 215 non-users) was analyzed using the Intact Proviral HIV DNA Assay, measuring intact provirus per 106 CD4+ T cells. FINDINGS: HIV latent reservoir size differed by cocaine use (ie, median [interquartile range]: 72 [14-193] for never users, 165 [63-387] for prior users, 184 [28-502] for current users), which was statistically significantly larger in both prior (P = 0.023) and current (P = 0.001) cocaine users compared with never users. CONCLUSIONS: Cocaine use may contribute to a larger replication competent HLR in CD4+ T cells among virologically suppressed women living with HIV. Our findings are important because women are underrepresented in HIV reservoir studies and in studies of the impact of cocaine use on outcomes among PLWH.
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Linfocitos T CD4-Positivos , Trastornos Relacionados con Cocaína , Infecciones por VIH , Carga Viral , Latencia del Virus , Humanos , Femenino , Infecciones por VIH/tratamiento farmacológico , Adulto , Persona de Mediana Edad , Trastornos Relacionados con Cocaína/epidemiología , Estudios Longitudinales , VIH-1/genética , Estados Unidos/epidemiología , ADN Viral , CocaínaAsunto(s)
Fármacos Anti-VIH , Farmacorresistencia Viral , Emtricitabina , Infecciones por VIH , VIH-1 , Compuestos Heterocíclicos con 3 Anillos , Oxazinas , Piperazinas , Piridonas , Tenofovir , Humanos , Infecciones por VIH/tratamiento farmacológico , VIH-1/efectos de los fármacos , VIH-1/genética , Emtricitabina/uso terapéutico , Piridonas/uso terapéutico , Piperazinas/uso terapéutico , Tenofovir/uso terapéutico , Compuestos Heterocíclicos con 3 Anillos/uso terapéutico , Fármacos Anti-VIH/uso terapéutico , Oxazinas/uso terapéutico , Compuestos Heterocíclicos de 4 o más Anillos/uso terapéutico , Compuestos Heterocíclicos de 4 o más Anillos/administración & dosificación , Hepatitis B/tratamiento farmacológico , Adenina/análogos & derivados , Adenina/uso terapéutico , Masculino , Femenino , AmidasRESUMEN
BACKGROUND: Resistance to antiretrovirals against human immunodeficiency virus (HIV) poses a threat to zero transmission of HIV by 2030. Few studies have been conducted on HIV drug resistance (HIVDR) mutations targeting adolescents. We determined the prevalence, pattern of HIVDR mutations, and factors associated with unsuppressed HIV viral load among adolescents on antiretroviral therapy (ART). METHODS: From March to June 2020, we conducted a cross-sectional study at the Infectious Disease Clinic in Dar es Salaam, Tanzania. HIV-1 viral load was tested using m2000rt Real-Time HIV-1 assay. A sample with a viral load equal or more than 1,000 copies/ml was tested for HIVDR mutations. We determined the factors associated with unsuppressed viral load using logistic regression. A p-value less than 0.05 was considered significant. RESULTS: We enrolled 131 participants with a median age (interquartile range) of 15 (13-18) years. Of all, 24(18.3%) had a viral load above 1000 copies/ml. HIVDR mutations were found in 19/24(68.4%). Mutation to protease inhibitors, nucleotide reverse transcriptase inhibitors, and non-nucleoside reverse transcriptase inhibitors were 1(5.2%), 9(47.4%), and 11(57.9%), respectively. Non-antiretroviral therapy and orphanages were independently associated with unsuppressed viral load. CONCLUSION: The prevalence of HIVDR and unsuppressed HIV viral load among adolescents are relatively high. The use of non-antiretroviral therapy and orphanage influenced the persistence of high viral load. Strategies for surveillance of HIVDR early warning signs should be devised among adolescents.
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Farmacorresistencia Viral , Infecciones por VIH , VIH-1 , Carga Viral , Humanos , Adolescente , Tanzanía/epidemiología , Infecciones por VIH/tratamiento farmacológico , Infecciones por VIH/virología , Infecciones por VIH/epidemiología , Estudios Transversales , Masculino , Femenino , Farmacorresistencia Viral/genética , Prevalencia , VIH-1/efectos de los fármacos , VIH-1/genética , Mutación , Fármacos Anti-VIH/uso terapéutico , Antirretrovirales/uso terapéuticoRESUMEN
INTRODUCTION: HIV drug resistance (HIVDR) is an important challenge in the fight against HIV/AIDS and can threaten progress toward achieving the target of HIV elimination by 2030. Genotyping pretreatment HIVDR testing (DRT) has been proposed as a potential solution. However, the cost-effectiveness of this intervention needs to be evaluated to determine its feasibility and potential impact on healthcare systems. This study aimed to assess the cost-effectiveness of DRT among people living with HIV (PLHIV) in Iran. METHODS: 1000 hypothetical PLHIV were simulated in terms of cost and effectiveness based on quality-adjusted life Years (QALY). The Markov Model was developed to calculate incremental cost-effectiveness ratio (ICER) using TreeAge Pro 2020. Deterministic and probabilistic analyses were performed for sensitivity analyses. RESULTS: Results showed that compared to not performing pretreatment HIVDR testing, this intervention gained 0.035999 QALY with an incremental cost of 1,695.32 USD. The ICER was calculated as 47,093.53 USD, indicating that pretreatment DRT was not cost-effective. The probability of opportunistic infection (OI) in people with viral failure, the effectiveness of Dolutegravir in people without drug resistance, and the quality of life (QoL) of people in the AIDS stage were found to be the most important variables affecting ICER. With an increasing willingness to pay more than 53,000 USD, pretreatment DRT testing will become cost-effective. CONCLUSION: Based on our findings, pretreatment HIVDR testing is not currently cost-effective in Iran as it imposes high costs on healthcare systems with few benefits for People living with HIV (PLHIV). However, if resources are available, drug resistance testing can be a valuable tool in generating HIV molecular data and molecular surveillance of HIV.
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Análisis Costo-Beneficio , Farmacorresistencia Viral , Infecciones por VIH , Años de Vida Ajustados por Calidad de Vida , Humanos , Infecciones por VIH/tratamiento farmacológico , Infecciones por VIH/virología , Infecciones por VIH/economía , Farmacorresistencia Viral/genética , Irán/epidemiología , Masculino , Femenino , Cadenas de Markov , Fármacos Anti-VIH/uso terapéutico , Fármacos Anti-VIH/economía , VIH-1/efectos de los fármacos , VIH-1/genética , Calidad de Vida , AdultoRESUMEN
HIV-1 CRF08_BC is a significant subtype in China, though its origin and spread remain incompletely understood. Previous studies using partial genomic data have provided insights but lack comprehensive analysis. Here, we investigate the early evolutionary and spatiotemporal dynamics of HIV-1 CRF08_BC in China and Myanmar using near-complete genome sequences. We analyzed 28 near-complete HIV-1 CRF08_BC genomes from China and Myanmar (1997-2013). Phylogenetic, molecular clock, and Bayesian discrete trait analyses were performed to infer the virus's origin, spread, and associated risk groups. Based on Bayesian time-scaled inference with the best-fitting combination of models determined by marginal likelihood estimation (MLE), we inferred the time to the most recent common ancestor (TMRCA) and evolutionary rate of HIV-1 CRF08_BC to be at 3 October 1991 (95% HPD: 22 February1989-27 November 1993) and 2.30 × 10-3 substitutions per site per year (95% HPD: 1.96 × 10-3-2.63 × 10-3), respectively. Our analysis suggests that HIV-1 CRF08_BC originated in Yunnan Province, China, among injecting drug users, and subsequently spread to other regions. This study provides valuable insights into the early dynamics of HIV-1 CRF08_BC through combined genomic and epidemiological data, which may inform effective prevention and mitigation efforts. However, the limited genomic data influenced the extent of our findings, and challenges in collecting accurate risk group information during surveillance were evident.
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Teorema de Bayes , Evolución Molecular , Genoma Viral , Infecciones por VIH , VIH-1 , Filogenia , VIH-1/genética , VIH-1/clasificación , Humanos , Infecciones por VIH/transmisión , Infecciones por VIH/epidemiología , Infecciones por VIH/virología , China/epidemiología , Mianmar/epidemiología , MasculinoRESUMEN
BACKGROUND: An increase in the prevalence of HIV drug resistance (HIVDR) has been reported in recent years, especially in persons on non-nucleoside reverse transcriptase inhibitors (NNRTIs) due to their low genetic barrier to mutations. However, there is a paucity of epidemiological data quantifying HIVDR in the era of new drugs like dolutegravir (DTG) in sub-Saharan Africa. We, therefore, sought to determine the prevalence and correlates of viral load (VL) suppression in adult people with HIV (PWH) on a fixed-dose combination of tenofovir disoproxil fumarate/lamivudine/dolutegravir (TLD) or tenofovir alafenamide/emtricitabine/dolutegravir (TAFED) and describe patterns of mutations in individuals failing treatment. METHODS: We conducted a cross-sectional study among 384 adults living with HIV aged ≥15 years between 5th June 2023 and 10th August 2023. Demographic, laboratory and clinical data were collected from electronic health records using a data collection form. Viral load suppression was defined as plasma HIV-1 RNA VL of <1000 copies/ml after being on ART for ≥ 6 months. SPSS version 22 to analyze the data. Descriptive statistics and logistic regression were the statistical methods used. RESULTS: The median (interquartile range (IQR)) age was 22 (IQR 18, 38) years, and 66.1% (n = 254) were females. VL suppression was 90.4% (n = 347); (95% confidence interval (CI) 87.6%-93.6%) after switching to TLD/TAFED. Among the virally suppressed, the majority (67.1%, n = 233) were female. Those who missed ≥2 doses in the last 30 days prior to the most recent review were less likely to attain viral suppression compared to those who did not miss any dose (adjusted odds ratio (AOR) 0.047; 95% CI 0.016-0.136; p<0.001). Four participants had resistance mutations to lamivudine and tenofovir. The most common NRTI mutations were M184MV and K65R while K101E was the most common NNRTI mutation. CONCLUSION: Our findings show that viral suppression was high after switching to TLD/TAFED; but lower than the last 95% target of the UNAIDS. Adherence to antiretroviral therapy was a significant correlate of VL suppression. We, therefore, recommend prompt switching of PWH to TLD/TAFED regimen and close monitoring to enhance adherence to therapy.
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Fármacos Anti-VIH , Farmacorresistencia Viral , Infecciones por VIH , VIH-1 , Lamivudine , Mutación , Piperazinas , Piridonas , Tenofovir , Carga Viral , Humanos , Femenino , Adulto , VIH-1/genética , VIH-1/efectos de los fármacos , Masculino , Infecciones por VIH/tratamiento farmacológico , Infecciones por VIH/virología , Farmacorresistencia Viral/genética , Carga Viral/efectos de los fármacos , Zambia/epidemiología , Estudios Transversales , Tenofovir/uso terapéutico , Tenofovir/farmacología , Fármacos Anti-VIH/uso terapéutico , Fármacos Anti-VIH/farmacología , Piperazinas/uso terapéutico , Lamivudine/uso terapéutico , Lamivudine/farmacología , Piridonas/uso terapéutico , Oxazinas/uso terapéutico , Compuestos Heterocíclicos con 3 Anillos/uso terapéutico , Compuestos Heterocíclicos con 3 Anillos/farmacología , Emtricitabina/uso terapéutico , Persona de Mediana Edad , Adulto Joven , Adolescente , Combinación de MedicamentosRESUMEN
BACKGROUND: Head-to-head data for bictegravir/emtricitabine/tenofovir alafenamide (BIC/F/TAF; B) and darunavir/cobicistat/emtricitabine/tenofovir alafenamide (DRV/c/F/TAF; D) are lacking in the context of rapid antiretroviral therapy (ART) initiation. This study, BIC-T&T, evaluates the efficacy and tolerability of B vs D in a UK test-and-treat setting. SETTING: BIC-T&T was a randomised, open-label, multi-centre, study in which participants initiated ART within 14 days after confirmed HIV-1 diagnosis before baseline laboratory. METHODS: The primary endpoint is the virological response (HIV RNA < 50copies/mL) at week 12 by time-weighted average change in log10 HIV RNA recorded in viral load assays from treatment initiation to week 12, using two-sample Wilcoxon rank-sum test. RESULTS: 36 participants were randomised: 94% were male, 53% white; mean (SD) age was 35 years (11.8). Baseline mean (±SD) log10 HIV-RNA was 4.79 (± 0.87) log10 copies/mL and CD4 505 (±253) cells/mm3. The mean (±SD) time from confirmed HIV diagnosis to ART initiation was 7.9 (± 3.7) days. The time-weighted mean decrease in log10 HIV RNA from treatment initiation to week 12 was significantly greater in B in comparison to D (3.1 vs. 2.6 log10 copies/mL, p < 0.001). Both regimens demonstrated good tolerability with infrequent laboratory abnormalities and no grade 3 or 4 adverse events. CONCLUSION: In this first head-to-head study in the context of ART initiation, HIV RNA decline from baseline to week 12 was significantly more rapid for BIC/F/TAF compared with DRV/c/F/TAF.
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Fármacos Anti-VIH , Emtricitabina , Infecciones por VIH , Tenofovir , Carga Viral , Humanos , Infecciones por VIH/tratamiento farmacológico , Infecciones por VIH/virología , Masculino , Femenino , Adulto , Tenofovir/uso terapéutico , Tenofovir/análogos & derivados , Fármacos Anti-VIH/uso terapéutico , Carga Viral/efectos de los fármacos , Emtricitabina/uso terapéutico , VIH-1/efectos de los fármacos , VIH-1/genética , Adenina/análogos & derivados , Adenina/uso terapéutico , Piperazinas/uso terapéutico , Compuestos Heterocíclicos con 3 Anillos/uso terapéutico , Compuestos Heterocíclicos de 4 o más Anillos/uso terapéutico , Darunavir/uso terapéutico , Alanina/uso terapéutico , Alanina/análogos & derivados , Resultado del Tratamiento , ARN Viral , Sulfonamidas/uso terapéutico , Persona de Mediana Edad , Cobicistat/uso terapéutico , Reino Unido , Combinación de Medicamentos , Amidas , PiridonasRESUMEN
Efforts towards an effective HIV-1 vaccine have remained mainly unsuccessful. There is increasing evidence for a potential role of HLA-C-restricted CD8+ T cell responses in HIV-1 control, including our recent report of HLA-C*03:02 among African children. However, there are no documented optimal HIV-1 CD8+ T cell epitopes restricted by HLA-C*03:02; additionally, the structural influence of HLA-C*03:02 on epitope binding is undetermined. Immunoinformatics approaches provide a fast and inexpensive method to discover HLA-restricted epitopes. Here, we employed immunopeptidomics to identify HLA-C*03:02 CD8+ T cell epitopes. We identified a clade-specific Gag-derived GY9 (GTEELRSLY) HIV-1 p17 matrix epitope potentially restricted to HLA-C*03:02. Residues E62, T142, and E151 in the HLA-C*03:02 binding groove and positions p3, p6, and p9 on the GY9 epitope are crucial in shaping and stabilizing the epitope binding. Our findings support the growing evidence of the contribution of HLA-C molecules to HIV-1 control and provide a prospect for vaccine strategies.
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Epítopos de Linfocito T , VIH-1 , Antígenos HLA-C , Productos del Gen gag del Virus de la Inmunodeficiencia Humana , Productos del Gen gag del Virus de la Inmunodeficiencia Humana/inmunología , Productos del Gen gag del Virus de la Inmunodeficiencia Humana/química , Productos del Gen gag del Virus de la Inmunodeficiencia Humana/genética , Humanos , Epítopos de Linfocito T/inmunología , Epítopos de Linfocito T/química , Antígenos HLA-C/inmunología , Antígenos HLA-C/metabolismo , Antígenos HLA-C/genética , VIH-1/inmunología , VIH-1/genética , Linfocitos T Citotóxicos/inmunología , Secuencia de Aminoácidos , Unión Proteica , Infecciones por VIH/inmunología , Infecciones por VIH/virología , Antígenos VIHRESUMEN
BACKGROUND: In China, the problem of HIV infection among the older people has become increasingly prominent. This study aimed to analyze the pattern and influencing factors of HIV transmission based on a genomic and spatial epidemiological analysis among this population. METHODS: A total of 432 older people who were aged ≥ 50 years, newly diagnosed with HIV-1 between January 2018 and December 2021 and without a history of ART were enrolled. HIV-1 pol gene sequence was obtained by viral RNA extraction and nested PCR. The molecular transmission network was constructed using HIV-TRACE and the spatial distribution analyses were performed in ArcGIS. The multivariate logistic regression analysis was performed to analyze the factors associated with clustering. RESULTS: A total of 382 sequences were successfully sequenced, of which CRF07_BC (52.3%), CRF01_AE (32.5%), and CRF08_BC (6.8%) were the main HIV-1 strains. A total of 176 sequences entered the molecular network, with a clustering rate of 46.1%. Impressively, the clustering rate among older people infected through commercial heterosexual contact was as high as 61.7% and three female sex workers (FSWs) were observed in the network. The individuals who were aged ≥ 60 years and transmitted the virus by commercial heterosexual contact had a higher clustering rate, while those who were retirees or engaged other occupations and with higher education degree were less likely to cluster. There was a positive spatial correlation of clustering rate (Global Moran I = 0.206, P < 0.001) at the town level and the highly aggregated regions were mainly distributed in rural area. We determined three large clusters which mainly spread in the intra-region of certain towns in rural areas. Notably, 54.5% of cases in large clusters were transmitted through commercial heterosexual contact. CONCLUSIONS: Our joint analysis of molecular and spatial epidemiology effectively revealed the spatial aggregation of HIV transmission and highlighted that towns of high aggregation were mainly located in rural area. Also, we found vital role of commercial heterosexual contact in HIV transmission among older people. Therefore, health resources should be directed towards highly aggregated rural areas and prevention strategy should take critical persons as entry points.
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Infecciones por VIH , VIH-1 , Epidemiología Molecular , Humanos , VIH-1/genética , VIH-1/clasificación , VIH-1/aislamiento & purificación , China/epidemiología , Infecciones por VIH/transmisión , Infecciones por VIH/epidemiología , Infecciones por VIH/virología , Femenino , Masculino , Persona de Mediana Edad , Anciano , Filogenia , Genotipo , ARN Viral/genética , Análisis Espacial , Análisis por Conglomerados , Anciano de 80 o más AñosRESUMEN
BACKGROUND: Surveillance of HIV-1 pre-treatment drug resistance (PDR) is essential for ensuring the success of first-line antiretroviral therapy (ART). Beside population-based surveys, sentinel surveillance of PDR and circulating HIV-1 clades in specific populations such as blood donors could efficiently inform decision-making on ART program. We therefore sought to ascertain HIV-1 residual infection, the threshold of PDR and viral diversity among recently-diagnosed blood donors in Gabon. METHODS: A sentinel surveillance was conducted among 381 consenting blood donors at the National Blood Transfusion Center (NBTC) in Gabon from August 3,2020 to August, 31, 2021. In order to determine the residual risk of HIV transmission, viral load and HIV-1 Sanger-sequencing were performed at the Chantal BIYA International Reference Center (CIRCB)-Cameroon on HIV samples previously tested seronegative with ELISA in Gabon. Phylogeny was performed using MEGA X, PDR threshold>10% was considered high and data were analysed using p≤0.05 for statistical significance. RESULTS: Five HIV-negative blood donors had a detectable viral load indicating a high residual risk of HIV transmission. Among the samples successfully sequenced, four participants had major drug resistance mutations (DRMs), giving a threshold of PDR of 25% (4/16). By drug class, major DRMs targeting NNRTI (K103N, E138G), NRTIs (L210W) and PI/r (M46L). The most representative viral clades were CRF02_AG and subtype A1. The genetic diversity of HIV-1 had no significant effect on the residual risk in blood transfusion (CRF02_AG, P = 0.3 and Recombinants, P = 0.5). CONCLUSION: This sentinel surveillance indicates a high residual risk of HIV-1 transfusion in Gabon, thereby underscoring the need for optimal screening strategy for blood safety. Moreover, HIV-1 transmission goes with high-risk of PDR, suggesting suboptimal efficacy of ART. Nonetheless, the genetic diversity has limited (if any effect) on the residual risk of infection and PDR in blood donors.
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Donantes de Sangre , Farmacorresistencia Viral , Infecciones por VIH , VIH-1 , Vigilancia de Guardia , Humanos , Donantes de Sangre/estadística & datos numéricos , VIH-1/genética , VIH-1/efectos de los fármacos , Gabón/epidemiología , Infecciones por VIH/epidemiología , Infecciones por VIH/virología , Infecciones por VIH/tratamiento farmacológico , Infecciones por VIH/transmisión , Masculino , Farmacorresistencia Viral/genética , Femenino , Adulto , Persona de Mediana Edad , Carga Viral , Filogenia , Adulto Joven , Adolescente , Fármacos Anti-VIH/uso terapéutico , Fármacos Anti-VIH/farmacologíaRESUMEN
The HIV-1 capsid is composed of capsid (CA) protein hexamers and pentamers (capsomers) that contain a central pore hypothesised to regulate capsid assembly and facilitate nucleotide import early during post-infection. These pore functions are mediated by two positively charged rings created by CA Arg-18 (R18) and Lys-25 (K25). Here we describe the forced evolution of viruses containing mutations in R18 and K25. Whilst R18 mutants fail to replicate, K25A viruses acquire compensating mutations that restore nearly wild-type replication fitness. These compensating mutations, which rescue reverse transcription and infection without reintroducing lost pore charges, map to three adaptation hot-spots located within and between capsomers. The second-site suppressor mutations act by restoring the formation of pentamers lost upon K25 mutation, enabling closed conical capsid assembly both in vitro and inside virions. These results indicate that there is no intrinsic requirement for K25 in either nucleotide import or capsid assembly. We propose that whilst HIV-1 must maintain a precise hexamer:pentamer equilibrium for proper capsid assembly, compensatory mutations can tune this equilibrium to restore fitness lost by mutation of the central pore.
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Proteínas de la Cápside , Cápside , VIH-1 , Mutación , Ensamble de Virus , Replicación Viral , VIH-1/genética , VIH-1/fisiología , Ensamble de Virus/genética , Proteínas de la Cápside/genética , Proteínas de la Cápside/metabolismo , Proteínas de la Cápside/química , Cápside/metabolismo , Humanos , Replicación Viral/genética , Virión/metabolismo , Virión/genética , Células HEK293 , Infecciones por VIH/virología , Infecciones por VIH/genéticaRESUMEN
BACKGROUND: Large-scale HIV genotype drug resistance study has not been conducted in Chongqing. METHODS: A retrospective study was conducted on people living with HIV(PLWH) who received HIV-1 genotype resistance testing at Chongqing Public Health Medical Center from May 2016 to June 2023. The HIV-1pol gene was amplified through RT-PCR and analyzed in terms of genotypic drug resistance. RESULTS: Of the 3015 PLWH tested for HIV-1 drug resistance, 1405 (46.6%) were resistant to at least one antiviral drug. Among non-nucleoside reverse transcriptase inhibitors (NNRTIs), 43.8% were resistant, compared to 29.5% for nucleoside reverse transcriptase inhibitors (NRTIs) and 3.4% for protease inhibitors (PIs). V179D/E and K103N/S were identified as the common mutation sites in the NNRTIs class of drugs, M184V/I and K65R/N were reported as the most common mutation sites in NRTIs, while thymidine analogue mutation (TAM) group was identified in 373 samples. L10FIV was the most common mutation in PIs. The dominant HIV-1 subtype was CRF07_BC. CONCLUSIONS: The high prevalence of HIV-1 drug resistance in Chongqing underscores the imperative for rigorous surveillance of the local HIV epidemic. Furthermore, TAMs are associated with HIV-1 multidrug resistance, and timely detection of drug resistance is helpful to reduce the emergence and spread of such drug-resistant strains.
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Fármacos Anti-VIH , Farmacorresistencia Viral , Genotipo , Infecciones por VIH , VIH-1 , Mutación , Humanos , VIH-1/genética , VIH-1/efectos de los fármacos , Infecciones por VIH/tratamiento farmacológico , Infecciones por VIH/virología , Infecciones por VIH/epidemiología , China/epidemiología , Farmacorresistencia Viral/genética , Estudios Retrospectivos , Masculino , Femenino , Adulto , Persona de Mediana Edad , Fármacos Anti-VIH/uso terapéutico , Fármacos Anti-VIH/farmacología , Adulto Joven , Inhibidores de la Transcriptasa Inversa/uso terapéutico , Inhibidores de la Transcriptasa Inversa/farmacología , Adolescente , AncianoRESUMEN
Understanding the interplay between the HIV reservoir and the host immune system may yield insights into HIV persistence during antiretroviral therapy (ART) and inform strategies for a cure. Here, we applied machine learning (ML) approaches to cross-sectional high-parameter HIV reservoir and immunology data in order to characterize host-reservoir associations and generate new hypotheses about HIV reservoir biology. High-dimensional immunophenotyping, quantification of HIV-specific T cell responses, and measurement of genetically intact and total HIV proviral DNA frequencies were performed on peripheral blood samples from 115 people with HIV (PWH) on long-term ART. Analysis demonstrated that both intact and total proviral DNA frequencies were positively correlated with T cell activation and exhaustion. Years of ART and select bifunctional HIV-specific CD4 T cell responses were negatively correlated with the percentage of intact proviruses. A leave-one-covariate-out inference approach identified specific HIV reservoir and clinical-demographic parameters, such as age and biological sex, that were particularly important in predicting immunophenotypes. Overall, immune parameters were more strongly associated with total HIV proviral frequencies than intact proviral frequencies. Uniquely, however, expression of the IL-7 receptor alpha chain (CD127) on CD4 T cells was more strongly correlated with the intact reservoir. Unsupervised dimension reduction analysis identified two main clusters of PWH with distinct immune and reservoir characteristics. Using reservoir correlates identified in these initial analyses, decision tree methods were employed to visualize relationships among multiple immune and clinical-demographic parameters and the HIV reservoir. Finally, using random splits of our data as training-test sets, ML algorithms predicted with approximately 70% accuracy whether a given participant had qualitatively high or low levels of total or intact HIV DNA . The techniques described here may be useful for assessing global patterns within the increasingly high-dimensional data used in HIV reservoir and other studies of complex biology.
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ADN Viral , Infecciones por VIH , Aprendizaje Automático , Humanos , Infecciones por VIH/tratamiento farmacológico , Infecciones por VIH/inmunología , Infecciones por VIH/virología , ADN Viral/sangre , Masculino , Femenino , Adulto , VIH-1/genética , VIH-1/inmunología , Estudios Transversales , Provirus/genética , Persona de Mediana Edad , Linfocitos T CD4-Positivos/inmunología , Antirretrovirales/uso terapéuticoRESUMEN
BACKGROUND: Coinfection with two phylogenetically distinct Human Immunodeficiency Virus-1 (HIV-1) variants might provide an opportunity for rapid viral expansion and the emergence of fit variants that drive disease progression. However, autologous neutralising immune responses are known to drive Envelope (Env) diversity which can either enhance replicative capacity, have no effect, or reduce viral fitness. This study investigated whether in vivo outgrowth of coinfecting variants was linked to pseudovirus and infectious molecular clones' infectivity to determine whether diversification resulted in more fit virus with the potential to increase disease progression. RESULTS: For most participants, emergent recombinants displaced the co-transmitted variants and comprised the major population at 52 weeks postinfection with significantly higher entry efficiency than other co-circulating viruses. Our findings suggest that recombination within gp41 might have enhanced Env fusogenicity which contributed to the increase in pseudovirus entry efficiency. Finally, there was a significant correlation between pseudovirus entry efficiency and CD4 + T cell count, suggesting that the enhanced replicative capacity of recombinant variants could result in more virulent viruses. CONCLUSION: Coinfection provides variants with the opportunity to undergo rapid recombination that results in more infectious virus. This highlights the importance of monitoring the replicative fitness of emergent viruses.
Asunto(s)
Coinfección , Infecciones por VIH , VIH-1 , Filogenia , Humanos , Infecciones por VIH/virología , Infecciones por VIH/complicaciones , VIH-1/genética , VIH-1/fisiología , Coinfección/virología , Evolución Molecular , Productos del Gen env del Virus de la Inmunodeficiencia Humana/genética , Proteína gp41 de Envoltorio del VIH/genética , Masculino , Femenino , Recombinación Genética , Internalización del Virus , Adulto , Recuento de Linfocito CD4 , Replicación ViralRESUMEN
BACKGROUND: HIV-1 has well-established mechanisms to disrupt essential pathways in people with HIV, such as inflammation and metabolism. Moreover, diversity of the amino acid sequences in fundamental HIV-1 proteins including Tat and Vif, have been linked to dysregulating these pathways, and subsequently influencing clinical outcomes in people with HIV. However, the relationship between Tat and Vif amino acid sequence variation and specific immune markers and metabolites of the tryptophan-kynurenine (Trp-Kyn) pathway remains unclear. Therefore, this study aimed to investigate the relationship between Tat/Vif amino acid sequence diversity and Trp-Kyn metabolites (quinolinic acid (QUIN), Trp, kynurenic acid (KA), Kyn and Trp/Kyn ratio), as well as specific immune markers (sCD163, suPAR, IL-6, NGAL and hsCRP) in n = 67 South African cART-naïve people with HIV. METHODS: Sanger sequencing was used to determine blood-derived Tat/Vif amino acid sequence diversity. To measure Trp-Kyn metabolites, a LC-MS/MS metabolomics platform was employed using a targeted approach. To measure immune markers, Enzyme-linked immunosorbent assays and the Particle-enhanced turbidimetric assay was used. RESULTS: After adjusting for covariates, sCD163 (p = 0.042) and KA (p = 0.031) were higher in participants with Tat signatures N24 and R57, respectively, and amino acid variation at position 24 (adj R2 = 0.048, ß = -0.416, p = 0.042) and 57 (adj R2 = 0.166, ß = 0.535, p = 0.031) of Tat were associated with sCD163 and KA, respectively. CONCLUSIONS: These preliminary findings suggest that amino acid variation in Tat may have an influence on underlying pathogenic HIV-1 mechanisms and therefore, this line of work merits further investigation.
Asunto(s)
Infecciones por VIH , VIH-1 , Inflamación , Quinurenina , Triptófano , Productos del Gen tat del Virus de la Inmunodeficiencia Humana , Humanos , Triptófano/metabolismo , Infecciones por VIH/virología , Infecciones por VIH/genética , Masculino , VIH-1/genética , Adulto , Femenino , Quinurenina/metabolismo , Productos del Gen tat del Virus de la Inmunodeficiencia Humana/genética , Productos del Gen tat del Virus de la Inmunodeficiencia Humana/metabolismo , Secuencia de Aminoácidos , Persona de Mediana Edad , Biomarcadores/sangre , Receptores de Superficie Celular , Antígenos de Diferenciación Mielomonocítica , Antígenos CDRESUMEN
Background: There is increasing focus on HIV-1 CRF55_01B in China. However, there is limited information regarding the dissemination of CRF55_01B across different regions and populations in Guangxi. This study was performed to elucidate the evolutionary history of the introduction and dissemination of CRF55_01B in Guangxi. Methods: Molecular network and phylogenetic analyses were used to investigate the transmission characteristics of CRF55_01B in China. The analyses particularly focused on the cross-provincial spatial and temporal transmission patterns between Guangdong Province and Guangxi, as well as the transmission dynamics among different regions and populations within Guangxi. Results: In total, 2226 partial pol sequences of CRF55_01B strains sampled from 2007 to 2022 were collected, including 1895 (85.09%) sequences from Guangdong, 199 (8.94%) sequences from Guangxi, and 172 (7.59%) sequences from other provinces of China. Most people living with HIV in Guangxi were infected with HIV-1 through heterosexuals (52.76%). Among these, 19.10% had a history of commercial heterosexual contact (CHC) and 15.58% had a history of non-marital non-commercial heterosexual contact (NMNCHC). Overall, 1418 sequences were identified in the molecular network. Notably, the sequences from Guangdong Province were most closely linked to those from Guangxi. Phylogenetic analysis showed that CRF55_01B was first introduced from Shenzhen City to Nanning City around 2007. Subsequently, CRF55_01B established local transmission within Guangxi, with Nanning City serving as the transmission center from 2008 to 2017. After 2017, the CRF55_01B strain spread to other regions of Guangxi. Men who have sex with men (MSM) and men with a history of CHC have played a significant role in the transmission of CRF55_01B among different populations in Guangxi. Conclusions: This study provides evidence on the transmission trajectory of CRF55_01B among different regions and populations in Guangxi. Given the bridging role of men with a history of CHC in the dissemination of CRF55_01B from MSM to the general population, it is imperative to enhance surveillance among key populations to mitigate the secondary transmission of HIV-1.
Asunto(s)
Infecciones por VIH , VIH-1 , Heterosexualidad , Homosexualidad Masculina , Filogenia , Humanos , China/epidemiología , Masculino , VIH-1/genética , VIH-1/clasificación , Infecciones por VIH/transmisión , Infecciones por VIH/epidemiología , Infecciones por VIH/virología , Adulto , Genotipo , Epidemiología Molecular , Femenino , Adulto Joven , Persona de Mediana Edad , Productos del Gen pol del Virus de la Inmunodeficiencia Humana/genéticaRESUMEN
HIV-1 polymerase, commonly known as HIV reverse transcriptase (RT), catalyzes the critical reaction of reverse transcription by synthesizing a double-stranded DNA copy of the viral genomic RNA. During the replication cycle, this synthesized DNA is integrated into the host genome. This entire process is essential for viral replication and is targeted by several antiviral drugs. Numerous studies in biochemistry and structural biology have led to a good understanding of HIV-1 RT functions. However, the discovery of epitranscriptomic marks, such as 2'-O-methylations, on the HIV-1 RNA genome raise the questions about RT's ability to copy RNAs decorated with these biochemical modifications. This review focuses on the importance of RT in the viral cycle, its structure and function and the impact of 2'-O-methylations on its activity and replication regulation, particularly in quiescent cells.
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Transcriptasa Inversa del VIH , VIH-1 , Replicación Viral , Transcriptasa Inversa del VIH/metabolismo , Transcriptasa Inversa del VIH/genética , Transcriptasa Inversa del VIH/química , VIH-1/fisiología , VIH-1/genética , Humanos , Metilación , ARN Viral/metabolismo , ARN Viral/genética , Transcripción Reversa , Infecciones por VIH/virología , Infecciones por VIH/tratamiento farmacológicoRESUMEN
OBJECTIVE: Assessing the prevalence of resistance and drug resistance mutations (DRMs) in HIV/AIDS patients towards integrase strand transfer inhibitors (INSTIs), particularly the 2nd-generation INSTIs, provides evidence for rational clinical drug use. METHODS: A systematic search was conducted on five databases to identify relevant literature reporting original data on INSTIs resistance. Meta-analyses, cumulative meta-analyses, subgroup analyses and meta-regression analyses were performed using selected models based on the results of heterogeneity tests. RESULTS: A total of 81 studies were included in this analysis. The prevalence of pre-treatment drug resistance (PDR) to 1st-generation INSTIs and 2nd-generation INSTIs were 0.41% (95% CI: 0.19%-0.70%) and 0.04% (95% CI: 0.00%-0.13%), respectively; and the prevalence of acquired drug resistance (ADR) were 7.60% (95% CI: 3.54%-12.92%) and 4.93% (95% CI: 1.78%-9.36%), respectively, and ADR showed an increasing and then decreasing time trend. The results of subgroup analyses showed differences in ADR to 2nd-generation INSTIs between regions and economic levels, with the highest ADR of 12.83% (95% CI: 3.24%-27.17%) in the European region. DRMs varied among HIV patients and reduced drug sensitivity to varying degrees. CONCLUSION: The prevalence of PDR and DRMs in 2nd-generation INSTIs is currently low, but as the use of DTG-based ART expands, population-level drug resistance monitoring and individual-level genetic testing should be strengthened in order to maximise treatment efficacy. Additionally, attention should be paid to ADR to INSTIs to provide personalised treatments for HIV-infected patients.
Asunto(s)
Farmacorresistencia Viral , Infecciones por VIH , Inhibidores de Integrasa VIH , Integrasa de VIH , VIH-1 , Mutación , Humanos , Farmacorresistencia Viral/genética , Infecciones por VIH/tratamiento farmacológico , Infecciones por VIH/virología , Integrasa de VIH/genética , Inhibidores de Integrasa VIH/uso terapéutico , Inhibidores de Integrasa VIH/farmacología , VIH-1/efectos de los fármacos , VIH-1/genética , PrevalenciaRESUMEN
The greatest obstacle for scientists is to develop an effective HIV vaccine. An effective vaccine represents the last hope for halting the unstoppable global spread of HIV and its catastrophic clinical consequences. Creating this vaccine has been challenging due to the virus's extensive genetic variability and the unique role of cytotoxic T lymphocytes (CTL) in containing it. Innovative methods to stimulate CTL have demonstrated significant therapeutic advantages in nonhuman primate model systems, unlike traditional vaccination techniques that are not expected to provide safe and efficient protection against HIV. Human clinical trials are currently evaluating these vaccination strategies, which involve plasmid DNA and live recombinant vectors. This review article covers the existing vaccines and ongoing trial vaccines. It also explores the different approaches used in developing HIV vaccines, including their molecular mechanisms, target site effectiveness, and potential side effects.
Asunto(s)
Vacunas contra el SIDA , Ensayos Clínicos como Asunto , Infecciones por VIH , Humanos , Vacunas contra el SIDA/inmunología , Infecciones por VIH/prevención & control , Infecciones por VIH/inmunología , Animales , Linfocitos T Citotóxicos/inmunología , Desarrollo de Vacunas , VIH-1/inmunología , VIH-1/genéticaRESUMEN
BACKGROUND: In September 2016, South Africa introduced the Universal Test and Treat (UTT) programme to manage HIV infection. However, the development of drug resistance and sustaining viral suppression are challenges to the success of treatment programmes. This prospective observational study describes virologic, immunologic, and drug resistance profiles in a test and treat cohort in north-eastern South Africa. METHODS: Five hundred and thirty-four HIV-1 positive antiretroviral naïve adults entering treatment programmes were enrolled between January 2016 and February 2018. Trends in CD4+ cell count, viral load, and drug resistance by examination of deep sequences were assessed at baseline and every three months, for 24 months. RESULTS: Seventy-five percent were late initiators into ART (that is baseline CD4+ cell counts < 500 cells/microliter) and 16% were early initiators into ART and baseline CD4 was not available for 9%. Eleven percent (12/104) achieved immunological response after 6 months, 39.4% (41 /104) after 12 months, and 97.5% (101/104) after 24 months. Seventy-one percent (381/534) had baseline viral loads >1000 RNA copies/ml. Nine percent (22/246) achieved viral suppression after 3 months, 50% (122/246) after 6 months and 73.6% (181/246) after 12 months. A slower viral suppression was observed for males than females (p value = 0.012). A total of 45.6% (52/114) individuals had at least one drug resistance mutation (DRM) detected at >20% threshold in any of the time points, and the number increased to 55% (63/114) when minor variants were accounted for. Forty-eight percent (14/29) had drug resistance mutations at >5% threshold as early as 3 months into treatment. CONCLUSION: The UNAIDS target of 95% viral suppression in individuals under treatment was not observed after 12 months of treatment, and this was less successful for males. Adherence and drug resistance monitoring could be beneficial for individuals harbouring resistant viruses early into treatment.