RESUMEN
Tunneling nanotubes (TNTs) are cellular connections, which represent a novel route for cell-to-cell communication. Strong evidence points to a role for TNTs in the intercellular transfer of signals, molecules, organelles, and pathogens, involving them in many cellular functions. In myeloid cells (e.g., monocytes/macrophages, dendritic cells, and osteoclasts), intercellular communication via TNT contributes to their differentiation and immune functions, by favoring material and pathogen transfer, as well as cell fusion. This chapter addresses the complexity of the definition and characterization of TNTs in myeloid cells, the different processes involved in their formation, their existence in vivo, and finally their function(s) in health and infectious diseases, with the example of HIV-1 infection.
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Comunicación Celular , Células Mieloides , Humanos , Comunicación Celular/fisiología , Animales , Infecciones por VIH/inmunología , VIH-1/fisiología , Estructuras de la Membrana Celular , NanotubosRESUMEN
BACKGROUND: The pathogenesis of HIV-associated neurocognitive (NC) impairment is multifactorial, and antiretroviral (ARV) neurotoxicity may contribute. However, interventional pharmacological studies are limited. METHODS: Single-blind, randomized (1:1), controlled trial to assess the change of NC performance (Global Deficit Score, GDS, and domain scores) in PLWH with NC impairment randomized to continue their standard of care treatment or to switch to a less neurotoxic ARV regimen: darunavir/cobicistat, maraviroc, emtricitabine (MARAND-X). Participants had plasma and cerebrospinal fluid HIV RNA< 50 copies/mL, R5-tropic HIV, and were on ARV regimens that did not include efavirenz and darunavir. The change of resting-state electroencephalography was also evaluated. The outcomes were assessed at week 24 of the intervention through tests for longitudinal paired data and mixed-effect models. RESULTS: Thirty-eight participants were enrolled and 28 completed the follow-up. Global Deficit Score improved over time but with no difference between arms in longitudinal adjusted models. Perceptual functions improved in the MARAND-X, while long-term memory improved only in participants within the MARAND-X for whom the central nervous system penetration-effectiveness (CNS penetration effectiveness) score increased by ≥3. No significant changes in resting-state electroencephalography were observed. CONCLUSIONS: In this small but well-controlled study, the use of less neurotoxic ARV showed no major beneficial effect over an unchanged regimen. The beneficial effects on the memory domain of increasing CNS penetration effectiveness score suggest that ARV neuropenetration may have a role in cognitive function.
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Fármacos Anti-VIH , Infecciones por VIH , Humanos , Masculino , Femenino , Adulto , Persona de Mediana Edad , Fármacos Anti-VIH/uso terapéutico , Fármacos Anti-VIH/efectos adversos , Infecciones por VIH/tratamiento farmacológico , Infecciones por VIH/complicaciones , Emtricitabina/uso terapéutico , Método Simple Ciego , VIH-1 , Complejo SIDA Demencia/tratamiento farmacológico , Maraviroc/uso terapéutico , Darunavir/uso terapéutico , Cobicistat/uso terapéutico , Trastornos Neurocognitivos/tratamiento farmacológico , Trastornos Neurocognitivos/etiología , Electroencefalografía , Cognición/efectos de los fármacosRESUMEN
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
Combination monoclonal broadly neutralizing antibodies (bnAbs) are currently being developed for preventing HIV-1 acquisition. Recent work has focused on predicting in vitro neutralization potency of both individual bnAbs and combination regimens against HIV-1 pseudoviruses using Env sequence features. To predict in vitro combination regimen neutralization potency against a given HIV-1 pseudovirus, previous approaches have applied mathematical models to combine individual-bnAb neutralization and have predicted this combined neutralization value; we call this the combine-then-predict (CP) approach. However, prediction performance for some individual bnAbs has exceeded that for the combination, leading to another possibility: combining the individual-bnAb predicted values and using these to predict combination regimen neutralization; we call this the predict-then-combine (PC) approach. We explore both approaches in both simulated data and data from the Los Alamos National Laboratory's Compile, Neutralize, and Tally NAb Panels repository. The CP approach is superior to the PC approach when the neutralization outcome of interest is binary (e.g., neutralization susceptibility, defined as inhibitory 80% concentration < 1 µg/mL). For continuous outcomes, the CP approach performs nearly as well as the PC approach when the individual-bnAb prediction algorithms have strong performance, and is superior to the PC approach when the individual-bnAb prediction algorithms have poor performance. This knowledge may be used when building prediction models for novel antibody combinations in the absence of in vitro neutralization data for the antibody combination; this, in turn, will aid in the evaluation and down-selection of these antibody combinations into prevention efficacy trials.
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Anticuerpos Monoclonales , Anticuerpos Neutralizantes , Anticuerpos Anti-VIH , VIH-1 , VIH-1/inmunología , VIH-1/efectos de los fármacos , Humanos , Anticuerpos Neutralizantes/inmunología , Anticuerpos Anti-VIH/inmunología , Anticuerpos Monoclonales/inmunología , Infecciones por VIH/inmunología , Infecciones por VIH/tratamiento farmacológico , Infecciones por VIH/virología , Pruebas de Neutralización/métodosRESUMEN
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
INTRODUCTION: CARISEL is an implementation-effectiveness "hybrid" study examining the perspectives of people living with HIV-1 (patient study participants [PSPs]) on cabotegravir (CAB) plus rilpivirine (RPV) long-acting (LA) dosed every 2 months (Q2M) across 5 European countries. METHODS: PSPs completed questionnaires on acceptability (Acceptability of Intervention Measure), appropriateness (Intervention Appropriateness Measure), and feasibility (Feasibility of Intervention Measure) at their first (Month [M] 1), third (M4), and seventh (M12) injection visits. Semistructured qualitative interviews were also conducted. RESULTS: Overall, 437 PSPs were enrolled, of whom 430 received treatment. Median (interquartile range) age was 44 (37-51) years, 25.3% (n = 109/430) were female (sex at birth), and 21.9% (n = 94/430) were persons of color. Across time points, PSPs found CAB + RPV LA highly acceptable, appropriate, and feasible (mean scores ≥4.47/5). Qualitative data supported these observations. CONCLUSIONS: PSPs found CAB + RPV LA Q2M to be an acceptable, appropriate, and feasible treatment option.
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Fármacos Anti-VIH , Infecciones por VIH , Piridonas , Rilpivirina , Humanos , Rilpivirina/uso terapéutico , Rilpivirina/administración & dosificación , Femenino , Masculino , Adulto , Infecciones por VIH/tratamiento farmacológico , Persona de Mediana Edad , Europa (Continente) , Fármacos Anti-VIH/uso terapéutico , Fármacos Anti-VIH/administración & dosificación , Piridonas/uso terapéutico , Piridonas/administración & dosificación , VIH-1/efectos de los fármacos , Encuestas y Cuestionarios , DicetopiperazinasRESUMEN
Combination antiretroviral therapy (cART) has dramatically reduced mortality in people with human immunodeficiency virus (HIV), but it does not completely eradicate the virus from the brain. Patients with long-term HIV-1 infection often show neurocognitive impairment, which severely affects the quality of life of those infected. Methamphetamine (METH) users are at a significantly higher risk of contracting HIV-1 through behaviors such as engaging in high-risk sex or sharing needles, which can lead to transmission of the virus. In addition, HIV-1-infected individuals who abuse METH exhibit higher viral loads and more severe cognitive dysfunction, suggesting that METH exacerbates the neurotoxicity associated with HIV-1. Therefore, this review focuses on various mechanisms underlying METH and HIV-1 infection co-induced neurotoxicity and existing interventions targeting the sigma 1 receptor, dopamine transporter protein, and other relevant targets are explored. The findings of this review are envisaged to systematically establish a theoretical framework for METH abuse and HIV-1 infection co-induced neurotoxicity, and to suggest novel clinical treatment targets.
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Infecciones por VIH , VIH-1 , Metanfetamina , Humanos , Metanfetamina/efectos adversos , Infecciones por VIH/tratamiento farmacológico , Infecciones por VIH/complicaciones , VIH-1/efectos de los fármacos , Síndromes de Neurotoxicidad/etiología , Animales , Trastornos Relacionados con Anfetaminas/complicaciones , Trastornos Relacionados con Anfetaminas/terapia , Receptor Sigma-1 , Proteínas de Transporte de Dopamina a través de la Membrana Plasmática/metabolismoRESUMEN
Plasma cytokine levels were quantified among 30 persons with HIV (PWH) identified as elite controllers (15 transient controllers [studied a median of 1.38 years before losing viral control] and 15 persistent controllers). Thirty antiretroviral therapy (ART)-naive PWH, 30 ART-treated PWH with undetectable viremia, and 30 HIV-uninfected controls also were studied. Higher levels of cytokines were recognized among PWH than among controls, with EC displaying the highest levels. Elevated levels of IP-10 and MIG were identified among transient controllers as predictors of the loss of viral control. These findings offer feasible biomarkers for predicting virologic outcome and loss of control in EC.
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Biomarcadores , Quimiocina CXCL10 , Quimiocina CXCL9 , Infecciones por VIH , Humanos , Infecciones por VIH/inmunología , Infecciones por VIH/sangre , Infecciones por VIH/tratamiento farmacológico , Infecciones por VIH/virología , Masculino , Quimiocina CXCL10/sangre , Femenino , Biomarcadores/sangre , Adulto , Persona de Mediana Edad , Quimiocina CXCL9/sangre , Carga Viral , VIH-1/inmunología , Sobrevivientes de VIH a Largo PlazoRESUMEN
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
Pathogenic changes in gut microbial composition precede the onset of HIV-1 infection in men who have sex with men (MSM). This process is associated with increased levels of systemic inflammatory biomarkers and risk for AIDS development. Using mediation analysis framework, in this report we link the effects of unprotected receptive intercourse among MSM prior to primary HIV-1 infection to higher levels of proinflammatory cytokines sCD14 and sCD163 in plasma and a significant decrease in the abundance of A. muciniphila, B. caccae, B. fragilis, B. uniformis, Bacteroides spp., Butyricimonas spp., and Odoribacter spp., and a potential increase in the abundance of Dehalobacterium spp. and Methanobrevibacter spp. in stools of MSM with the highest number of sexual partners. These differences in microbiota, together with a reduction in the pairwise correlations among commensal and short-chain fatty acid-producing bacteria with a number of sexual partners, support an increase in gut dysbiosis with the number of sexual partners. These results demonstrate the interconnectedness of sexual behavior, immune response, and microbiota composition, notably among MSM participating in high-risk sexual behaviors.
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Microbioma Gastrointestinal , Infecciones por VIH , VIH-1 , Homosexualidad Masculina , Inflamación , Conducta Sexual , Masculino , Humanos , Infecciones por VIH/microbiología , Infecciones por VIH/inmunología , Infecciones por VIH/virología , Adulto , Inflamación/microbiología , VIH-1/fisiología , Disbiosis/microbiología , Persona de Mediana EdadRESUMEN
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.
Asunto(s)
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.
Asunto(s)
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.
Asunto(s)
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
Blood-brain barrier (BBB) injury and dysfunction following infection with the human immunodeficiency virus (HIV) enables viral entry into the brain, infection of resident brain cells, neuronal injury and subsequent neurodegeneration leading to HIV-associated neurocognitive disorders (HAND). Although combination antiretroviral therapy has significantly reduced the incidence and prevalence of acquired immunodeficiency syndrome and increased the life expectancy of people living with HIV, the prevalence of HAND remains high. With aging of people living with HIV associated with increased comorbidities, the prevalence of HIV-related central nervous system (CNS) complications is expected to remain high. Considering the principal role of the brain endothelium in HIV infection of the CNS and HAND, the purpose of this manuscript is to review the current literature on the pathobiology of the brain endothelium structural and functional dysregulation in HIV infection, including in the presence of HIV-1 and viral proteins (gp120, Tat, Nef, and Vpr). We summarize evidence from human and animal studies, in vitro studies, and associated mechanisms. We further summarize evidence of synergy or lack thereof between commonly abused substances (cocaine, methamphetamine, alcohol, tobacco, opioids, and cannabinoids) and HIV- or viral protein-induced BBB injury and dysfunction.