RESUMO
Antiretroviral treatment of HIV infected individuals cannot eliminate the HIV reservoir and immune control of HIV is rarely seen upon treatment interruption. In long-term non-progressors (LTNP), an effective CD8 T cell response is thought to contribute to be immune control of HIV. Here we studied the transcriptional profile of virus specific CD8 T cells during the asymptomatic phase of disease, to gain molecular insights in CD8 T cell functionality in HIV progressors and different groups of LTNP: HLA-B*57 LTNP, non-HLA-B*57 LTNP and individuals carrying the MAVS minor genotype (rs7262903/rs7269320). Principal component analysis revealed distinct overall transcriptional profiles between the groups. The transcription profile of HIV-specific CD8 T cells of LTNP groups was associated with increased cytokine/IL-12 signaling and protein/RNA metabolism pathways, indicating an increased CD8 T cell functionality. Although the transcription profile of CMV-specific CD8 T cells differed from that of HIV-specific CD8 T cells, with mainly an upregulation of gene expression in progressors, similar affected pathways were identified. Moreover, CMV-specific CD8 T cells from progressors showed increased expression of genes related to effector functions and suggests recent antigen exposure. Our data shows that changes in cytokine signaling and the energy demanding RNA and protein metabolism are related to CD8 T cell dysfunction, which may indicate that mitochondrial dysfunction is an important driver of T cell dysfunctionality during chronic HIV infection. Indeed, improvement of mitochondrial function by IL-12 and mitoTempo treatment, enhanced in vitro IFNγ release by PBMC from PWH upon HIV gag and CMV pp65 peptide stimulation. Our study provides new insights into the molecular pathways associated with CD8 T cell mediated immune control of chronic HIV infection which is important for the design of novel treatment strategies to restore or improve the HIV-specific immune response.
Assuntos
Linfócitos T CD8-Positivos , Infecções por HIV , Humanos , Linfócitos T CD8-Positivos/imunologia , Linfócitos T CD8-Positivos/metabolismo , Infecções por HIV/imunologia , Infecções por HIV/genética , Infecções por HIV/virologia , Masculino , Metabolismo Energético , Adulto , HIV-1/imunologia , RNA/genética , RNA/metabolismo , Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Proteínas Adaptadoras de Transdução de Sinal/genética , Feminino , Doença Crônica , Antígenos HLA-B/genética , Antígenos HLA-B/metabolismo , Pessoa de Meia-IdadeAssuntos
Fármacos Anti-HIV , Farmacorresistência Viral , Infecções por HIV , Adulto , Humanos , Adenina/análogos & derivados , Adenina/uso terapêutico , Fármacos Anti-HIV/uso terapêutico , Negro ou Afro-Americano , Compostos Bicíclicos Heterocíclicos com Pontes/uso terapêutico , Combinação de Medicamentos , Emtricitabina/uso terapêutico , Compostos Heterocíclicos com 3 Anéis/uso terapêutico , Compostos Heterocíclicos de 4 ou mais Anéis/uso terapêutico , Infecções por HIV/tratamento farmacológico , Infecções por HIV/virologia , Adesão à Medicação/estatística & dados numéricos , Piperazinas/uso terapêutico , Piridonas/uso terapêutico , Tenofovir/uso terapêutico , Tenofovir/análogos & derivados , Resultado do Tratamento , Estados UnidosRESUMO
During antiretroviral therapy (ART), most people living with HIV-1 have undetectable HIV-1 RNA in their plasma. However, they occasionally present with new or progressive neurologic deficits and detectable HIV-1 RNA in the cerebrospinal fluid (CSF), a condition defined as neurosymptomatic HIV-1 CSF escape (NSE). We explored the source of neuropathogenesis and HIV-1 RNA in the CSF during NSE by characterizing HIV-1 populations and inflammatory biomarkers in CSF from 25 individuals with NSE. HIV-1 populations in the CSF were uniformly drug resistant and adapted to replication in CD4+ T cells, but differed greatly in genetic diversity, with some having low levels of diversity similar to those observed during untreated primary infection and others having high levels like those during untreated chronic infection. Higher diversity in the CSF during NSE was associated with greater CNS inflammation. Finally, optimization of ART regimen was associated with viral suppression and improvement of neurologic symptoms. These results are consistent with CNS inflammation and neurologic injury during NSE being driven by replication of partially drug-resistant virus in CNS CD4+ T cells. This is unlike nonsuppressible viremia in the plasma during ART, which typically lacks clinical consequences and is generated by virus expression without replication.
Assuntos
Linfócitos T CD4-Positivos , Infecções por HIV , HIV-1 , RNA Viral , Replicação Viral , Humanos , HIV-1/imunologia , Masculino , Feminino , Infecções por HIV/tratamento farmacológico , Infecções por HIV/imunologia , Infecções por HIV/líquido cefalorraquidiano , Infecções por HIV/virologia , Infecções por HIV/sangue , Linfócitos T CD4-Positivos/imunologia , Linfócitos T CD4-Positivos/metabolismo , Linfócitos T CD4-Positivos/virologia , Adulto , RNA Viral/líquido cefalorraquidiano , RNA Viral/sangue , Pessoa de Meia-Idade , Inflamação/imunologia , Inflamação/líquido cefalorraquidianoRESUMO
Background: When individuals infected with human immunodeficiency virus (HIV) experience pulmonary infections, they often exhibit severe symptoms and face a grim prognosis. Consequently, early, rapid, and accurate pathogen diagnosis is vital for informing effective treatment strategies. This study aimed to use metagenomic next-generation sequencing (mNGS) and targeted mNGS (tNGS) to elucidate the characteristics of pulmonary infections in HIV and non-HIV individuals. Methods: This study enrolled 90 patients with pulmonary infection at the Department of Infectious Diseases of The First Hospital of Jilin University from June 2022 to May 2023, and they were divided into HIV (n=46) and non-HIV (n=44) infection groups. Their bronchoalveolar lavage fluid (BALF) was collected for mNGS analysis to evaluate the differences in pulmonary infection pathogens, and tNGS detection was performed on BALF samples from 15 HIV-infected patients. Results: A total of 37 pathogens were identified in this study, including 21 bacteria, 5 fungi, 5 viruses, 5 mycobacteria, and 1 mycoplasma. The sensitivity of mNGS was 78.9% (71/90), which is significantly higher than that of conventional methods (CTM) (39/90, P=1.5E-8). The combination of mNGS with CTM can greatly enhance the sensitivity of pathogen detection. The prevalence of Pneumocystis jirovecii (82.6% vs. 9.1%), cytomegalovirus (CMV) (58.7% vs. 0%), and Epstein-Barr virus (EBV) (17.4% vs. 2.3%) was significantly higher in the HIV infection group than in the non-HIV infection group (P<0.05). Although no statistically significant difference was observed, the detection rate of Mycobacteria was higher in HIV-infected patients (17.4%) than in the non-HIV group (6.8%). Furthermore, the tNGS results of BALF from 15 HIV-infected patients were not entirely consistent with the mNGS results., and the concordance rate of tNGS for the detection of main pathogens reached 86.7% (13/15). Conclusion: Next-generation sequencing (NGS) can accurately detect pathogens in the BALF of patients with pulmonary infection. The sensitivity of tNGS is comparable to that of mNGS. Therefore, this technique should be promoted in the clinic for better patient outcomes.
Assuntos
Líquido da Lavagem Broncoalveolar , Infecções por HIV , Sequenciamento de Nucleotídeos em Larga Escala , Metagenômica , Humanos , Sequenciamento de Nucleotídeos em Larga Escala/métodos , Infecções por HIV/complicações , Infecções por HIV/virologia , Masculino , Feminino , Metagenômica/métodos , Líquido da Lavagem Broncoalveolar/microbiologia , Líquido da Lavagem Broncoalveolar/virologia , Pessoa de Meia-Idade , Adulto , Bactérias/genética , Bactérias/isolamento & purificação , Bactérias/classificação , Idoso , Sensibilidade e Especificidade , Vírus/genética , Vírus/isolamento & purificação , Vírus/classificação , Metagenoma , Infecções Respiratórias/virologia , Infecções Respiratórias/microbiologia , Infecções Respiratórias/diagnósticoRESUMO
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.
Assuntos
Coinfecção , Infecções por HIV , HIV-1 , Filogenia , Humanos , Infecções por HIV/virologia , Infecções por HIV/complicações , HIV-1/genética , HIV-1/fisiologia , Coinfecção/virologia , Evolução Molecular , Produtos do Gene env do Vírus da Imunodeficiência Humana/genética , Proteína gp41 do Envelope de HIV/genética , Masculino , Feminino , Recombinação Genética , Internalização do Vírus , Adulto , Contagem de Linfócito CD4 , Replicação ViralRESUMO
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.
Assuntos
Infecções por HIV , HIV-1 , Inflamação , Cinurenina , Triptofano , Produtos do Gene tat do Vírus da Imunodeficiência Humana , Humanos , Triptofano/metabolismo , Infecções por HIV/virologia , Infecções por HIV/genética , Masculino , HIV-1/genética , Adulto , Feminino , Cinurenina/metabolismo , Produtos do Gene tat do Vírus da Imunodeficiência Humana/genética , Produtos do Gene tat do Vírus da Imunodeficiência Humana/metabolismo , Sequência de Aminoácidos , Pessoa de Meia-Idade , Biomarcadores/sangue , Receptores de Superfície Celular , Antígenos de Diferenciação Mielomonocítica , Antígenos CDRESUMO
BACKGROUND: Antiretroviral therapy (ART) use during pregnancy is essential to prevent vertical transmission of HIV, but it may also increase the risk of adverse birth outcomes. This study investigated the impact of both maternal HIV infection and the timing of ART initiation on birth outcomes in women living with HIV in South Africa. METHODS: This secondary data analysis examined the dataset from an earlier cohort study involving 1709 pregnant women living with HIV who delivered their babies at three major maternity centres in the Eastern Cape province of South Africa between September 2015 and May 2018. The associations between adverse birth outcomes (stillbirth, preterm birth, very preterm birth, and low birth weight) and the timing of maternal ART initiation, peripartum CD4 count, and HIV viral load were examined using logistic regression analysis. RESULTS: The observed rates of stillbirth, preterm birth, very preterm birth, and low birth weight were 1.4%, 33.5%, 5.4% and 18.0%, respectively. In the multivariable analysis, low birth weight was associated with ART initiated during the second trimester (adjusted odds ratio [aOR] 1.38; 95% confidence interval [CI], 1.03-1.85), low-level viraemia (21-999 copies/ml) (aOR, 1.62; 95% CI, 1.17-2.22), and high-level viraemia (≥1000 copies/ml) (aOR, 1.66; 95% CI, 1.66-2.38) during the peripartum period. Preterm birth was associated with low-level viraemia (aOR, 1.44; 95% CI, 1.16-1.79) and a CD4 count of less than 200 cells/mm3 (aOR, 1.35; 95% CI, 1.01-1.82). Very preterm birth was associated with detectable maternal viraemia. CONCLUSION: Adverse birth outcomes are common among pregnant women living with HIV, especially those with unsuppressed viraemia. Clinicians and programme managers should prioritise timeous ART initiation and virological suppression in all pregnant women living with HIV.
Assuntos
Infecções por HIV , Complicações Infecciosas na Gravidez , Resultado da Gravidez , Carga Viral , Humanos , Feminino , Gravidez , África do Sul/epidemiologia , Infecções por HIV/tratamento farmacológico , Infecções por HIV/virologia , Adulto , Contagem de Linfócito CD4 , Complicações Infecciosas na Gravidez/tratamento farmacológico , Complicações Infecciosas na Gravidez/virologia , Recém-Nascido , Nascimento Prematuro/epidemiologia , Transmissão Vertical de Doenças Infecciosas/prevenção & controle , Adulto Jovem , Recém-Nascido de Baixo Peso , Fármacos Anti-HIV/uso terapêutico , Natimorto/epidemiologia , Análise de Dados SecundáriosRESUMO
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.
Assuntos
Análise Custo-Benefício , Farmacorresistência Viral , Infecções por HIV , Anos de Vida Ajustados por Qualidade de Vida , Humanos , Infecções por HIV/tratamento farmacológico , Infecções por HIV/virologia , Infecções por HIV/economia , Farmacorresistência Viral/genética , Irã (Geográfico)/epidemiologia , Masculino , Feminino , Cadeias de Markov , Fármacos Anti-HIV/uso terapêutico , Fármacos Anti-HIV/economia , HIV-1/efeitos dos fármacos , HIV-1/genética , Qualidade de Vida , AdultoRESUMO
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.
Assuntos
Teorema de Bayes , Evolução Molecular , Genoma Viral , Infecções por HIV , HIV-1 , Filogenia , HIV-1/genética , HIV-1/classificação , Humanos , Infecções por HIV/transmissão , Infecções por HIV/epidemiologia , Infecções por HIV/virologia , China/epidemiologia , Mianmar/epidemiologia , MasculinoRESUMO
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.
Assuntos
Fármacos Anti-HIV , Farmacorresistência Viral , Infecções por HIV , HIV-1 , Lamivudina , Mutação , Piperazinas , Piridonas , Tenofovir , Carga Viral , Humanos , Feminino , Adulto , HIV-1/genética , HIV-1/efeitos dos fármacos , Masculino , Infecções por HIV/tratamento farmacológico , Infecções por HIV/virologia , Farmacorresistência Viral/genética , Carga Viral/efeitos dos fármacos , Zâmbia/epidemiologia , Estudos Transversais , Tenofovir/uso terapêutico , Tenofovir/farmacologia , Fármacos Anti-HIV/uso terapêutico , Fármacos Anti-HIV/farmacologia , Piperazinas/uso terapêutico , Lamivudina/uso terapêutico , Lamivudina/farmacologia , Piridonas/uso terapêutico , Oxazinas/uso terapêutico , Compostos Heterocíclicos com 3 Anéis/uso terapêutico , Compostos Heterocíclicos com 3 Anéis/farmacologia , Emtricitabina/uso terapêutico , Pessoa de Meia-Idade , Adulto Jovem , Adolescente , Combinação de MedicamentosAssuntos
Infecções por HIV , Humanos , Infecções por HIV/tratamento farmacológico , Infecções por HIV/diagnóstico , Infecções por HIV/complicações , Infecções por HIV/virologia , Linfoma Relacionado a AIDS/diagnóstico , Linfoma Relacionado a AIDS/tratamento farmacológico , Linfoma Relacionado a AIDS/terapia , Linfoma Relacionado a AIDS/virologia , Seguimentos , Estadiamento de NeoplasiasRESUMO
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.
Assuntos
Epitopos de Linfócito T , HIV-1 , Antígenos HLA-C , Produtos do Gene gag do Vírus da Imunodeficiência Humana , Produtos do Gene gag do Vírus da Imunodeficiência Humana/imunologia , Produtos do Gene gag do Vírus da Imunodeficiência Humana/química , Produtos do Gene gag do Vírus da Imunodeficiência Humana/genética , Humanos , Epitopos de Linfócito T/imunologia , Epitopos de Linfócito T/química , Antígenos HLA-C/imunologia , Antígenos HLA-C/metabolismo , Antígenos HLA-C/genética , HIV-1/imunologia , HIV-1/genética , Linfócitos T Citotóxicos/imunologia , Sequência de Aminoácidos , Ligação Proteica , Infecções por HIV/imunologia , Infecções por HIV/virologia , Antígenos HIVRESUMO
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.
Assuntos
Proteínas do Capsídeo , Capsídeo , HIV-1 , Mutação , Montagem de Vírus , Replicação Viral , HIV-1/genética , HIV-1/fisiologia , Montagem de Vírus/genética , Proteínas do Capsídeo/genética , Proteínas do Capsídeo/metabolismo , Proteínas do Capsídeo/química , Capsídeo/metabolismo , Humanos , Replicação Viral/genética , Vírion/metabolismo , Vírion/genética , Células HEK293 , Infecções por HIV/virologia , Infecções por HIV/genéticaRESUMO
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.
Assuntos
Microbioma Gastrointestinal , Infecções por HIV , HIV-1 , Homossexualidade Masculina , Inflamação , Comportamento Sexual , Masculino , Humanos , Infecções por HIV/microbiologia , Infecções por HIV/imunologia , Infecções por HIV/virologia , Adulto , Inflamação/microbiologia , HIV-1/fisiologia , Disbiose/microbiologia , Pessoa de Meia-IdadeRESUMO
Background: The human immunodeficiency virus (HIV) pandemic is a global health emergency. Studies suggest a connection between heat shock proteins (HSPs) and HIV-1 infection pathogenesis. This systematic review aims to summarize HSPs' role in HIV-1 infection pathogenesis. Materials and Methods: A systematic literature search was undertaken across the National Library of Medicine (MEDLINE-PubMed), Science Direct, Web of Science, Scopus, SpringerLink, Sage, ProQuest, and Google Scholar databases, using related keywords to synthesize the HSPs' role in HIV-1 infection pathogenesis. This literature review was conducted according to Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines, and the protocol was registered in the Open Science Framework (OSF) database under DOI 10.17605/OSF.IO/VK3DJ. Results: A database search revealed 3,332 articles, with 14 in vitro studies analysing the interaction between HSPs and HIV-1 across different cell types. HSPs are involved in HIV-1 infection through direct interactions and indirect responses to cellular stress, including HSP40, HSP70, HSPBP1, and HSP90. The study explores HSP interactions at various stages of the viral life cycle, including entry, uncoating, replication, transmission, and latency reactivation. Conclusion: HSPs are crucial for the HIV lifecycle and immune response, offering the potential for new therapeutic strategies. Further research is needed to understand the clinical significance and target potential.
Assuntos
Infecções por HIV , HIV-1 , Proteínas de Choque Térmico , Humanos , HIV-1/patogenicidade , Infecções por HIV/metabolismo , Infecções por HIV/imunologia , Infecções por HIV/virologia , Proteínas de Choque Térmico/metabolismo , Replicação ViralRESUMO
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.
Assuntos
Anticorpos Monoclonais , Anticorpos Neutralizantes , Anticorpos Anti-HIV , HIV-1 , HIV-1/imunologia , HIV-1/efeitos dos fármacos , Humanos , Anticorpos Neutralizantes/imunologia , Anticorpos Anti-HIV/imunologia , Anticorpos Monoclonais/imunologia , Infecções por HIV/imunologia , Infecções por HIV/tratamento farmacológico , Infecções por HIV/virologia , Testes de Neutralização/métodosRESUMO
HIV-1 infection requires passage of the viral core through the nuclear pore of the cell, a process that depends on functions of the viral capsid. Recent studies have shown that HIV-1 cores enter the nucleus prior to capsid disassembly. Interactions of the viral capsid with the nuclear pore complex are necessary but not sufficient for nuclear entry, and the mechanism by which the viral core traverses the comparably sized nuclear pore is unknown. Here we show that the HIV-1 core is highly elastic and that this property is linked to nuclear entry and infectivity. Using atomic force microscopy-based approaches, we found that purified wild type cores rapidly returned to their normal conical morphology following a severe compression. Results from independently performed molecular dynamic simulations of the mature HIV-1 capsid also revealed its elastic property. Analysis of four HIV-1 capsid mutants that exhibit impaired nuclear entry revealed that the mutant viral cores are brittle. Adaptation of two of the mutant viruses in cell culture resulted in additional substitutions that restored elasticity and rescued infectivity and nuclear entry. We also show that capsid-targeting compound PF74 and the antiviral drug Lenacapavir reduce core elasticity and block HIV-1 nuclear entry at concentrations that preserve interactions between the viral core and the nuclear envelope. Our results indicate that elasticity is a fundamental property of the HIV-1 core that enables nuclear entry, thereby facilitating infection. These results provide new insights into the role of the capsid in HIV-1 nuclear entry and the antiviral mechanisms of HIV-1 capsid inhibitors.
Assuntos
Elasticidade , Infecções por HIV , HIV-1 , HIV-1/fisiologia , Humanos , Infecções por HIV/virologia , Infecções por HIV/metabolismo , Internalização do Vírus , Capsídeo/metabolismo , Núcleo Celular/metabolismo , Núcleo Celular/virologia , Simulação de Dinâmica Molecular , Microscopia de Força Atômica , Poro Nuclear/metabolismo , Indóis , Fenilalanina/análogos & derivadosRESUMO
This study investigates the prevalence and patterns of transmitted drug resistance mutations (TDRMs) and HIV-1 subtypes among antiretroviral therapy (ART) naïve individuals in Veneto, Italy, from 2017 to 2024. This research aims to understand the dynamic landscape of TDRMs and HIV-1 genetic diversity to inform treatment strategies effectively. We included all adult ART-naïve people with HIV (PWH) from seven infectious disease units in Veneto, Italy. We collected the genotypic resistance testing conducted to predict drug susceptibility and subtype distribution using the Stanford HIVdb algorithm. We included 762 PWH, showing a slight but statistically significant decline in the B subtype among Italian PWH (p = 0.045) and an increase in non-B subtypes among foreigners, though it was not statistically significant (p = 0.333). The most frequent mutations were in Non-nucleoside Reverse Transcriptase Inhibitors (NNRTIs), especially in non-B subtypes, with a notable rise from 10.7% in 2017-2019 to 15.5% in 2020-2024. Notably, TDRMs were consistently detected, highlighting an ongoing challenge despite the stable prevalence observed over the years. In addition, the data revealed a concerning rise in mutations against newer drug classes, such as integrase inhibitors. Conclusively, the study underscores the necessity of continuous surveillance of HIV subtypes and resistance patterns to adapt ART regimens optimally. Despite the stable levels of drug resistance, the emergence of resistance against newer drugs necessitates ongoing vigilance and possible adjustment in treatment protocols to enhance clinical outcomes and manage HIV drug resistance effectively.
Assuntos
Fármacos Anti-HIV , Farmacorresistência Viral , Genótipo , Infecções por HIV , HIV-1 , Mutação , Humanos , HIV-1/genética , HIV-1/efeitos dos fármacos , HIV-1/classificação , Itália/epidemiologia , Infecções por HIV/virologia , Infecções por HIV/tratamento farmacológico , Infecções por HIV/epidemiologia , Farmacorresistência Viral/genética , Masculino , Adulto , Feminino , Fármacos Anti-HIV/farmacologia , Fármacos Anti-HIV/uso terapêutico , Prevalência , Pessoa de Meia-Idade , Adulto Jovem , Variação GenéticaRESUMO
M184V is a single-base mutation in the YMDD domain of reverse transcriptase (RT). The M184V resistance-associated mutation (RAM) is related to virological unresponsiveness to lamivudine (3TC) and emtricitabine (FTC) and induces high-level resistance to these two antiretroviral agents. M184V is rapidly selected in the setting of non-suppressive antiretroviral therapy (ART) and accumulates in the HIV reservoir. There were continuous efforts to evaluate the impact of the M184V mutation on the treatment outcomes in people living with HIV (PLWH). Since 3TC remains an extensively used part of recommended antiretroviral combinations, M184V is commonly detected in patients with virological failure (VF). ART guidelines do not recommend the use of drugs impacted by RAMs as they have been confirmed to comprise a risk factor for VF. However, there is evidence that 3TC/FTC can remain active even in the presence of M184V. Given the potential benefits of 3TC in ART combinations, the investigation of M184V remains of high interest to clinicians and researchers, especially in certain regions with limited resources, and especially for its unusual effects. This is a review of the literature on the challenges in treating both naïve and experienced individuals carrying the M184V mutation, including virological failure, virological suppression, and resistance to ART.
Assuntos
Fármacos Anti-HIV , Farmacorresistência Viral , Infecções por HIV , HIV-1 , Mutação , Humanos , HIV-1/genética , HIV-1/efeitos dos fármacos , Infecções por HIV/tratamento farmacológico , Infecções por HIV/virologia , Farmacorresistência Viral/genética , Fármacos Anti-HIV/uso terapêutico , Transcriptase Reversa do HIV/genética , Lamivudina/uso terapêutico , Emtricitabina/uso terapêuticoRESUMO
BACKGROUND: Next-generation sequencing (NGS) is gradually replacing Sanger sequencing for HIV genotypic drug resistance testing (GRT). This work evaluated the concordance among different NGS-GRT interpretation tools in a real-life setting. METHODS: Routine NGS-GRT data were generated from viral RNA at 11 Italian laboratories with the AD4SEQ HIV-1 Solution v2 commercial kit. NGS results were interpreted by the SmartVir system provided by the kit and by two online tools (HyDRA Web and Stanford HIVdb). NGS-GRT was considered valid when the coverage was >100 reads (100×) at each PR/RT/IN resistance-associated position listed in the HIVdb 9.5.1 algorithm. RESULTS: Among 629 NGS-GRT, 75.2%, 74.2%, and 70.9% were valid according to SmartVir, HyDRA Web, and HIVdb. Considering at least two interpretation tools, 463 (73.6%) NGS-GRT had a valid coverage for resistance analyses. The proportion of valid samples was affected by viremia <10,000-1000 copies/mL and non-B subtypes. Mutations at an NGS frequency >10% showed fair concordance among different interpretation tools. CONCLUSION: This Italian survey on NGS resistance testing suggests that viremia levels and HIV subtype affect NGS-GRT coverage. Within the current routine method for NGS-GRT, only mutations with frequency >10% seem reliably detected across different interpretation tools.