RESUMO
Understanding the drivers and markers of clonally expanding HIV-1-infected CD4+ T cells is essential for HIV-1 eradication. We used single-cell ECCITE-seq, which captures surface protein expression, cellular transcriptome, HIV-1 RNA, and TCR sequences within the same single cell to track clonal expansion dynamics in longitudinally archived samples from six HIV-1-infected individuals (during viremia and after suppressive antiretroviral therapy) and two uninfected individuals, in unstimulated conditions and after CMV and HIV-1 antigen stimulation. Despite antiretroviral therapy, persistent antigen and TNF responses shaped T cell clonal expansion. HIV-1 resided in Th1-polarized, antigen-responding T cells expressing BCL2 and SERPINB9 that may resist cell death. HIV-1 RNA+ T cell clones were larger in clone size, established during viremia, persistent after viral suppression, and enriched in GZMB+ cytotoxic effector memory Th1 cells. Targeting HIV-1-infected cytotoxic CD4+ T cells and drivers of clonal expansion provides another direction for HIV-1 eradication.
Assuntos
Infecções por HIV , HIV-1 , Linfócitos T CD4-Positivos , Células Clonais , Humanos , RNA , ViremiaRESUMO
Type I IFNs play a pivotal role in immune response modulation, yet dysregulation is implicated in various disorders. Therefore, it is crucial to develop tools that facilitate the understanding of their mechanism of action and enable the development of more effective anti-IFN therapeutic strategies. In this study, we isolated, cloned, and characterized anti-IFN-α and anti-IFN-ß Abs from PBMCs of individuals treated with IFN-α or IFN-ß, harboring confirmed neutralizing Abs. Clones AH07856 and AH07857 were identified as neutralizing anti-IFN-α-specific with inhibition against IFN-α2a, -α2b, and -αK subtypes. Clones AH07859 and AH07866 were identified as neutralizing anti-IFN-ß1a-specific signaling and able to block lipopolysaccharide or S100 calcium-binding protein A14-induced IFN-ß signaling effects. Cloned Abs bind rhesus but not murine IFNs. The specificity of inhibition between IFN-α and IFN-ß suggests potential for diverse research and clinical applications.
RESUMO
Despite effective combination antiretroviral therapy (cART), people living with HIV (PLWH) continue to harbor replication-competent and transcriptionally active virus in infected cells, which in turn can lead to ongoing viral antigen production, chronic inflammation, and increased risk of age-related comorbidities. To identify new agents that may inhibit postintegration HIV beyond cART, we screened a library of 512 pure compounds derived from natural products and identified (-)-hopeaphenol as an inhibitor of HIV postintegration transcription at low to submicromolar concentrations without cytotoxicity. Using a combination of global RNA sequencing, plasmid-based reporter assays, and enzyme activity studies, we document that hopeaphenol inhibits protein kinase C (PKC)- and downstream NF-κB-dependent HIV transcription as well as a subset of PKC-dependent T-cell activation markers, including interleukin-2 (IL-2) cytokine and CD25 and HLA-DRB1 RNA production. In contrast, it does not substantially inhibit the early PKC-mediated T-cell activation marker CD69 production of IL-6 or NF-κB signaling induced by tumor necrosis factor alpha (TNF-α). We further show that hopeaphenol can inhibit cyclin-dependent kinase 9 (CDK9) enzymatic activity required for HIV transcription. Finally, it inhibits HIV replication in peripheral blood mononuclear cells (PBMCs) infected in vitro and dampens viral reactivation in CD4+ cells from PLWH. Our study identifies hopeaphenol as a novel inhibitor that targets a subset of PKC-mediated T-cell activation pathways in addition to CDK9 to block HIV expression. Hopeaphenol-based therapies could complement current antiretroviral therapy otherwise not targeting cell-associated HIV RNA and residual antigen production in PLWH.
Assuntos
Infecções por HIV , Estilbenos , Humanos , NF-kappa B/genética , NF-kappa B/metabolismo , Proteína Quinase C/genética , Quinase 9 Dependente de Ciclina/metabolismo , Leucócitos Mononucleares/metabolismo , Replicação Viral , Latência Viral , Estilbenos/farmacologia , Infecções por HIV/metabolismo , RNARESUMO
Despite effective antiretroviral therapy, HIV-1 persistence in latent reservoirs remains a major obstacle to a cure. We postulate that HIV-1 silencing factors suppress HIV-1 reactivation and that inhibition of these factors will increase HIV-1 reactivation. To identify HIV-1 silencing factors, we conducted a genome-wide CRISPR inhibition (CRISPRi) screen using four CRISPRi-ready, HIV-1-d6-GFP-infected Jurkat T cell clones with distinct integration sites. We sorted cells with increased green fluorescent protein (GFP) expression and captured single guide RNAs (sgRNAs) via targeted deep sequencing. We identified 18 HIV-1 silencing factors that were significantly enriched in HIV-1-d6-GFPhigh cells. Among them, SLTM (scaffold attachment factor B-like transcription modulator) is an epigenetic and transcriptional modulator having both DNA and RNA binding capacities not previously known to affect HIV-1 transcription. Knocking down SLTM by CRISPRi significantly increased HIV-1-d6-GFP expression (by 1.9- to 4.2-fold) in three HIV-1-d6-GFP-Jurkat T cell clones. Furthermore, SLTM knockdown increased the chromatin accessibility of HIV-1 and the gene in which HIV-1 is integrated but not the housekeeping gene POLR2A. To test whether SLTM inhibition can reactivate HIV-1 and further induce cell death of HIV-1-infected cells ex vivo, we established a small interfering RNA (siRNA) knockdown method that reduced SLTM expression in CD4+ T cells from 10 antiretroviral therapy (ART)-treated, virally suppressed, HIV-1-infected individuals ex vivo. Using limiting dilution culture, we found that SLTM knockdown significantly reduced the frequency of HIV-1-infected cells harboring inducible HIV-1 by 62.2% (0.56/106 versus 1.48/106 CD4+ T cells [P = 0.029]). Overall, our study indicates that SLTM inhibition reactivates HIV-1 in vitro and induces cell death of HIV-1-infected cells ex vivo. Our study identified SLTM as a novel therapeutic target. IMPORTANCE HIV-1-infected cells, which can survive drug treatment and immune cell killing, prevent an HIV-1 cure. Immune recognition of infected cells requires HIV-1 protein expression; however, HIV-1 protein expression is limited in infected cells after long-term therapy. The ways in which the HIV-1 provirus is blocked from producing protein are unknown. We identified a new host protein that regulates HIV-1 gene expression. We also provided a new method of studying HIV-1-host factor interactions in cells from infected individuals. These improvements may enable future strategies to reactivate HIV-1 in infected individuals so that infected cells can be killed by immune cells, drug treatment, or the virus itself.
Assuntos
Infecções por HIV , Soropositividade para HIV , HIV-1 , Ativação Viral , Terapia Antirretroviral de Alta Atividade , Linfócitos T CD4-Positivos , Cromatina/genética , Cromatina/metabolismo , Repetições Palindrômicas Curtas Agrupadas e Regularmente Espaçadas/genética , Técnicas de Silenciamento de Genes , Infecções por HIV/fisiopatologia , Soropositividade para HIV/genética , HIV-1/fisiologia , Humanos , Células Jurkat , Proteínas de Ligação à Região de Interação com a Matriz/antagonistas & inibidores , Proteínas de Ligação à Região de Interação com a Matriz/metabolismo , Ativação Viral/genéticaRESUMO
OBJECTIVES: Our objective was to compare the immunological responses to commonly used antiretroviral therapy (ART) regimens among people with advanced HIV in the USA and to assess virological outcomes and regimen persistence. METHODS: This study included ART-naïve adults with advanced HIV infection (CD4 cell count <200 cells/µL) initiating ART with bictegravir/emtricitabine/tenofovir alafenamide (B/F/TAF), boosted darunavir (bDRV), dolutegravir (DTG), or elvitegravir (EVG/c)-containing regimens between 1 January 2018 and 31 December 2020 in the Observational Pharmaco-Epidemiology Research and Analysis (OPERA) cohort. Cox proportional hazards models and linear mixed models with random intercept were fit with inverse probability of treatment weighting. RESULTS: Overall, 1349 people with advanced HIV (816 B/F/TAF, 253 DTG, 146 EVG/c, 134 bDRV) were followed for a median of 22 months. Compared with B/F/TAF, a lower likelihood of achieving a CD4 cell count ≥200 cells/µL was observed with bDRV (hazard ratio [HR] 0.76; 95% confidence interval [CI] 0.60-0.96), DTG (HR 0.82; 95% CI 0.69-0.98), and EVG/c (HR 0.73; 95% CI 0.57-0.93). All groups had a similar pattern of CD4:CD8 ratio changes: a rapid increase in the first 6 months (ranging from +0.15 to +0.16 units), followed by a slower increase thereafter. Only 40 individuals (4%) achieved CD4:CD8 ratio normalization (≥1). B/F/TAF was associated with a faster time to virological suppression (viral load <200 copies/mL) and a slower time to discontinuation compared with other regimens. CONCLUSIONS: Among people with advanced HIV infection, B/F/TAF initiation was associated with faster CD4 cell count recovery and favourable virological outcomes compared with bDRV-, DTG-, and EVG/c-based regimens, although no difference was observed in CD4:CD8 ratio changes over time across regimens.
Assuntos
Fármacos Anti-HIV , Infecções por HIV , Adulto , Humanos , Infecções por HIV/tratamento farmacológico , Tenofovir/uso terapêutico , Combinação de Medicamentos , Darunavir/uso terapêutico , Compostos Heterocíclicos com 3 Anéis/uso terapêutico , Imunidade , Fármacos Anti-HIV/uso terapêutico , Emtricitabina/uso terapêuticoRESUMO
In untreated HIV-1 infection, rapid viral evolution allows escape from immune responses. Viral replication can be blocked by antiretroviral therapy. However, HIV-1 persists in a latent reservoir in resting CD4+ T cells, and rebound viremia occurs following treatment interruption. The reservoir, which is maintained in part by clonal expansion, can be measured using quantitative viral outgrowth assays (QVOAs) in which latency is reversed with T cell activation to allow viral outgrowth. Recent studies have shown that viruses detected in QVOAs prior to treatment interruption often differ from rebound viruses. We hypothesized that autologous neutralizing antibodies directed at the HIV-1 envelope (Env) protein might block outgrowth of some reservoir viruses. We modified the QVOA to reflect pressure from low concentrations of autologous antibodies and showed that outgrowth of a substantial but variable fraction of reservoir viruses is blocked by autologous contemporaneous immunoglobulin G (IgG). A reduction in outgrowth of >80% was seen in 6 of 15 individuals. This effect was due to direct neutralization. We established a phylogenetic relationship between rebound viruses and viruses growing out in vitro in the presence of autologous antibodies. Some large infected cell clones detected by QVOA carried neutralization-sensitive viruses, providing a cogent explanation for differences between rebound virus and viruses detected in standard QVOAs. Measurement of the frequency of reservoir viruses capable of outgrowth in the presence of autologous IgG might allow more accurate prediction of time to viral rebound. Ultimately, therapeutic immunization targeting the subset of variants resistant to autologous IgG might contribute to a functional cure.
Assuntos
Anticorpos Neutralizantes/imunologia , Anticorpos Anti-HIV/imunologia , Infecções por HIV/terapia , HIV-1/imunologia , Replicação Viral/imunologia , Adulto , Fármacos Anti-HIV/farmacologia , Fármacos Anti-HIV/uso terapêutico , Anticorpos Neutralizantes/sangue , Anticorpos Neutralizantes/isolamento & purificação , Anticorpos Neutralizantes/uso terapêutico , Transfusão de Sangue Autóloga/métodos , Linfócitos T CD4-Positivos/efeitos dos fármacos , Linfócitos T CD4-Positivos/imunologia , Linfócitos T CD4-Positivos/virologia , Células Cultivadas , Terapia Combinada/métodos , Feminino , Anticorpos Anti-HIV/sangue , Anticorpos Anti-HIV/isolamento & purificação , Anticorpos Anti-HIV/uso terapêutico , Infecções por HIV/sangue , Infecções por HIV/imunologia , Infecções por HIV/virologia , HIV-1/efeitos dos fármacos , Humanos , Imunoglobulina G/sangue , Imunoglobulina G/imunologia , Imunoglobulina G/isolamento & purificação , Imunoglobulina G/uso terapêutico , Leucaférese , Masculino , Pessoa de Meia-Idade , Cultura Primária de Células , Latência Viral/efeitos dos fármacos , Latência Viral/imunologia , Replicação Viral/efeitos dos fármacos , Produtos do Gene env do Vírus da Imunodeficiência Humana/imunologiaRESUMO
The potential of immunotherapy strategies utilizing broadly neutralizing antibodies (BNAbs), such as 3BNC117 and 10-1074, to limit viral replication while also facilitating clearance of HIV infected cells has heightened interest in identifying the predominant NK effector subset(s) capable of mediating antibody dependent cellular cytotoxicity (ADCC). Utilizing advanced polychromatic flow cytometry, we identified that CD57 positive NK cells from ART-suppressed in People Living With HIV (PLWH) expressed significantly higher levels of the CD16 FcγR receptor, 2B4 ADCC coreceptor, and HLA-DR activation marker while NKG2C positive NK cells expressed significantly higher levels of the CD2 ADCC coreceptor (p < 0.001, n = 32). Functionally, CD57 positive NK cells from ART-suppressed PLWH with either high or low NKG2C expansion exhibited significantly enhanced degranulation and IFN-γ production against heterologous gp120-coated ADCC targets coated with HIV reference plasma compared to CD57 negative NK cells (p = 0.0029, n = 11). CD57 positive NK cells from control donors lacking NKG2C expansion also exhibited significantly more degranulation and IFN-γ production at every timepoint tested against both heterologous ADCC targets (p = 0.019, n = 9) and HIV-1 infected autologous CD4+ primary T cells coated with BNAbs. Together, our data support CD57 positive and NKG2C positive NK cells as the predominant ADCC effector subsets capable of targeting HIV-infected CD4+ cells in the presence of 3BNC117 and 10-1074 immunotherapy.
Assuntos
Citotoxicidade Celular Dependente de Anticorpos/imunologia , Anticorpos Amplamente Neutralizantes/imunologia , Anticorpos Anti-HIV/imunologia , Infecções por HIV/imunologia , Células Matadoras Naturais/imunologia , Subpopulações de Linfócitos/imunologia , HumanosRESUMO
Five new minor sesterterpenoids, ansellones H (4), I (5), J (6), and K (7) and phorone C (8), have been isolated from a Phorbas sp. marine sponge collected in British Columbia. Their structures have been elucidated by detailed analysis of NMR and MS data. Ansellone J (6) and phorone C (8) are potent in vitro HIV-1 latency reversal agents that are more potent than the reference compound and control protein kinase C activator prostratin (3). The most potent Phorbas sesterterpenoid, ansellone J (6), was evaluated for HIV latency reversal in a primary cell context using CD4+ T cells obtained directly from four combination antiretroviral therapy-suppressed donors with HIV. To a first approximation, ansellone J (6) induced HIV latency reversal at levels similar to prostratin (3) ex vivo, but at a 10-fold lower concentration.
Assuntos
Infecções por HIV , HIV-1 , Poríferos , Animais , Colúmbia Britânica , Linfócitos T CD4-Positivos , Poríferos/química , Sesterterpenos/química , Latência ViralRESUMO
A sterilizing or functional cure for HIV is currently precluded by resting CD4+ T cells that harbor latent but replication-competent provirus. The "shock-and-kill" pharmacological ap-proach aims to reactivate provirus expression in the presence of antiretroviral therapy and target virus-expressing cells for elimination. However, no latency reversal agent (LRA) to date effectively clears viral reservoirs in humans, suggesting a need for new LRAs and LRA combinations. Here, we screened 216 compounds from the pan-African Natural Product Library and identified knipholone anthrone (KA) and its basic building block anthralin (dithranol) as novel LRAs that reverse viral latency at low micromolar concentrations in multiple cell lines. Neither agent's activity depends on protein kinase C; nor do they inhibit class I/II histone deacetylases. However, they are differentially modulated by oxidative stress and metal ions and induce distinct patterns of global gene expression from established LRAs. When applied in combination, both KA and anthralin synergize with LRAs representing multiple functional classes. Finally, KA induces both HIV RNA and protein in primary cells from HIV-infected donors. Taken together, we describe two novel LRAs that enhance the activities of multiple "shock-and-kill" agents, which in turn may inform ongoing LRA combination therapy efforts.
Assuntos
Antracenos/farmacologia , Antralina/farmacologia , Infecções por HIV/tratamento farmacológico , HIV-1/fisiologia , Latência Viral/efeitos dos fármacos , Avaliação Pré-Clínica de Medicamentos , Infecções por HIV/metabolismo , Infecções por HIV/patologia , Humanos , Células JurkatRESUMO
Accurate characterization of the human immunodeficiency virus (HIV) reservoir is imperative to develop an effective cure. HIV was measured in antiretroviral therapy-suppressed individuals using the intact proviral DNA assay (IPDA), along with assays for total or integrated HIV DNA, and inducible HIV RNA or p24. Intact provirus correlated with total and integrated HIV.
Assuntos
Infecções por HIV , HIV-1 , Linfócitos T CD4-Positivos , DNA Viral/genética , Infecções por HIV/tratamento farmacológico , HIV-1/genética , Humanos , Provírus/genética , Latência ViralRESUMO
BACKGROUND: Tenofovir alafenamide shows high antiviral efficacy and improved renal and bone safety compared with tenofovir disoproxil fumarate when used for HIV treatment. Here, we report primary results from a blinded phase 3 study evaluating the efficacy and safety of pre-exposure prophylaxis (PrEP) with emtricitabine and tenofovir alafenamide versus emtricitabine and tenofovir disoproxil fumarate for HIV prevention. METHODS: This study is an ongoing, randomised, double-blind, multicentre, active-controlled, phase 3, non-inferiority trial done at 94 community, public health, and hospital-associated clinics located in regions of Europe and North America, where there is a high incidence of HIV or prevalence of people living with HIV, or both. We enrolled adult cisgender men who have sex with men and transgender women who have sex with men, both with a high risk of acquiring HIV on the basis of their self-reported sexual behaviour in the past 12 weeks or their recent history (within 24 weeks of enrolment) of bacterial sexually transmitted infections. Participants with current or previous use of PrEP with emtricitabine and tenofovir disoproxil fumarate were not excluded. We used a computer-generated random allocation sequence to randomly assign (1:1) participants to receive either emtricitabine (200 mg) and tenofovir alafenamide (25 mg) tablets daily, with matched placebo tablets (emtricitabine and tenofovir alafenamide group), or emtricitabine (200 mg) and tenofovir disoproxil fumarate (300 mg) tablets daily, with matched placebo tablets (emtricitabine and tenofovir disoproxil fumarate group). As such, all participants were given two tablets. The trial sponsor, investigators, participants, and the study staff who provided the study drugs, assessed the outcomes, and collected the data were masked to group assignment. The primary efficacy outcome was incident HIV infection, which was assessed when all participants had completed 48 weeks of follow-up and half of all participants had completed 96 weeks of follow-up. This full analysis set included all randomly assigned participants who had received at least one dose of the assigned study drug and had at least one post-baseline HIV test. Non-inferiority of emtricitabine and tenofovir alafenamide to emtricitabine and tenofovir disoproxil fumarate was established if the upper bound of the 95·003% CI of the HIV incidence rate ratio (IRR) was less than the prespecified non-inferiority margin of 1·62. We prespecified six secondary bone mineral density and renal biomarker safety endpoints to evaluate using the safety analysis set. This analysis set included all randomly assigned participants who had received at least one dose of the assigned study drug. This trial is registered with ClinicalTrials.gov, NCT02842086, and is no longer recruiting. FINDINGS: Between Sept 13, 2016, and June 30, 2017, 5387 (92%) of 5857 participants were randomly assigned and received emtricitabine and tenofovir alafenamide (n=2694) or emtricitabine and tenofovir disoproxil fumarate (n=2693). At the time of the primary efficacy analysis (ie, when all participants had completed 48 weeks and 50% had completed 96 weeks) emtricitabine and tenofovir alafenamide was non-inferior to emtricitabine and tenofovir disoproxil fumarate for HIV prevention, as the upper limit of the 95% CI of the IRR, was less than the prespecified non-inferiority margin of 1·62 (IRR 0·47 [95% CI 0·19-1·15]). After 8756 person-years of follow-up, 22 participants were diagnosed with HIV, seven participants in the emtricitabine and tenofovir alafenamide group (0·16 infections per 100 person-years [95% CI 0·06-0·33]), and 15 participants in the emtricitabine and tenofovir disoproxil fumarate group (0·34 infections per 100 person-years [0·19-0·56]). Both regimens were well tolerated, with a low number of participants reporting adverse events that led to discontinuation of the study drug (36 [1%] of 2694 participants in the emtricitabine and tenofovir alafenamide group vs 49 [2%] of 2693 participants in the emtricitabine and tenofovir disoproxil fumarate group). Emtricitabine and tenofovir alafenamide was superior to emtricitabine and tenofovir disoproxil fumarate in all six prespecified bone mineral density and renal biomarker safety endpoints. INTERPRETATION: Daily emtricitabine and tenofovir alafenamide shows non-inferior efficacy to daily emtricitabine and tenofovir disoproxil fumarate for HIV prevention, and the number of adverse events for both regimens was low. Emtricitabine and tenofovir alafenamide had more favourable effects on bone mineral density and biomarkers of renal safety than emtricitabine and tenofovir disoproxil fumarate. FUNDING: Gilead Sciences.
Assuntos
Adenina/análogos & derivados , Fármacos Anti-HIV/uso terapêutico , Combinação Emtricitabina e Fumarato de Tenofovir Desoproxila/uso terapêutico , Emtricitabina/uso terapêutico , Infecções por HIV/tratamento farmacológico , Tenofovir/uso terapêutico , Adenina/efeitos adversos , Adenina/uso terapêutico , Adulto , Fármacos Anti-HIV/efeitos adversos , Método Duplo-Cego , Emtricitabina/efeitos adversos , Combinação Emtricitabina e Fumarato de Tenofovir Desoproxila/efeitos adversos , Europa (Continente)/epidemiologia , Feminino , Infecções por HIV/epidemiologia , Infecções por HIV/prevenção & controle , HIV-1/efeitos dos fármacos , Homossexualidade Masculina/etnologia , Humanos , Masculino , América do Norte/epidemiologia , Placebos/administração & dosagem , Profilaxia Pré-Exposição/métodos , Prevalência , Segurança , Minorias Sexuais e de Gênero , Tenofovir/efeitos adversos , Resultado do TratamentoRESUMO
We previously reported that pegylated IFN-α2a (Peg-IFN-α2a) added to antiretroviral therapy (ART)-suppressed, HIV-infected subjects resulted in plasma HIV control and integrated HIV DNA decrease. We now evaluated whether innate NK cell activity or PBMC transcriptional profiles were associated with decreases in HIV measures. Human peripheral blood was analyzed prior to Peg-IFN-α2a administration (ART, baseline), after 5 wk of ART+Peg-IFN-α2a, and after 12 wk of Peg-IFN-α2a monotherapy (primary endpoint). After 5 wk of ART+Peg-IFN-α2a, immune subset frequencies were preserved, and induction of IFN-stimulated genes was noted in all subjects except for a subset in which the lack of IFN-stimulated gene induction was associated with increased expression of microRNAs. Viral control during Peg-IFN-α2a monotherapy was associated with 1) higher levels of NK cell activity and IFN-γ-induced protein 10 (IP-10) on ART (preimmunotherapy) and 2) downmodulation of NK cell KIR2DL1 and KIR2DL2/DL3 expression, transcriptional enrichment of expression of genes associated with NK cells in HIV controller subjects, and higher ex vivo IFN-α-induced NK cytotoxicity after 5 wk of ART+Peg-IFN-α2a. Integrated HIV DNA decline after immunotherapy was also associated with gene expression patterns indicative of cell-mediated activation and NK cytotoxicity. Overall, an increase in innate activity and NK cell cytotoxicity were identified as correlates of Peg-IFN-α2a-mediated HIV control.
Assuntos
Terapia Antirretroviral de Alta Atividade/métodos , Infecções por HIV/tratamento farmacológico , HIV-1/efeitos dos fármacos , Interferon-alfa/uso terapêutico , Células Matadoras Naturais/imunologia , Polietilenoglicóis/uso terapêutico , Células Cultivadas , Quimiocina CXCL10/metabolismo , Infecções por HIV/imunologia , HIV-1/imunologia , Humanos , MicroRNAs/biossíntese , MicroRNAs/genética , Receptores KIR2DL1/biossíntese , Receptores KIR2DL2/biossíntese , Proteínas Recombinantes/uso terapêuticoRESUMO
BACKGROUND: HLA-B*57:01 screening was added to clinical care guidelines in 2008 to reduce the risk of hypersensitivity reaction from abacavir. The uptake of HLA-B*57:01 screening and incidence of hypersensitivity reaction were assessed in a prospective clinical cohort in the United States to evaluate the effectiveness of this intervention. METHODS: We included all patients initiating an abacavir-containing regimen for the first time in the pre-HLA-B*57:01 screening period (January 1, 1999 to June 14, 2008) or the post-HLA-B*57:01 screening period (June 15, 2008 to January 1, 2016). Yearly incidence of both HLA-B*57:01 screening and physician panel-adjudicated hypersensitivity reactions were calculated and compared. RESULTS: Of the 9619 patients eligible for the study, 33% initiated abacavir in the pre-screening period and 67% in the post-screening period. Incidence of HLA-B*57:01 screening prior to abacavir initiation increased from 43% in 2009 to 84% in 2015. The incidence of definite or probable hypersensitivity reactions decreased from 1.3% in the pre-screening period to 0.8% in 2009 and further to 0.2% in 2015 in the post-screening period. CONCLUSIONS: Frequency of HLA-B*57:01 screening increased steadily since its first inclusion in treatment guidelines in the United States. This increase in screening was accompanied by a decreasing incidence of definite or probable hypersensitivity reactions over the same period. However, a considerable proportion of patients initiating abacavir were not screened, representing a failed opportunity to prevent hypersensitivity reactions. Where HLA-B*57:01 screening is standard of care, patients should be confirmed negative for this allele before starting abacavir treatment.
Assuntos
Fármacos Anti-HIV/efeitos adversos , Didesoxinucleosídeos/efeitos adversos , Hipersensibilidade a Drogas/prevenção & controle , Infecções por HIV/epidemiologia , Antígenos HLA-B/genética , Adulto , Terapia Antirretroviral de Alta Atividade , Registros Eletrônicos de Saúde , Feminino , Infecções por HIV/tratamento farmacológico , Humanos , Masculino , Programas de Rastreamento , Pessoa de Meia-Idade , Guias de Prática Clínica como Assunto , Estudos ProspectivosRESUMO
HIV-infected smokers lose more years of life to tobacco-related disease than HIV. Since neurocognitive deficits are common among those with HIV and are associated with smoking persistence, these deficits may be a unique barrier to smoking cessation among HIV-infected smokers. Documenting unique differences in and correlates of cognition among HIV-infected smokers is a critical step towards developing a population-specific tobacco cessation treatment. We compared neurocognitive function between HIV-infected (n = 103) and HIV-uninfected smokers (n = 70), accounting for demographic and smoking-related variables. We also evaluated whether HIV-related health outcomes (e.g., CD4 count, viral load, depression ratings, quality of life [QoL]) and HAART adherence were associated with cognition. Participants completed neurocognitive tasks (N-back and Continuous Performance Task [CPT]) measuring working memory, attention, and processing speed, and intra-individual variability. Stepwise regression models were conducted and validated with resampling techniques. HIV-infected smokers performed worse than HIV-uninfected smokers on working memory, processing speed, and intra-individual variability (all p < 0.01). ROC analysis for the model including cognitive measures demonstrated 85% area under the curve, which indicates "good prediction" for distinguishing between HIV-infected and HIV-uninfected smokers. This was a significant improvement over the model including demographic and smoking-related variables only (p = 0.0003). Among HIV-infected smokers, neurocognitive performance was negatively associated with QoL and depression ratings. Smoking cessation interventions for HIV-infected smokers should consider cognitive neurorehabilitation as a potential strategy to decrease the likelihood of nicotine relapse and decrease tobacco-related morbidity in this population.
Assuntos
Disfunção Cognitiva/fisiopatologia , Infecções por HIV/fisiopatologia , Qualidade de Vida/psicologia , Fumar Tabaco/fisiopatologia , Adulto , Fármacos Anti-HIV/uso terapêutico , Terapia Antirretroviral de Alta Atividade , Atenção/fisiologia , Contagem de Linfócito CD4 , Disfunção Cognitiva/tratamento farmacológico , Disfunção Cognitiva/imunologia , Disfunção Cognitiva/virologia , Feminino , Infecções por HIV/tratamento farmacológico , Infecções por HIV/imunologia , Infecções por HIV/virologia , HIV-1/fisiologia , Humanos , Masculino , Memória de Curto Prazo/fisiologia , Pessoa de Meia-Idade , Testes Neuropsicológicos , Cooperação do Paciente/estatística & dados numéricos , Curva ROC , Abandono do Hábito de Fumar/estatística & dados numéricos , Carga ViralRESUMO
UNLABELLED: Although monocytes and macrophages are targets of HIV-1-mediated immunopathology, the impact of high viremia on activation-induced monocyte apoptosis relative to monocyte and macrophage activation changes remains undetermined. In this study, we determined constitutive and oxidative stress-induced monocyte apoptosis in uninfected and HIV(+) individuals across a spectrum of viral loads (n = 35; range, 2,243 to 1,355,998 HIV-1 RNA copies/ml) and CD4 counts (range, 26 to 801 cells/mm(3)). Both constitutive apoptosis and oxidative stress-induced apoptosis were positively associated with viral load and negatively associated with CD4, with an elevation in apoptosis occurring in patients with more than 40,000 (4.6 log) copies/ml. As expected, expression of Rb1 and interferon-stimulated genes (ISGs), plasma soluble CD163 (sCD163) concentration, and the proportion of CD14(++) CD16(+) intermediate monocytes were elevated in viremic patients compared to those in uninfected controls. Although CD14(++) CD16(+) frequencies, sCD14, sCD163, and most ISG expression were not directly associated with a change in apoptosis, sCD14 and ISG expression showed an association with increasing viral load. Multivariable analysis of clinical values and monocyte gene expression identified changes in IFI27, IFITM2, Rb1, and Bcl2 expression as determinants of constitutive apoptosis (P = 3.77 × 10(-5); adjusted R(2) = 0.5983), while changes in viral load, IFITM2, Rb1, and Bax expression were determinants of oxidative stress-induced apoptosis (P = 5.59 × 10(-5); adjusted R(2) = 0.5996). Our data demonstrate differential activation states in monocytes between levels of viremia in association with differences in apoptosis that may contribute to greater monocyte turnover with high viremia. IMPORTANCE: This study characterized differential monocyte activation, apoptosis, and apoptosis-related gene expression in low- versus high-level viremic HIV-1 patients, suggesting a shift in apoptosis regulation that may be associated with disease state. Using single and multivariable analysis of monocyte activation parameters and gene expression, we supported the hypothesis that monocyte apoptosis in HIV disease is a reflection of viremia and activation state with contributions from gene expression changes within the ISG and Bcl2 gene families. Understanding monocyte apoptosis response may inform HIV immunopathogenesis, retention of infected macrophages, and monocyte turnover in low- or high-viral-load states.
Assuntos
Apoptose , Infecções por HIV/imunologia , Infecções por HIV/virologia , HIV-1/imunologia , Monócitos/imunologia , Carga Viral , Adulto , Idoso de 80 Anos ou mais , Doença Crônica , Feminino , Perfilação da Expressão Gênica , Humanos , Masculino , Pessoa de Meia-Idade , Monócitos/fisiologia , Proteínas Proto-Oncogênicas c-bcl-2/biossíntese , Proteína do Retinoblastoma/biossíntese , Adulto JovemRESUMO
BACKGROUND: Coinfection with human immunodeficiency virus (HIV) and hepatitis C virus (HCV) is associated with reduced bone mineral density (BMD) and increased fracture rates, particularly in women. The structural underpinnings for skeletal fragility in coinfected women have not been characterized. We used tibial peripheral quantitative computed tomography to evaluate skeletal parameters in women, by HIV/HCV status. METHODS: We conducted a cross-sectional study among 50 HIV/HCV-coinfected, 51 HCV-monoinfected, and 50 HIV-monoinfected women. Tibial volumetric BMD and cortical dimensions were determined with peripheral quantitative computed tomography. Race-specific z scores for age were generated using 263 female reference participants without HIV infection or liver disease. RESULTS: Coinfected participants had lower mean z scores for trabecular volumetric BMD (-0.85), cortical volumetric BMD (-0.67), cortical area (-0.61), and cortical thickness (-0.77) than reference participants (all P < .001). The smaller cortical dimensions were due to greater mean z scores for endosteal circumference (+0.67; P < .001) and comparable z scores for periosteal circumference (+0.04; P = .87). Trabecular volumetric BMD was lower in coinfected than in HCV- or HIV-monoinfected participants. HCV-infected women with stage 3-4 liver fibrosis had lower mean z scores for trabecular volumetric BMD, cortical thickness, and total hip BMD those with stage 0-2 fibrosis. CONCLUSIONS: Compared with healthy reference patients, HIV/HCV-coinfected women had decreased tibial trabecular volumetric BMD, diminished cortical dimensions, and significant endocortical bone loss.
Assuntos
Coinfecção/complicações , Infecções por HIV/complicações , Hepatite C/complicações , Osteoporose/etiologia , Adulto , Densidade Óssea , Coinfecção/virologia , Estudos Transversais , Citocinas/genética , Citocinas/metabolismo , Feminino , Regulação da Expressão Gênica , Infecções por HIV/virologia , Hepatite C/virologia , Humanos , Cirrose Hepática/patologia , Cirrose Hepática/virologia , Pessoa de Meia-Idade , Vitamina D/metabolismoRESUMO
The identification of immune correlates of HIV control is important for the design of immunotherapies that could support cure or antiretroviral therapy (ART) intensification-related strategies. ART interruptions may facilitate this task through exposure of an ART partially reconstituted immune system to endogenous virus. We investigated the relationship between set-point plasma HIV viral load (VL) during an ART interruption and innate/adaptive parameters before or after interruption. Dendritic cell (DC), natural killer (NK) cell and HIV Gag p55-specific T-cell functional responses were measured in paired cryopreserved peripheral blood mononuclear cells obtained at the beginning (on ART) and at set-point of an open-ended interruption from 31 ART-suppressed chronically HIV-1(+) patients. Spearman correlation and linear regression modeling were used. Frequencies of plasmacytoid DC (pDC), and HIV Gag p55-specific CD3(+) CD4(-) perforin(+) IFN-γ(+) cells at the beginning of interruption associated negatively with set-point plasma VL. Inclusion of both variables with interaction into a model resulted in the best fit (adjusted R(2) = 0·6874). Frequencies of pDC or HIV Gag p55-specific CD3(+) CD4(-) CSFE(lo) CD107a(+) cells at set-point associated negatively with set-point plasma VL. The dual contribution of pDC and anti-HIV T-cell responses to viral control, supported by our models, suggests that these variables may serve as immune correlates of viral control and could be integrated in cure or ART-intensification strategies.
Assuntos
Células Dendríticas/imunologia , Infecções por HIV/imunologia , HIV-1/imunologia , Precursores de Proteínas/imunologia , Linfócitos T/imunologia , Carga Viral/imunologia , Adulto , Idoso , Fármacos Anti-HIV/uso terapêutico , Complexo CD3/imunologia , Linfócitos T CD8-Positivos/efeitos dos fármacos , Linfócitos T CD8-Positivos/imunologia , Linfócitos T CD8-Positivos/virologia , Células Cultivadas , Células Dendríticas/efeitos dos fármacos , Infecções por HIV/sangue , Infecções por HIV/tratamento farmacológico , HIV-1/efeitos dos fármacos , HIV-1/metabolismo , Interações Hospedeiro-Patógeno/efeitos dos fármacos , Interações Hospedeiro-Patógeno/imunologia , Humanos , Interferon gama/imunologia , Proteína 1 de Membrana Associada ao Lisossomo/imunologia , Pessoa de Meia-Idade , Perforina/imunologia , Estudos Retrospectivos , Linfócitos T/efeitos dos fármacos , Linfócitos T/virologia , Fatores de Tempo , Resultado do Tratamento , Carga Viral/efeitos dos fármacosRESUMO
Andersen's Behavioral Model (ABM) provides a framework for understanding how patient and environmental factors impact health behaviors and outcomes. We compared patient-identified barriers/facilitators to retention in care and antiretroviral therapy (ART) adherence and evaluated how they mapped to ABM. Qualitative semi-structured interviews with 51 HIV-infected adults at HIV clinics in Philadelphia, PA, in 2013 were used to explore patients' experiences with HIV care and treatment. Interview data were analyzed for themes using a grounded theory approach. Among those interviewed, 53% were male and 88% were nonwhite; 49% were retained in care, 96% were on ART, and 57% were virally suppressed. Patients discussed 18 barriers/facilitators to retention in care and ART adherence: 11 common to both behaviors (stigma, mental illness, substance abuse, social support, reminder strategies, housing, insurance, symptoms, competing life activities, colocation of services, provider factors), 3 distinct to retention (transportation, clinic experiences, appointment scheduling), and 4 distinct to adherence (medication characteristics, pharmacy services, health literacy, health beliefs). Identified barriers/facilitators mapped to all ABM domains. These data support the use of ABM as a framework for classifying factors influencing HIV-specific health behaviors and have the potential to inform the design of interventions to improve retention in care and ART adherence.
Assuntos
Fármacos Anti-HIV/uso terapêutico , Infecções por HIV/psicologia , Adesão à Medicação/psicologia , Aceitação pelo Paciente de Cuidados de Saúde/psicologia , Medicina Baseada em Evidências , Infecções por HIV/tratamento farmacológico , Infecções por HIV/epidemiologia , Comportamentos Relacionados com a Saúde , Conhecimentos, Atitudes e Prática em Saúde , Humanos , Adesão à Medicação/estatística & dados numéricos , Aceitação pelo Paciente de Cuidados de Saúde/estatística & dados numéricos , Philadelphia , Guias de Prática Clínica como Assunto , Pesquisa Qualitativa , Estigma Social , Apoio Social , Fatores SocioeconômicosRESUMO
BACKGROUND: Retention in HIV care improves survival and reduces the risk of HIV transmission to others. Multiple quantitative studies have described demographic and clinical characteristics associated with retention in HIV care. However, qualitative studies are needed to better understand barriers and facilitators. METHODS: Semi-structured interviews were conducted with 51 HIV-infected individuals, 25 who were retained in care and 26 not retained in care, from 3 urban clinics. Interview data were analyzed for themes using a modified grounded theory approach. Identified themes were compared between the two groups of interest: patients retained in care and those not retained in care. RESULTS: Overall, participants identified 12 barriers and 5 facilitators to retention in HIV care. On average, retained individuals provided 3 barriers, while persons not retained in care provided 5 barriers. Both groups commonly discussed depression/mental illness, feeling sick, and competing life activities as barriers. In addition, individuals not retained in care commonly reported expensive and unreliable transportation, stigma, and insufficient insurance as barriers. On average, participants in both groups referenced 2 facilitators, including the presence of social support, patient-friendly clinic services (transportation, co-location of services, scheduling/reminders), and positive relationships with providers and clinic staff. CONCLUSIONS: In our study, patients not retained in care faced more barriers, particularly social and structural barriers, than those retained in care. Developing care models where social and financial barriers are addressed, mental health and substance abuse treatment is integrated, and patient-friendly services are offered is important to keeping HIV-infected individuals engaged in care.
Assuntos
Infecções por HIV/terapia , Adulto , Idoso , Instituições de Assistência Ambulatorial , Atenção à Saúde , Feminino , Serviços de Saúde , Humanos , Masculino , Pessoa de Meia-Idade , Pesquisa Qualitativa , Apoio Social , Adulto JovemRESUMO
As patients with HIV age, they are at risk of developing non-AIDS defining malignancies. We performed a questionnaire study to evaluate colorectal and breast cancer screening among HIV-positive and HIV-negative patients seeking care from either an integrated (HIV/primary care), nonintegrated (specialized HIV), or general internal medicine clinic between August 2010 and July 2011. We performed a logistic regression to determine the odds of cancer screening. A total of 813 surveys were collected, and 762 were included in the analysis. As much as 401 were from HIV-positive patients. Patients with HIV were less likely to be current with their colorectal cancer screening (CRCS) (54.4% versus 65.0%, p=0.009); mammography rates were 24.3% versus 62.3% if done during the past year (p<0.001), and 42.0% versus 86.7% if done during the past 5 years (p<0.001). In adjusted models, the odds of colorectal cancer screening in HIV-positive patients compared to negative controls was not statistically significant (OR 0.8; 95% CI 0.5-1.3); however, HIV-positive women remained significantly less likely to be current with breast cancer screening (BCS) whether their mammogram was completed within 1 year (OR 0.1, 95% CI 0.1-0.2) or within 5 years (OR 0.1, 95% CI 0.0-0.2). Integrated care was not associated with improved screening; however, having frequent visits to a primary care physician (PCP) increased the likelihood of getting screened. BCS was lower in HIV-positive compared to HIV-negative women. Frequent visits to a PCPs improved cancer screening.