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Despite tremendous advances in HIV research, women and gender diverse people-particularly women from racial and ethnic groups under-represented in research, transgender women, and young women-remain disproportionately affected by HIV. Women and gender diverse people face unique challenges and have been under-represented in HIV research. The National Institutes of Health (NIH) is tasked to apply fundamental knowledge about the nature and behaviour of living systems to enhance health, lengthen life, and reduce disability. Rigorous exploration of-and interventions for-the individual, social, biological, structural, and environmental factors that influence HIV prevention, transmission, treatment, and cure is crucial to advance research for women, girls, and gender diverse people across the lifespan. In this Position Paper, we introduce a framework for an intersectional, equity-informed, data-driven approach to research on HIV and women and highlight selected issues for women and gender diverse people, including HIV prevention, HIV cure, ageing with HIV, substance use and misuse, violence, pregnancy, and breastfeeding or chestfeeding. This framework underlines a new HIV and Women Signature Programme from the NIH Office of AIDS Research and Office of Research on Women's Health that advances the NIH vision for women's health, in which all women receive evidence-based HIV prevention, treatment, and care across their lifespan tailored to their unique needs, circumstances, and goals. The time is now to centre the health of women, girls, and gender diverse people across the HIV research continuum.
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Síndrome da Imunodeficiência Adquirida , Infecções por HIV , Humanos , Feminino , Infecções por HIV/diagnóstico , Infecções por HIV/epidemiologia , Infecções por HIV/prevenção & controle , Saúde da Mulher , Identidade de Gênero , ViolênciaRESUMO
Introduction: Factors influencing vaccine immune priming in the first year of life involve both innate and adaptive immunity but there are gaps in understanding how these factors sustain vaccine antibody levels in healthy infants. The hypothesis was that bioprofiles associated with B cell survival best predict sustained vaccine IgG levels at one year. Methods: Longitudinal study of plasma bioprofiles in 82 term, healthy infants, who received standard recommended immunizations in the United States, with changes in 15 plasma biomarker concentrations and B cell subsets associated with germinal center development monitored at birth, soon after completion of the initial vaccine series at 6 months, and prior to the 12-month vaccinations. Post vaccination antibody IgG levels to Bordetella pertussis, tetanus toxoid, and conjugated Haemophilus influenzae type B (HiB) were outcome measures. Results: Using a least absolute shrinkage and selection operator (lasso) regression model, cord blood (CB) plasma IL-2, IL-17A, IL-31, and soluble CD14 (sCD14) were positively associated with pertussis IgG levels at 12 months, while CB plasma concentrations of APRIL and IL-33 were negatively associated. In contrast, CB concentrations of sCD14 and APRIL were positively associated with sustained tetanus IgG levels. A separate cross-sectional analysis of 18 mother/newborn pairs indicated that CB biomarkers were not due to transplacental transfer, but rather due to immune activation at the fetal/maternal interface. Elevated percentages of cord blood switched memory B cells were positively associated with 12-month HiB IgG levels. BAFF concentrations at 6 and 12 months were positively associated with pertussis and HiB IgG levels respectively. Discussion: Sustained B cell immunity is highly influenced by early life immune dynamics beginning prior to birth. The findings provide important insights into how germinal center development shapes vaccine responses in healthy infants and provide a foundation for studies of conditions that impair infant immune development.
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Coqueluche , Recém-Nascido , Humanos , Lactente , Estudos Longitudinais , Sangue Fetal , Estudos Transversais , Receptores de Lipopolissacarídeos , Toxoide Tetânico , Imunoglobulina GRESUMO
BACKGROUND: Marijuana's putative anti-inflammatory properties may benefit HIV-associated comorbidities. How recreational marijuana use affects gene expression in peripheral blood cells (PBC) among youth with HIV-1 (YWH) is unknown. APPROACH: YWH with defined substance use (n = 54) receiving similar antiretroviral therapy (ART) were assigned to one of four analysis groups: YWH with detectable plasma HIV-1 (> 50 RNA copies/ml) who did not use substances (H+V+S-), and YWH with undetectable plasma HIV-1 who did not use substances (H+V-S-), or used marijuana alone (H+V-S+[M]), or marijuana in combination with tobacco (H+V-S+[M/T]). Non-substance using youth without HIV infection (H-S-, n = 25) provided a reference group. PBC mRNA was profiled by Affymetrix GeneChip Human Genome U133 Plus 2.0 Array. Differentially expressed genes (DEG) within outcome groups were identified by Significance Analysis of Microarrays and used for Hierarchical Clustering, Principal Component Analysis, and Ingenuity Pathways Analysis. RESULTS: HIV-1 replication resulted in > 3000 DEG involving 27 perturbed pathways. Viral suppression reduced DEG to 313, normalized all 27 pathways, and down-regulated two additional pathways, while marijuana use among virally suppressed YWH resulted in 434 DEG and no perturbed pathways. Relative to H+V-S-, multiple DEG normalized in H+V-S+[M]. In contrast, H+V-S+[M/T] had 1140 DEG and 10 dysregulated pathways, including multiple proinflammatory genes and six pathways shared by H+V+S-. CONCLUSIONS: YWH receiving ART display unique transcriptome bioprofiles based on viral replication and substance use. In the context of HIV suppression, marijuana use, alone or combined with tobacco, has opposing effects on inflammatory gene expression.
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Cannabis , Infecções por HIV , HIV-1 , Transtornos Relacionados ao Uso de Substâncias , Produtos do Tabaco , Adolescente , Infecções por HIV/tratamento farmacológico , HIV-1/genética , HumanosRESUMO
ABSTRACT: In 2019, approximately 1.2 M persons were living with HIV and an estimated 34,800 new HIV infections occurred in the United States (U.S.). Significant disparities in HIV burden exist among persons of color, those with male-to-male sexual contact, young people, and persons experiencing barriers to consistent uptake of HIV interventions and services. These disparities are the root of major gaps in coverage of HIV testing, linkage to prevention and treatment, adherence, and retention in services in the United States. These gaps help fuel the American HIV epidemic. The Ending the HIV Epidemic in the U.S. Initiative (EHE) is built on 4 decades of federal domestic and international responses to HIV/AIDS. As the largest health research agency in the world, the National Institutes for Health (NIH) funds extensive basic, clinical, translational, and implementation HIV research that is crucial to achieving HIV epidemic control. Addressing the gaps and meeting EHE milestones will be accomplished in part through a combination of adaptation, implementation, and scale-up of existing HIV interventions. New discoveries will also be needed to create improved and novel diagnostics, monitor viral loads, and develop new prevention and treatment tools and approaches. HIV implementation research is essential to demonstrate the most effective strategies to facilitate the adaptation, adoption, and integration of evidence-based HIV interventions in real-world settings. This article outlines current NIH research plans to reduce and identify new HIV infections, improve treatment coverage and outcomes among persons with HIV, and effectively respond to HIV transmission outbreaks in the United States.
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Epidemias , Infecções por HIV , Adolescente , Epidemias/prevenção & controle , Infecções por HIV/tratamento farmacológico , Infecções por HIV/epidemiologia , Infecções por HIV/prevenção & controle , Teste de HIV , Humanos , Masculino , Comportamento Sexual , Estados Unidos/epidemiologia , Carga ViralRESUMO
Therapeutic pressure by protease inhibitors (PIs) contributes to accumulation of mutations in the HIV type 1 (HIV-1) protease (PR) leading to development of drug resistance with subsequent therapy failure. Current PIs target the active site of PR in a competitive manner. Identification of molecules that exploit non-active site mechanisms of inhibition is essential to overcome resistance to current PIs. Potential non-active site HIV-1 protease (PR) inhibitors (PI) were identified by in silico screening of almost 140,000 molecules targeting the hinge region of PR. Inhibitory activity of best docking compounds was tested in an in vitro PR inhibition biochemical assay. Five compounds inhibited PR from multiple HIV-1 sub-types in vitro and reduced replicative capacity by PI-sensitive or multi-PI resistant HIV-1 variants in human cells ex vivo. Antiviral activity was boosted when combined with Ritonavir, potentially diminishing development of drug resistance, while providing effective treatment for drug resistant HIV-1 variants.
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Mother-to-child transmission (MTCT) through breastfeeding remains a major source of pediatric HIV-1 infection worldwide. To characterize plasma HIV-1 subtype C populations from infected mothers during pregnancy that related to subsequent breast milk transmission, an exploratory study was designed to apply next generation sequencing and a custom bioinformatics pipeline for HIV-1 gp41 extending from heptad repeat region 2 (HR2) through the membrane proximal external region (MPER) and the membrane spanning domain (MSD). MPER harbors linear and highly conserved epitopes that repeatedly elicits HIV-1 neutralizing antibodies with exceptional breadth. Viral populations during pregnancy from women who transmitted by breastfeeding, compared to those who did not, displayed greater biodiversity, more frequent amino acid polymorphisms, lower hydropathy index and greater positive charge. Viral characteristics were restricted to MPER, failed to extend into flanking HR2 or MSD regions, and were unrelated to predicted neutralization resistance. Findings provide novel parameters to evaluate an association between maternal MPER variants present during gestation and lactogenesis with subsequent transmission outcomes by breastfeeding. IMPORTANCE: HIV-1 transmission through breastfeeding accounts for 39% of MTCT and continues as a major route of pediatric infection in developing countries where access to interventions for interrupting transmission is limited. Identifying women who are likely to transmit HIV-1 during breastfeeding would focus therapies, such as broad neutralizing HIV monoclonal antibodies (bn-HIV-Abs), during the breastfeeding period to reduce MTCT. Findings from our pilot study identify novel characteristics of gestational viral MPER quasispecies related to transmission outcomes and raise the possibility for predicting MTCT by breastfeeding based on identifying mothers with high-risk viral populations.
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PURPOSE: Adenosine deaminase (ADA) deficiency causes severe combined immunodeficiency (SCID) through an accumulation of toxic metabolites within lymphocytes. Recently, ADA deficiency has been successfully treated using lentiviral-transduced autologous CD34+ cells carrying the ADA gene. T and B cell function appears to be fully restored, but in many patients' B cell numbers remain low, and assessments of the immunoglobulin heavy (IgHV) repertoire following gene therapy are lacking. METHODS: We performed deep sequencing of IgHV repertoire in peripheral blood lymphocytes from a child following lentivirus-based gene therapy for ADA deficiency and compared to the IgHV repertoire in healthy infants and adults. RESULTS: After gene therapy, Ig diversity increased over time as evidenced by V, D, and J gene usage, N-additions, CDR3 length, extent of somatic hypermutation, and Ig class switching. There was the emergence of predominant IgHM, IgHG, and IgHA CDR3 lengths after gene therapy indicating successful oligoclonal expansion in response to antigens. This provides proof of concept for the feasibility and utility of molecular monitoring in following B cell reconstitution following gene therapy for ADA deficiency. CONCLUSION: Based on deep sequencing, gene therapy resulted in an IgHV repertoire with molecular diversity similar to healthy infants.
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Agamaglobulinemia/imunologia , Cadeias Pesadas de Imunoglobulinas/imunologia , Imunodeficiência Combinada Severa/imunologia , Adenosina Desaminase/deficiência , Adenosina Desaminase/uso terapêutico , Agamaglobulinemia/terapia , Terapia de Reposição de Enzimas , Feminino , Terapia Genética , Humanos , Lactente , Contagem de Linfócitos , Imunodeficiência Combinada Severa/terapiaRESUMO
In light of the increasing global burden of new HIV infections, growing financial requirements, and shifting funding landscape, the global health community must accelerate the development and delivery of an HIV cure to complement existing prevention modalities. An effective curative intervention could prevent new infections, overcome the limitations of antiretroviral treatment, combat stigma and discrimination, and provide a sustainable financial solution for pandemic control. We propose steps to plan for an HIV cure now, including defining a target product profile and establishing the HIV Cure Africa Acceleration Partnership (HCAAP), a multidisciplinary public-private partnership that will catalyse and promote HIV cure research through diverse stakeholder engagement. HCAAP will convene stakeholders, including people living with HIV, at an early stage to accelerate the design, social acceptability, and rapid adoption of HIV-cure products.
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Infecções por HIV/epidemiologia , HIV , Gerenciamento Clínico , Desenvolvimento de Medicamentos , Infecções por HIV/tratamento farmacológico , Infecções por HIV/prevenção & controle , Infecções por HIV/virologia , Pesquisas sobre Atenção à Saúde , Recursos em Saúde , Humanos , Parcerias Público-Privadas , Qualidade de Vida , Estigma Social , Fatores SocioeconômicosRESUMO
OBJECTIVE: HIV-associated neurocognitive disorders persist despite early antiretroviral therapy (ART) and optimal viral suppression. We examined the relationship between immunopathogenesis driven by various pathways of immune activation and discrete neurocognitive performance domains in youth with HIV (YWH). DESIGN: Observational cross-sectional study. METHODS: YWH, ages 20-28 years, enrolled in Adolescent Medicine Trials Network 071/101 were assessed for biomarkers of macrophage, lymphocyte activation, and vascular inflammation using ELISA/multiplex assays. Standardized neurocognitive tests were performed, and demographically adjusted z-scores were combined to form indices of attention, motor, executive function, verbal, and visuospatial memory. Cross-sectional analysis of the relationship between 18 plasma inflammatory biomarkers and each neurocognitive domain was performed. Linear regression models were fit for each combination of log-transformed biomarker value and neurocognitive domain score, and were adjusted for demographics, socioeconomic status, substance use, depression, CD4 T-cell count, HIV viral load, and ART status. RESULTS: Study included 128 YWH [mean age 23.8 (SD 1.7) years, 86% men, 68% African American]. Verbal and visuospatial memory domains were most significantly impaired in the cohort (zâ=â-1.59 and -1.0, respectively). Higher sCD14 was associated with impaired visuospatial memory, which remained robust after adjusting for other biomarkers, demographics, and HIV-associated covariates. Among biomarkers of vascular inflammation, sICAM-1 was negatively associated with verbal memory and attention, whereas sVCAM-1 was positively associated with executive function and visuospatial memory. Specific neurocognitive domains were not associated with sCD163, LPS, or CCL2 levels. CONCLUSION: Impaired visuospatial memory in YWH is associated with immune activation, as reflected by higher sCD14.
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Disfunção Cognitiva/etiologia , Infecções por HIV/complicações , Infecções por HIV/psicologia , Receptores de Lipopolissacarídeos/sangue , Memória de Curto Prazo , Adulto , Terapia Antirretroviral de Alta Atividade , Biomarcadores/sangue , Contagem de Linfócito CD4 , Disfunção Cognitiva/diagnóstico , Estudos Transversais , Feminino , Infecções por HIV/tratamento farmacológico , Humanos , Modelos Lineares , Ativação Linfocitária , Masculino , Testes de Estado Mental e Demência , Estudos Prospectivos , Porto Rico , Solubilidade , Percepção Espacial , Estados Unidos , Carga Viral , Percepção Visual , Adulto JovemRESUMO
OPPORTUNITY STATEMENT: Key topics discussed in this article were previously presented at the Center for AIDS Research Social and Behavioral Sciences Network's 12th National Scientific Meeting in August 2018. This article highlights the importance of behavioral and social sciences research (BSSR) in addressing the HIV/AIDS pandemic. APPROACH: NIH has made significant investments in HIV/AIDS-related BSSR. These investments support the development of effective, evidence-based sociobehavioral HIV prevention, treatment, and care strategies. DISCUSSION: The implementation and use of evidence-based sociobehavioral approaches in combination with biomedical strategies provide the availability of multiple tools to end the HIV epidemic in the United Sates and the pandemic globally. FUTURE DIRECTIONS: BSSR-related opportunities to mitigate the persistent challenges HIV/AIDS presents include, but are not limited to, further incorporating BSSR into HIV vaccine and cure research; improving interventions that address stigma and the social determinants of health that perpetuate HIV transmission within key populations; and conducting implementation science research that shapes national and international policies impacting HIV prevention, treatment, and care.
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Ciências do Comportamento , Infecções por HIV/prevenção & controle , National Institutes of Health (U.S.) , Ciências Sociais , Ciências do Comportamento/economia , Ciências do Comportamento/tendências , Medicina Baseada em Evidências , Humanos , Ciências Sociais/economia , Ciências Sociais/tendências , Estigma Social , Pesquisa Translacional Biomédica , Estados UnidosRESUMO
Both HIV infection and tenofovir disoproxil fumarate (TDF) treatment adversely impact bone metabolism and may lead to osteopenia, which has critical implications for youth with HIV (YWH). This study evaluates changes in the biomarkers of bone metabolism and inflammation among YWH receiving initial treatment with TDF- and non-TDF-containing antiretroviral therapies (ARTs). YWH [n = 23, median age 21 years (range 18-24), 87% male, 61% African American] were assessed for inflammatory and bone metabolism biomarkers at enrollment, after 48 weeks of TDF-containing ART, and 96 weeks of ART without TDF with continued viral suppression. Spearman's rank correlation evaluated biomarker associations. Bone alkaline phosphatase, parathyroid hormone, and osteopontin increased after TDF treatment. All fell after TDF was discontinued. Levels of RANKL and osteoprotegerin did not change throughout the study. There was little correlation between biomarkers of bone metabolism and either macrophage or lymphocyte activation at any time point. Our results establish baseline associations between bone metabolism and immune biomarkers for this population, and find that before CD4 T cell decline chronic inflammation does not perturb biomarkers of bone metabolism among YWH. The adverse effects of TDF on bone health may be marginal for YWH at the early stages of disease.
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Fármacos Anti-HIV/efeitos adversos , Densidade Óssea/efeitos dos fármacos , Doenças Ósseas Metabólicas/induzido quimicamente , Infecções por HIV/tratamento farmacológico , Tenofovir/efeitos adversos , Adolescente , Fosfatase Alcalina/análise , Fármacos Anti-HIV/uso terapêutico , Biomarcadores/análise , Osso e Ossos/metabolismo , Feminino , Humanos , Ativação Linfocitária/efeitos dos fármacos , Ativação de Macrófagos/efeitos dos fármacos , Macrófagos/imunologia , Masculino , Osteopontina/análise , Osteoprotegerina/análise , Hormônio Paratireóideo/análise , Ligante RANK/análise , Tenofovir/uso terapêutico , Adulto JovemRESUMO
The APEC Mental Health Roadmap has a vision to strengthen mental health and reduce the economic impact of mental illness in the Asia Pacific. To facilitate its implementation, the APEC Digital Hub will heighten exchange and dissemination of best practices in Asia Pacific mental health partnerships, and increase multi-sectoral recognition to invest in mental health to support economic growth.
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BACKGROUND: Human immunodeficiency virus (HIV) infection is associated with chronic immune activation, and concurrent sexually transmitted infections (STIs) may increase immune activation. OBJECTIVES: Because HIV-infected youth are at high risk of STIs and little is known about the impact of STIs on immune activation in HIV-infected youth, we conducted an exploratory study examining the association between STIs and systemic inflammation and immune activation among HIV-infected adolescents. STUDY DESIGN: Forty-nine behaviorally infected U.S. youth ages 18-24 years with baseline CD4+ T-cells >350 who maintained viral suppression on therapy by week 48 were included. Evaluation for STIs (herpes simplex virus [HSV], Chlamydia trachomatis, syphilis, Neisseria gonorrhoeae) was conducted as standard of care and reported on case report forms. Measures of T-cell subsets, systemic immune activation, and soluble factors were examined at week 48 for differences between participants with an STI diagnosis during the 48 weeks compared to those without an STI. RESULTS: Forty-three participants (88%) were male; 57% had baseline CD4+ T-cell counts >500 cells/mm3. Eighteen youth were reported to have ≥1 STI. At week 48, participants with STIs demonstrated lower CD4+ T-cell counts (any STI vs. no STI, pâ¯=â¯0.024; HSV vs. no STI, pâ¯=â¯0.022) and evidence of increased systemic immune activation, including higher CD57 intensity, higher HLA-DR intensity, and lower CD28 percentage, when compared to those without STIs. There were no differences in soluble factors between STI groups. CONCLUSIONS: Results indicate novel activation of CD4+ T-cells among HIV-infected youth who have STIs other than HSV, which may contribute to disease progression.
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Infecções por HIV/tratamento farmacológico , Infecções por HIV/imunologia , Ativação Linfocitária , Infecções Sexualmente Transmissíveis/imunologia , Adolescente , Terapia Antirretroviral de Alta Atividade , Contagem de Linfócito CD4 , Linfócitos T CD4-Positivos/imunologia , Feminino , Infecções por HIV/complicações , Humanos , Masculino , Infecções Sexualmente Transmissíveis/complicações , Infecções Sexualmente Transmissíveis/epidemiologia , Subpopulações de Linfócitos T/imunologia , Estados Unidos/epidemiologia , Adulto JovemRESUMO
OBJECTIVE: To define inflammatory pathways in youth living with HIV infection (YLWH), assessments of biomarkers associated with lymphocyte and macrophage activation, vascular injury, or bone metabolism were performed in YLWH in comparison with healthy controls (HC). DESIGN: Longitudinal multicenter study comparing biomarkers in YLWH suppressed on antiretroviral therapy (ART), those with ongoing viral replication, and HC were compared using single blood samples obtained at end of study. METHODS: Twenty-three plasma proteins were measured by ELISA or multiplex assays. Principal component analysis (PCA) was used to define contributions of individual biomarkers to define outcome groups. RESULTS: The study cohort included 129 predominantly African American, male participants, 21-25 years old at entry. Nine biomarkers of lymphocyte and macrophage activation and cardiovascular injury differed between HC and YLWH. Significant positive correlations were identified between lymphocyte and macrophage activation biomarkers among HC and YLWH. Correlations distinct to YLWH were predominantly between biomarkers of macrophage and vascular inflammation. PCA of outcome groups showed HC and suppressed YLWH clustering together for lymphocyte activation biomarkers, whereas macrophage activation markers showed all YLWH clustering distinct from HC. Cardiovascular biomarkers were indistinguishable across groups. Averaged variable importance projection to assess single biomarkers that maximally contribute to discriminate among outcome groups identified soluble CD27, CD14, and CD163 as the 3 most important with TNFα and LPS also highly relevant in providing separation. CONCLUSIONS: Soluble inflammatory and lymphocyte biomarkers sufficiently distinguish YLWH from HC. Persistent macrophage activation biomarkers may provide a means to monitor consequences of HIV infection in fully suppressed YLWH.
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Antígenos CD/sangue , Antígenos de Diferenciação Mielomonocítica/sangue , Terapia Antirretroviral de Alta Atividade , Biomarcadores/sangue , Infecções por HIV/sangue , Infecções por HIV/imunologia , Receptores de Lipopolissacarídeos/sangue , Receptores de Superfície Celular/sangue , Membro 7 da Superfamília de Receptores de Fatores de Necrose Tumoral/sangue , Adulto , Estudos de Casos e Controles , Feminino , HIV/imunologia , Infecções por HIV/complicações , Infecções por HIV/tratamento farmacológico , Humanos , Estudos Longitudinais , Ativação Linfocitária/imunologia , Ativação de Macrófagos/imunologia , Masculino , Carga Viral , Adulto JovemRESUMO
Repeated measures are common in clinical trials and epidemiological studies. Designing studies with repeated measures requires reasonably accurate specifications of the variances and correlations to select an appropriate sample size. Underspecifying the variances leads to a sample size that is inadequate to detect a meaningful scientific difference, while overspecifying the variances results in an unnecessarily large sample size. Both lead to wasting resources and placing study participants in unwarranted risk. An internal pilot design allows sample size recalculation based on estimates of the nuisance parameters in the covariance matrix. We provide the theoretical results that account for the stochastic nature of the final sample size in a common class of linear mixed models. The results are useful for designing studies with repeated measures and balanced design. Simulations examine the impact of misspecification of the covariance matrix and demonstrate the accuracy of the approximations in controlling the type I error rate and achieving the target power. The proposed methods are applied to a longitudinal study assessing early antiretroviral therapy for youth living with HIV.
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Modelos Lineares , Tamanho da Amostra , Ensaios Clínicos como Assunto , Simulação por Computador , Humanos , Estudos Longitudinais , Análise Multivariada , Projetos Piloto , Projetos de Pesquisa , Processos EstocásticosRESUMO
Macrophages play important roles in HIV-1 pathogenesis as targets for viral replication and mediators of chronic inflammation. Similar to IFNγ-priming, HIV-1 primes macrophages, resulting in hyperresponsiveness to subsequent toll-like receptor (TLR) stimulation and increased inflammatory cytokine production. However, the specific molecular mechanism of HIV-1 priming and whether cells must be productively infected or if uninfected bystander cells also are primed by HIV-1 remains unclear. To explore these questions, human macrophages were primed by IFNγ or infected with HIV-1 before activation by TLR ligands. Transcriptome profiling by microarray revealed a gene expression profile for IFNγ-primed cells that was further modulated by the addition of lipopolysaccharide (LPS). HIV-1 infection elicited a gene expression profile that correlated strongly with the profile induced by IFNγ (r = .679, p = .003). Similar to IFNγ, HIV-1 enhanced TLR ligand-induced tumor necrosis factor (TNF) protein expression and release. Increased TNF production was limited to productively infected cells. Specific signal transducer and activator of transcription (STAT)1 and STAT3 inhibitors suppressed HIV-1-mediated enhancement of TLR-induced TNF expression as well as HIV-1 replication. These findings indicate that viral replication and inflammation are linked through a common IFNγ-like, STAT-dependent pathway and that HIV-1-induced STAT1 and STAT3 signaling are involved in both inflammation and HIV-1 replication. Systemic innate immune activation is a hallmark of active HIV-1 replication. Our study shows that inflammation may develop as a consequence of HIV-1 triggering STAT-IFN pathways to support viral replication.
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Infecções por HIV/patologia , HIV-1/fisiologia , Interferon gama/metabolismo , Macrófagos/imunologia , Fator de Transcrição STAT1/metabolismo , Fator de Transcrição STAT3/metabolismo , Replicação Viral , Células Cultivadas , Perfilação da Expressão Gênica , Infecções por HIV/virologia , Humanos , Inflamação/patologia , Análise em Microsséries , Transdução de SinaisRESUMO
Multiple-type human papillomaviruses (HPV) infection presents a greater risk for persistence in asymptomatic individuals and may accelerate cancer development. To extend the scope of HPV types defined by probe-based assays, multiplexing deep sequencing of HPV L1, coupled with an HPV-QUEST genotyping server and a bioinformatic pipeline, was established and applied to survey the diversity of HPV genotypes among a subset of healthy men from the HPV in Men (HIM) Multinational Study. Twenty-one HPV genotypes (12 high-risk and 9 low-risk) were detected in the genital area from 18 asymptomatic individuals. A single HPV type, either HPV16, HPV6b or HPV83, was detected in 7 individuals, while coinfection by 2 to 5 high-risk and/or low-risk genotypes was identified in the other 11 participants. In two individuals studied for over one year, HPV16 persisted, while fluctuations of coinfecting genotypes occurred. HPV L1 regions were generally identical between query and reference sequences, although nonsynonymous and synonymous nucleotide polymorphisms of HPV16, 18, 31, 35h, 59, 70, 73, cand85, 6b, 62, 81, 83, cand89 or JEB2 L1 genotypes, mostly unidentified by linear array, were evident. Deep sequencing coupled with HPV-QUEST provides efficient and unambiguous classification of HPV genotypes in multiple-type HPV infection in host ecosystems.