RESUMO
We identified a cluster of mpox exposures among key populations in Kenya through retrospective serologic screening. We identified strong seropositivity among sex workers and gay, bisexual, and other men who have sex with men. These findings demonstrate the need for increased mpox surveillance among mpox-endemic and mpox-endemic-adjacent regions in Africa.
Assuntos
Anticorpos Antivirais , Orthopoxvirus , Humanos , Quênia/epidemiologia , Estudos Soroepidemiológicos , Masculino , Anticorpos Antivirais/sangue , Estudos Retrospectivos , Adulto , Orthopoxvirus/imunologia , Feminino , Infecções por Poxviridae/epidemiologia , Infecções por Poxviridae/imunologia , Adulto Jovem , Pessoa de Meia-Idade , AdolescenteRESUMO
BACKGROUND: 1.5 million new HIV infections occurred in 2021, suggesting new prevention methods are needed. Inflammation increases the risk for HIV acquisition by attracting HIV target cells to the female genital tract (FGT). In a pilot study, acetylsalicylic acid (ASA/Aspirin) decreased the proportion of FGT HIV target cells by 35â¯%. However, the mechanism remains unknown. METHODS: Women from Nairobi, Kenya took low-dose ASA (81â¯mg) daily for 6-weeks. Free oxylipins in the plasma were quantified by high-performance liquid chromatography-tandem mass spectroscopy. RESULTS: Oxylipins from 9 fatty acid substrates were detected, with more than one analyte from 4 substrates reduced post-ASA. Summary analysis found ASA downregulated cyclooxygenase and lipoxygenase but not cytochrome P450 activity with a lower n-6/n-3 oxylipin profile, reflecting reduced inflammation post-ASA. CONCLUSIONS: Inflammation is associated with increased lipoxygenase activity and HIV risk. Our data suggests ASA reduces inflammation through downregulation of oxylipins. Understanding how ASA reduces inflammation may lead to novel HIV prevention approaches.
RESUMO
BACKGROUND: Serological surveys are used to ascertain influenza infection and immunity, but evidence for the utility of mucosal immunoglobulin A (IgA) as a correlate of infection or protection is limited. METHODS: We performed influenza-like illness (ILI) surveillance on 220 individuals living or working in a retirement community in Gainesville, Florida from January to May 2018, and took pre- and postseason nasal samples of 11 individuals with polymerase chain reaction (PCR)-confirmed influenza infection and 60 randomly selected controls. Mucosal IgA against 10 strains of influenza was measured from nasal samples. RESULTS: Overall, 28.2% and 11.3% of individuals experienced a 2-fold and 4-fold rise, respectively, in mucosal IgA to at least 1 influenza strain. Individuals with PCR-confirmed influenza A had significantly lower levels of preseason IgA to influenza A. Influenza-associated respiratory illness was associated with a higher rise in mucosal IgA to influenza strains of the same subtype, and H3N2-associated respiratory illness was associated with a higher rise in mucosal IgA to other influenza A strains. CONCLUSIONS: By comparing individuals with and without influenza illness, we demonstrated that mucosal IgA is a correlate of influenza infection. There was evidence for cross-reactivity in mucosal IgA across influenza A subtypes.
Assuntos
Vacinas contra Influenza , Influenza Humana , Humanos , Vírus da Influenza A Subtipo H3N2 , Estações do Ano , Assistência de Longa Duração , Imunidade nas Mucosas , Influenza Humana/prevenção & controle , Mucosa Nasal , Imunoglobulina A , Casas de Saúde , Anticorpos AntiviraisRESUMO
COVID-19 and influenza are both highly contagious respiratory diseases that have been serious threats to global public health. It is necessary to develop a bivalent vaccine to control these two infectious diseases simultaneously. In this study, we generated three attenuated replicating recombinant vesicular stomatitis virus (rVSV)-based vaccine candidates against both SARS-CoV-2 and influenza viruses. These rVSV-based vaccines coexpress SARS-CoV-2 Delta spike protein (SP) bearing the C-terminal 17 amino acid (aa) deletion (SPΔC) and I742A point mutation, or the SPΔC with a deletion of S2 domain, or the RBD domain, and a tandem repeat harboring four copies of the highly conserved influenza M2 ectodomain (M2e) that fused with the Ebola glycoprotein DC-targeting/activation domain. Animal immunization studies have shown that these rVSV bivalent vaccines induced efficient humoral and cellular immune responses against both SARS-CoV-2 SP and influenza M2 protein, including high levels of neutralizing antibodies against SARS-CoV-2 Delta and other variant SP-pseudovirus infections. Importantly, immunization of the rVSV bivalent vaccines effectively protected hamsters or mice against the challenges of SARS-CoV-2 Delta variant and lethal H1N1 and H3N2 influenza viruses and significantly reduced respiratory viral loads. Overall, this study provides convincing evidence for the high efficacy of this bivalent vaccine platform to be used and/or easily adapted to produce new vaccines against new or reemerging SARS-CoV-2 variants and influenza A virus infections. IMPORTANCE Given that both COVID-19 and influenza are preferably transmitted through respiratory droplets during the same seasons, it is highly advantageous to develop a bivalent vaccine that could simultaneously protect against both COVID-19 and influenza. In this study, we generated the attenuated replicating recombinant vesicular stomatitis virus (rVSV)-based vaccine candidates that target both spike protein of SARS-Cov-2 Delta variant and the conserved influenza M2 domain. Importantly, these vaccine candidates effectively protected hamsters or mice against the challenges of SARS-CoV-2 Delta variant and lethal H1N1 and H3N2 influenza viruses and significantly reduced respiratory viral loads.
Assuntos
COVID-19 , Vírus da Influenza A Subtipo H1N1 , Vacinas contra Influenza , Influenza Humana , Vacinas Combinadas , Estomatite Vesicular , Aminoácidos/genética , Animais , Anticorpos Neutralizantes , Anticorpos Antivirais , COVID-19/prevenção & controle , Cricetinae , Glicoproteínas/genética , Glicoproteínas/imunologia , Humanos , Vírus da Influenza A Subtipo H3N2 , Vacinas contra Influenza/genética , Vacinas contra Influenza/imunologia , Influenza Humana/prevenção & controle , Camundongos , SARS-CoV-2/genética , SARS-CoV-2/imunologia , Glicoproteína da Espícula de Coronavírus/genética , Glicoproteína da Espícula de Coronavírus/imunologia , Vacinas Combinadas/imunologia , Vacinas Sintéticas/genética , Vesiculovirus/imunologiaRESUMO
BACKGROUND: The hormonal contraceptive depot medroxyprogesterone acetate (DMPA) may be associated with an increased risk of acquiring human immunodeficiency virus (HIV). We hypothesize that DMPA use influences the ectocervical tissue architecture and HIV target cell localization. METHODS: Quantitative image analysis workflows were developed to assess ectocervical tissue samples collected from DMPA users and control subjects not using hormonal contraception. RESULTS: Compared to controls, the DMPA group exhibited a significantly thinner apical ectocervical epithelial layer and a higher proportion of CD4+CCR5+ cells with a more superficial location. This localization corresponded to an area with a nonintact E-cadherin net structure. CD4+Langerin+ cells were also more superficially located in the DMPA group, although fewer in number compared to the controls. Natural plasma progesterone levels did not correlate with any of these parameters, whereas estradiol levels were positively correlated with E-cadherin expression and a more basal location for HIV target cells of the control group. CONCLUSIONS: DMPA users have a less robust epithelial layer and a more apical distribution of HIV target cells in the human ectocervix, which could confer a higher risk of HIV infection. Our results highlight the importance of assessing intact genital tissue samples to gain insights into HIV susceptibility factors.
Assuntos
Anticoncepcionais Femininos , Infecções por HIV , Colo do Útero/metabolismo , Anticoncepcionais Femininos/efeitos adversos , Feminino , HIV , Humanos , Acetato de Medroxiprogesterona/efeitos adversosRESUMO
BACKGROUND: Mucosa-associated invariant T (MAIT) cells are innate-like T cells with specialized antimicrobial functions. Circulating MAIT cells are depleted in chronic human immunodeficiency virus (HIV) infection, but studies examining this effect in peripheral tissues, such as the female genital tract, are lacking. METHODS: Flow cytometry was used to investigate circulating MAIT cells in a cohort of HIV-seropositive (HIV+) and HIV-seronegative (HIV-) female sex workers (FSWs), and HIV- lower-risk women (LRW). In situ staining and quantitative polymerase chain reaction were performed to explore the phenotype of MAIT cells residing in paired cervicovaginal tissue. The cervicovaginal microbiome was assessed by means of 16S ribosomal RNA gene sequencing. RESULTS: MAIT cells in the HIV+ FSW group were low in frequency in the circulation but preserved in the ectocervix. MAIT cell T-cell receptor gene segment usage differed between the HIV+ and HIV- FSW groups. The TRAV1-2-TRAJ20 transcript was the most highly expressed MAIT TRAJ gene detected in the ectocervix in the HIV+ FSW group. MAIT TRAVJ usage was not associated with specific genera in the vaginal microbiome. CONCLUSIONS: MAIT cells residing in the ectocervix are numerically preserved irrespective of HIV infection status and displayed dominant expression of TRAV1-2-TRAJ20. These findings have implications for understanding the role of cervical MAIT cells in health and disease.
Assuntos
Infecções por HIV , Células T Invariantes Associadas à Mucosa , Profissionais do Sexo , Feminino , Infecções por HIV/metabolismo , Humanos , Células T Invariantes Associadas à Mucosa/metabolismo , Mucosa/metabolismo , Receptores de Antígenos de Linfócitos T alfa-beta/genética , Receptores de Antígenos de Linfócitos T alfa-beta/metabolismoRESUMO
BACKGROUND: Hormonal changes during the menstrual cycle play a key role in shaping immunity in the cervicovaginal tract. Cervicovaginal fluid contains cytokines, chemokines, immunoglobulins, and other immune mediators. Many studies have shown that the concentrations of these immune mediators change throughout the menstrual cycle, but the studies have often shown inconsistent results. Our understanding of immunological correlates of the menstrual cycle remains limited and could be improved by meta-analysis of the available evidence. METHODS: We performed a systematic review and meta-analysis of cervicovaginal immune mediator concentrations throughout the menstrual cycle using individual participant data. Study eligibility included strict definitions of the cycle phase (by progesterone or days since the last menstrual period) and no use of hormonal contraception or intrauterine devices. We performed random-effects meta-analyses using inverse-variance pooling to estimate concentration differences between the follicular and luteal phases. In addition, we performed a new laboratory study, measuring select immune mediators in cervicovaginal lavage samples. RESULTS: We screened 1570 abstracts and identified 71 eligible studies. We analyzed data from 31 studies, encompassing 39,589 concentration measurements of 77 immune mediators made on 2112 samples from 871 participants. Meta-analyses were performed on 53 immune mediators. Antibodies, CC-type chemokines, MMPs, IL-6, IL-16, IL-1RA, G-CSF, GNLY, and ICAM1 were lower in the luteal phase than the follicular phase. Only IL-1α, HBD-2, and HBD-3 were elevated in the luteal phase. There was minimal change between the phases for CXCL8, 9, and 10, interferons, TNF, SLPI, elafin, lysozyme, lactoferrin, and interleukins 1ß, 2, 10, 12, 13, and 17A. The GRADE strength of evidence was moderate to high for all immune mediators listed here. CONCLUSIONS: Despite the variability of cervicovaginal immune mediator measurements, our meta-analyses show clear and consistent changes during the menstrual cycle. Many immune mediators were lower in the luteal phase, including chemokines, antibodies, matrix metalloproteinases, and several interleukins. Only interleukin-1α and beta-defensins were higher in the luteal phase. These cyclical differences may have consequences for immunity, susceptibility to infection, and fertility. Our study emphasizes the need to control for the effect of the menstrual cycle on immune mediators in future studies.
Assuntos
Elafina , beta-Defensinas , Feminino , Fator Estimulador de Colônias de Granulócitos , Humanos , Imunoglobulinas , Fatores Imunológicos , Interferons , Proteína Antagonista do Receptor de Interleucina 1 , Interleucina-16 , Interleucina-1alfa , Interleucina-6 , Interleucinas , Lactoferrina , Ciclo Menstrual , Muramidase , ProgesteronaRESUMO
HIV causes several forms of immune dysfunction that need to be addressed in a functional cure for HIV. Immune exhaustion describes a dysfunctional phenotype caused by chronic cellular activation. Lymphocyte activation gene-3 (LAG3) is one of several negative coreceptors known as immune checkpoints that contribute to this exhaustion phenotype. Antibodies targeting immune checkpoints are now used clinically to restore immunity against cancer and hold promise in restoring immunity during HIV infection. Here, we summarize current knowledge surrounding LAG3 and discuss its relevance during HIV infection and the potential for LAG3-targeting antibodies in a functional HIV cure.
Assuntos
Antígenos CD/fisiologia , Infecções por HIV/imunologia , Anticorpos , Antígenos CD/genética , Antígenos CD/imunologia , Antígenos CD/metabolismo , Linfócitos T CD8-Positivos/imunologia , Humanos , Ativação Linfocitária , Receptor de Morte Celular Programada 1/imunologia , Transdução de Sinais , Proteína do Gene 3 de Ativação de LinfócitosRESUMO
BACKGROUND: Inflammation and immune activation are key factors in sexual transmission of human immunodeficiency virus (HIV). We sought to define the impact of hormonal cycling on the mucosal immune environment and HIV risk in sex workers with a natural menstrual cycle. METHODS: We compared soluble mucosal immune factors and cervical mononuclear cells during hormone titer-defined phases of the menstrual cycle among 37 sex workers from Nairobi, Kenya. Systemic and mucosal samples were collected 14 days apart to distinguish the follicular and luteal phases of the menstrual cycle, and phases were confirmed by hormone measurements. Vaginal concentrations of 19 immune modulators and cervical T-cell activation markers were measured. RESULTS: The follicular phase signature was characterized by an elevated CCL2 level, decreased interleukin 1α and interleukin 1ß cervical concentrations, and a significant increase in the proportion of CD4+ T cells that expressed CD69. The genital concentration of CCL2 was the best marker to distinguish the follicular from the luteal phase in univariate and multivariate analyses and remained independent of elevated genital inflammation and bacterial vaginosis. CONCLUSION: The follicular phase of the menstrual cycle was associated with an elevated CCL2 level and retention of resident memory CD4+ T cells, which has implications for increased susceptibility to HIV infection.
Assuntos
Colo do Útero/imunologia , Infecções por HIV/imunologia , Ciclo Menstrual/imunologia , Vagina/imunologia , Biomarcadores/análise , Linfócitos T CD4-Positivos/imunologia , Linfócitos T CD4-Positivos/metabolismo , Colo do Útero/citologia , Quimiocina CCL2/análise , Feminino , Infecções por HIV/transmissão , Humanos , Quênia , Profissionais do Sexo , Vagina/citologia , Vaginose Bacteriana/imunologiaRESUMO
Neutrophil migration is an essential step in leukocyte trafficking during inflammatory responses. Semaphorins, originally discovered as axon guidance cues in neural development, have been shown to regulate cell migration beyond the nervous system. However, the potential contribution of semaphorins in the regulation of neutrophil migration is not well understood. This study examines the possible role of a secreted chemorepellent, Semaphorin 3E (Sema3E), in neutrophil migration. In this study, we demonstrated that human neutrophils constitutively express Sema3E high-affinity receptor, PlexinD1. Sema3E displayed a potent ability to inhibit CXCL8/IL-8-induced neutrophil migration as determined using a microfluidic device coupled to real-time microscopy and a transwell system in vitro. The antimigratory effect of Sema3E on human neutrophil migration was associated with suppression of CXCL8/IL-8-mediated Ras-related C3 botulinum toxin substrate 1 GTPase activity and actin polymerization. We further addressed the regulatory role of Sema3E in the regulation of neutrophil migration in vivo. Allergen airway exposure induced higher neutrophil recruitment into the lungs of Sema3e-/- mice compared with wild-type controls. Administration of exogenous recombinant Sema3E markedly reduced allergen-induced neutrophil recruitment into the lungs, which was associated with alleviation of allergic airway inflammation and improvement of lung function. Our data suggest that Sema3E could be considered an essential regulatory mediator involved in modulation of neutrophil migration throughout the course of neutrophilic inflammation.
Assuntos
Neutrófilos/fisiologia , Semaforinas/fisiologia , Actinas/metabolismo , Moléculas de Adesão Celular Neuronais/análise , Movimento Celular , Quimiotaxia de Leucócito , Humanos , Interleucina-8/fisiologia , Peptídeos e Proteínas de Sinalização Intracelular , Dispositivos Lab-On-A-Chip , Glicoproteínas de Membrana , Proteínas rac1 de Ligação ao GTP/metabolismoRESUMO
For over three decades, HIV infection has had a tremendous impact on the lives of individuals and public health. Microbicides and vaccines studies have shown that immune activation at the genital tract is a risk factor for HIV infection. Furthermore, lower level of immune activation, or what we call immune quiescence, has been associated with a lower risk of HIV acquisition. This unique phenotype is observed in highly-exposed seronegative individuals from different populations including female sex workers from the Pumwani cohort in Nairobi, Kenya. Here, we review the link between immune activation and susceptibility to HIV infection. We also describe a new concept in prevention where, instead of targeting the virus, we modulate the host immune system to resist HIV infection. Mimicking the immune quiescence phenotype might become a new strategy in the toolbox of biomedical methods to prevent HIV infection. Clinical trial registration on clinicaltrial.gov: #NCT02079077.
Assuntos
Genitália Feminina/efeitos dos fármacos , Genitália Feminina/imunologia , Infecções por HIV/imunologia , Infecções por HIV/prevenção & controle , Imunidade nas Mucosas/efeitos dos fármacos , Aspirina/administração & dosagem , Aspirina/uso terapêutico , Suscetibilidade a Doenças , Feminino , Genitália Feminina/citologia , Infecções por HIV/epidemiologia , Infecções por HIV/virologia , Soronegatividade para HIV , HIV-1/imunologia , Humanos , Hidroxicloroquina/administração & dosagem , Hidroxicloroquina/uso terapêutico , Imunidade Inata , Quênia/epidemiologia , Ensaios Clínicos Controlados Aleatórios como Assunto , Fatores de Risco , Profissionais do SexoRESUMO
BACKGROUND: LAG-3 is a potent negative regulator of the immune response but its impact in HIV infection in poorly understood. Unlike exhaustion markers such as PD-1, Tim-3, 2B4 and CD160, LAG-3 is poorly expressed on bulk and antigen-specific T cells during chronic HIV infection and its expression on innate lymphocyte subsets is not well understood. The aim of this study was to assess LAG-3 expression and association with cellular dysfunction on T cells, NK cells and iNKT cells among a cohort of healthy and HIV-infected female sex workers in Nairobi, Kenya. RESULTS: Ex vivo LAG-3 expression was measured by multiparametric flow cytometry, and plasma cytokine/chemokine concentrations measured by bead array. Although LAG-3 expression on bulk T cells was significantly increased among HIV-infected women, the proportion of cells expressing the marker was extremely low. In contrast, LAG-3 was more highly expressed on NK and iNKT cells and was not reduced among women treated with ART. To assess the functional impact of LAG-3 on iNKT cells, iNKT cytokine production was measured in response to lipid (αGalCer) and PMA/Io stimulation by both flow cytometry and cytokine bead array. iNKT cytokine production is profoundly altered by both HIV infection and treatment, and LAG-3, but not PD-1, expression is associated with a reduction in iNKT IFNγ production. CONCLUSIONS: LAG-3 does not appear to mediate T cell exhaustion in this African population, but is instead expressed on innate lymphocyte subsets including iNKT cells. HIV infection alters iNKT cytokine production patterns and LAG-3 expression is uniquely associated with iNKT dysfunction. The continued expression of LAG-3 during treatment suggests it may contribute to the lack of innate immune reconstitution commonly observed during ART.
Assuntos
Antígenos CD/metabolismo , Citocinas/metabolismo , Infecções por HIV/imunologia , HIV-1/imunologia , Interações Hospedeiro-Patógeno , Células T Matadoras Naturais/imunologia , Receptor de Morte Celular Programada 1/metabolismo , Adulto , Estudos de Coortes , Feminino , Expressão Gênica , Voluntários Saudáveis , Humanos , Quênia , Pessoa de Meia-Idade , Profissionais do Sexo , Regulação para Cima , Proteína do Gene 3 de Ativação de LinfócitosRESUMO
BACKGROUND: Unprotected intercourse and seminal discharge are powerful activators of the mucosal immune system and are important risk factors for transmission of human immunodeficiency virus (HIV). This study was designed to determine if female sex work is associated with changes in the mucosal immunity. METHODS: Cervicovaginal lavage and plasma from 122 HIV-uninfected female sex workers (FSW) and 44 HIV-uninfected low-risk non-FSW from the same socioeconomic district of Nairobi were analyzed for evidence of immune activation (IA). The cervico-mononuclear cells (CMC) were analyzed for cellular activation by flow cytometry. RESULTS: Lower IA was observed in FSW compared to the low-risk women as demonstrated by the lower level of MIP-3α (P < .001), ITAC (P < .001), MIG (p.0001), IL-1α (P < .001), IL-1ß (P < .001), IL-1Rα (P = .0002), IL-6 (P < .001), IL-8 (P < .001), IL-10 (P = .01), IP-10 (P = .0001), MDC (P < .001), MIP-1α, (P < .001), MIP-1ß (P = .005), MCP-1 (P = .03), and TNF-α (P = .006). Significant differences were noted as early as 1 year following initiation of sex work and increased with duration of sex work. CONCLUSION: This study showed that sex work is associated with important changes in the mucosal immune system. By analyzing chemokine/cytokine levels and CMC activation, we observed a lower mucosal IA in HIV-uninfected FSW compared to low-risk women.
Assuntos
Citocinas/metabolismo , Imunidade nas Mucosas , Leucócitos Mononucleares/imunologia , Profissionais do Sexo , Adulto , Idoso , Feminino , Humanos , Ativação Linfocitária , Pessoa de Meia-Idade , Plasma/química , Plasma/imunologia , Vagina/química , Vagina/imunologia , Adulto JovemRESUMO
Natural killer T cells (NKT cells) represent a subset of T lymphocytes that express natural killer (NK) cell surface markers. A subset of NKT cells, termed invariant NKT cells (iNKT), express a highly restricted T cell receptor (TCR) and respond to CD1d-restricted lipid ligands. iNKT cells are now appreciated to play an important role in linking innate and adaptive immune responses and have been implicated in infectious disease, allergy, asthma, autoimmunity, and tumor surveillance. Advances in iNKT identification and purification have allowed for the detailed study of iNKT activity in both humans and mice during a variety of chronic and acute infections. Comparison of iNKT function between non-pathogenic simian immunodeficiency virus (SIV) infection models and chronic HIV-infected patients implies a role for iNKT activity in controlling immune activation. In vitro studies of influenza infection have revealed novel effector functions of iNKT cells including IL-22 production and modulation of myeloid-derived suppressor cells, but ex vivo characterization of human iNKT cells during influenza infection are lacking. Similarly, as recent evidence suggests iNKT involvement in dengue virus pathogenesis, iNKT cells may modulate responses to a number of emerging pathogens. This Review will summarize current knowledge of iNKT involvement in responses to viral infections in both human and mouse models and will identify critical gaps in knowledge and opportunities for future study. We will also highlight recent efforts to harness iNKT ligands as vaccine adjuvants capable of improving vaccination-induced cellular immune responses.
Assuntos
Imunidade Celular , Imunidade Inata , Células T Matadoras Naturais/imunologia , Viroses/imunologia , Doença Aguda , Animais , Antígenos CD1d/imunologia , Doença Crônica , Interleucinas/imunologia , Lipídeos/imunologia , Camundongos , Vacinação , Vacinas Virais/imunologia , Vacinas Virais/uso terapêutico , Viroses/prevenção & controle , Interleucina 22RESUMO
Currently, no effective vaccine to prevent human immunodeficiency virus (HIV) infection is available, and various platforms are being examined. The vesicular stomatitis virus (VSV) vaccine vehicle can induce robust humoral and cell-mediated immune responses, making it a suitable candidate for the development of an HIV vaccine. Here, we analyze the protective immunological impacts of recombinant VSV vaccine vectors that express chimeric HIV Envelope proteins (Env) in rhesus macaques. To improve the immunogenicity of these VSV-HIV Env vaccine candidates, we generated chimeric Envs containing the transmembrane and cytoplasmic tail of the simian immunodeficiency virus (SIV), which increases surface Env on the particle. Additionally, the Ebola virus glycoprotein was added to the VSV-HIV vaccine particles to divert tropism from CD4 T cells and enhance their replications both in vitro and in vivo. Animals were boosted with DNA constructs that encoded matching antigens. Vaccinated animals developed non-neutralizing antibody responses against both the HIV Env and the Ebola virus glycoprotein (EBOV GP) as well as systemic memory T-cell activation. However, these responses were not associated with observable protection against simian-HIV (SHIV) infection following repeated high-dose intra-rectal SHIV SF162p3 challenges.
RESUMO
Aberrant immune activation is a strong correlate of HIV disease progression, but little is known about how immune activation alters susceptibility to HIV infection. Susceptibility to HIV infection varies between individuals, but the immunological determinants of HIV transmission are not well understood. Here, we present evidence from studies of HIV transmission in the context of clinical trials and HIV-exposed seronegative (HESN) cohorts that implicates elevated immune activation as a risk factor for acquiring HIV. We propose a model of protection from infection based on a phenotype of low baseline immune activation referred to as immune quiescence. Immune quiescence is evidenced by reduced expression of T cell activation markers, low levels of generalized gene transcription and low levels of proinflammatory cytokine and chemokine production in the periphery and genital mucosa of HESN. Since HIV preferentially replicates in activated CD4+ T cells, immune quiescence may protect against infection by limiting HIV target cell availability. Although the determinants of immune quiescence are unclear, several potential factors have been identified that may be involved in driving this phenotype. HESN were shown to have elevated proportions of regulatory T cells (Tregs), which are known to suppress T cell activation. Likewise, proteins involved in controlling inflammation in the genital tract have been found to be elevated in HESN. Furthermore, expression of interferon regulatory factor 1 (IRF-1) is reduced in HESN as a consequence of genetic polymorphisms and differential epigenetic regulation. Since IRF-1 is an important regulator of immune responses, it may play a role in maintaining immune quiescence. Based on this model, we propose a novel avenue for HIV prevention targeted based on reducing host mucosal immune activation.
Assuntos
Resistência à Doença/imunologia , Infecções por HIV/imunologia , HIV-1/imunologia , Imunidade Inata , Infecções por HIV/prevenção & controle , Interações Hospedeiro-Patógeno , Humanos , Imunidade Ativa/fisiologia , Ativação Linfocitária/imunologia , Contagem de Linfócitos , Fatores de Risco , Linfócitos T Reguladores/fisiologia , Linfócitos T Reguladores/virologiaRESUMO
Invariant Natural Killer T (iNKT) cells undergo immune exhaustion during chronic activation caused by cancer and viral infections, such as HIV. Exhaustion is marked by cell dysfunction and increased expression of immune checkpoint proteins programmed cell-death-1 (PD-1) and lymphocyte-activation-gene-3 (LAG-3). We hypothesize that blockade of PD-1 and/or LAG-3 will enhance iNKT cell function. Utilizing peripheral blood mononuclear cells from healthy donors, LAG-3 and PD-1 expression on iNKT cells was assessed using flow cytometry following in vitro stimulation with iNKT-specific stimulant α-galactosylceramide (n = 4). Efficacy of anti-LAG-3 and/or anti-PD-1 antibody blockades in enhancing iNKT cell function was assessed by determining proliferative capacity and IFN-γ production (n = 9). LAG-3 and PD-1 expression on iNKT cells peaked at Day 4 (98.8%; p ≤ 0.0001 and 98.8%; p = 0.005, respectively), followed by steep decrease by Day 10, coinciding with peak iNKT cell proliferation. In a 10-day blocking assay, both the anti-PD-1 alone and dual anti-PD-1 and anti-LAG-3 significantly increased iNKT proliferation (6 and 6.29 log2 fold-change respectively) compared to the no blockade control (ANOVA-p = 0.0005) with the dual blockade system being more effective (t-test-p = 0.013). This provides proof-of-concept for LAG-3 and PD-1 as immunotherapeutic targets to enhance human iNKT cell function, with the long-term goal of addressing immune exhaustion.
Assuntos
Inibidores de Checkpoint Imunológico , Células T Matadoras Naturais , Humanos , Linfócitos T CD8-PositivosRESUMO
COVID-19 and influenza both cause enormous disease burdens, and vaccines are the primary measures for their control. Since these viral diseases are transmitted through the mucosal surface of the respiratory tract, developing an effective and convenient mucosal vaccine should be a high priority. We previously reported a recombinant vesicular stomatitis virus (rVSV)-based bivalent vaccine (v-EM2/SPΔC1Delta) that protects animals from both SARS-CoV-2 and influenza viruses via intramuscular and intranasal immunization. Here, we further investigated the immune response induced by oral immunization with this vaccine and its protective efficacy in mice. The results demonstrated that the oral delivery, like the intranasal route, elicited strong and protective systemic immune responses against SARS-CoV-2 and influenza A virus. This included high levels of neutralizing antibodies (NAbs) against SARS-CoV-2, as well as strong anti-SARS-CoV-2 spike protein (SP) antibody-dependent cellular cytotoxicity (ADCC) and anti-influenza M2 ADCC responses in mice sera. Furthermore, it provided efficient protection against challenge with influenza H1N1 virus in a mouse model, with a 100% survival rate and a significantly low lung viral load of influenza virus. All these findings provide substantial evidence for the effectiveness of oral immunization with the rVSV bivalent vaccine.
RESUMO
BACKGROUND: In the context of the current COVID-19 pandemic, there is still limited information about how people suffering from autoimmune diseases respond to the different COVID vaccines. The fact that they are taking an immunosuppressant or other drugs that aim to decrease the immune system activities, such as hydroxychloroquine (HCQ), could also impact their ability to respond to a COVID vaccine and vaccines in general. METHODS: Heathy donors were given 200mg of HCQ daily for 6-weeks to assess HCQs impact on the systemic T cells and humoral immune response. Peripheral blood mononuclear cells (PBMC) and plasma were obtained at baseline and 6-weeks after starting daily HCQ. Flow cytometry assays were designed to determine changes in T cell activation and T cell responses. Bead array multiplex were used to analyse antibodies and cytokine levels before and after HCQ intake. RESULTS: As anticipated, HCQ treatment decreased ex vivo T cell activation. We observed a decrease in CD4+CD161- expressing CCR5 (p = 0.015) and CD69 (p = 0.004) as well as in CD8+CCR5+ (p = 0.003), CD8+CD161+CCR5+ (p = 0.002) and CD8+CD161+CD95+ (p = 0.004). Additionally, HCQ decreased the proportion of Th17 expressing CD29 (p = 0.019), a subset associated with persistent inflammation. The proportion of T regulatory cells expressing the inhibitory molecule TIGIT was also reduced by HCQ (p = 0.003). As well, T cells from people on HCQ were less responsive to activation and cytokine production following stimulation with recall antigens and memory T cells were less likely to produce both IFNγ and TNFα following stimulation. CONCLUSION: This study shows HCQ is associated with lower T cell activation and decreased T cell cytokine production. While this study was not performed with the intent of looking at COVID vaccine response, it does provide important information about the changes in immune response that may occur in patient taking HCQ as a treatment for their autoimmune disease.
Assuntos
COVID-19 , Hidroxicloroquina , Humanos , Hidroxicloroquina/farmacologia , Hidroxicloroquina/uso terapêutico , Leucócitos Mononucleares , Membro 7 da Superfamília de Receptores de Fatores de Necrose Tumoral , Vacinas contra COVID-19 , Pandemias , Tratamento Farmacológico da COVID-19 , CitocinasRESUMO
BACKGROUND: The majority of studies characterizing female genital tract microbiota have focused on luminal organisms, while the presence and impact of tissue-adherent ectocervical microbiota remain incompletely understood. Studies of luminal and tissue-associated bacteria in the gastrointestinal tract suggest that these communities may have distinct roles in health and disease. Here, we performed a multi-omics characterization of paired luminal and tissue samples collected from a cohort of Kenyan female sex workers. RESULTS: We identified a tissue-adherent bacterial microbiome, with a higher alpha diversity than the luminal microbiome, in which dominant genera overall included Gardnerella and Lactobacillus, followed by Prevotella, Atopobium, and Sneathia. About half of the L. iners-dominated luminal samples had a corresponding Gardnerella-dominated tissue microbiome. Broadly, the tissue-adherent microbiome was associated with fewer differentially expressed host genes than the luminal microbiome. Gene set enrichment analysis revealed that L. crispatus-dominated tissue-adherent communities were associated with protein translation and antimicrobial activity, whereas a highly diverse microbial community was associated with epithelial remodeling and pro-inflammatory pathways. Tissue-adherent communities dominated by L. iners and Gardnerella were associated with lower host transcriptional activity. Tissue-adherent microbiomes dominated by Lactobacillus and Gardnerella correlated with host protein profiles associated with epithelial barrier stability, although with a more pro-inflammatory profile for the Gardnerella-dominated microbiome group. Tissue samples with a highly diverse composition had a protein profile representing cell proliferation and pro-inflammatory activity. CONCLUSION: We identified ectocervical tissue-adherent bacterial communities in all study participants of a female sex worker cohort. These communities were distinct from cervicovaginal luminal microbiota in a significant proportion of individuals. We further revealed that bacterial communities at both sites correlated with distinct host gene expression and protein levels. The tissue-adherent bacterial community could possibly act as a reservoir that seed the lumen with less optimal, non-Lactobacillus, bacteria. Video Abstract.