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1.
Cell ; 186(22): 4851-4867.e20, 2023 10 26.
Artigo em Inglês | MEDLINE | ID: mdl-37848036

RESUMO

Post-acute sequelae of COVID-19 (PASC, "Long COVID") pose a significant global health challenge. The pathophysiology is unknown, and no effective treatments have been found to date. Several hypotheses have been formulated to explain the etiology of PASC, including viral persistence, chronic inflammation, hypercoagulability, and autonomic dysfunction. Here, we propose a mechanism that links all four hypotheses in a single pathway and provides actionable insights for therapeutic interventions. We find that PASC are associated with serotonin reduction. Viral infection and type I interferon-driven inflammation reduce serotonin through three mechanisms: diminished intestinal absorption of the serotonin precursor tryptophan; platelet hyperactivation and thrombocytopenia, which impacts serotonin storage; and enhanced MAO-mediated serotonin turnover. Peripheral serotonin reduction, in turn, impedes the activity of the vagus nerve and thereby impairs hippocampal responses and memory. These findings provide a possible explanation for neurocognitive symptoms associated with viral persistence in Long COVID, which may extend to other post-viral syndromes.


Assuntos
Síndrome de COVID-19 Pós-Aguda , Serotonina , Humanos , COVID-19/complicações , Progressão da Doença , Inflamação , Síndrome de COVID-19 Pós-Aguda/sangue , Síndrome de COVID-19 Pós-Aguda/patologia , Serotonina/sangue , Viroses
2.
J Infect Dis ; 230(4): 912-918, 2024 Oct 16.
Artigo em Inglês | MEDLINE | ID: mdl-39011957

RESUMO

Host metabolic dysregulation, especially in tryptophan metabolism, is intricately linked to coronavirus disease 2019 (COVID-19) severity and its postacute sequelae (long COVID). People living with human immunodeficiency virus (HIV; PLWH) experience similar metabolic dysregulation and face an increased risk of developing long COVID. However, whether preexisting HIV-associated metabolic dysregulations contribute in predisposing PLWH to severe COVID-19 outcomes remains underexplored. Analyzing prepandemic samples from PLWH with documented postinfection outcomes, we found specific metabolic alterations, including increased tryptophan catabolism, predicting an elevated risk of severe COVID-19 and the incidence of long COVID. These alterations warrant further investigation for their potential prognostic and mechanistic significance in determining COVID-19 complications.


Assuntos
COVID-19 , Infecções por HIV , SARS-CoV-2 , Índice de Gravidade de Doença , Humanos , COVID-19/metabolismo , COVID-19/complicações , COVID-19/epidemiologia , Infecções por HIV/complicações , Masculino , Incidência , Feminino , Pessoa de Meia-Idade , Triptofano/metabolismo , Adulto , Síndrome de COVID-19 Pós-Aguda
3.
Proteomics ; 23(19): e2300023, 2023 10.
Artigo em Inglês | MEDLINE | ID: mdl-37525324

RESUMO

The epidemy of metabolic syndrome (MetS) is typically preceded by adoption of a "risky" lifestyle (e.g., dietary habit) among populations. Evidence shows that those with low socioeconomic status (SES) are at an increased risk for MetS. To investigate this, we recruited 123 obese subjects (body mass index [BMI] ≥ 30) from Chicago. Multi-omic data were collected to interrogate fecal microbiota, systemic markers of inflammation and immune activation, plasma metabolites, and plasma glycans. Intestinal permeability was measured using the sugar permeability testing. Our results suggest a heterogenous metabolic dysregulation among obese populations who are at risk of MetS. Systemic inflammation, linked to poor diet, intestinal microbiome dysbiosis, and gut barrier dysfunction may explain the development of MetS in these individuals. Our analysis revealed 37 key features associated with increased numbers of MetS features. These features were used to construct a composite metabolic-inflammatory (MI) score that was able to predict progression of MetS among at-risk individuals. The MI score was correlated with several markers of poor diet quality as well as lower levels of gut microbial diversity and abnormalities in several species of bacteria. This study reveals novel targets to reduce the burden of MetS and suggests access to healthy food options as a practical intervention.


Assuntos
Síndrome Metabólica , Microbiota , Humanos , Síndrome Metabólica/metabolismo , Síndrome Metabólica/microbiologia , Multiômica , Disparidades Socioeconômicas em Saúde , Dieta , Obesidade/metabolismo , Inflamação , Disbiose/complicações , Disbiose/microbiologia
4.
Curr HIV/AIDS Rep ; 19(3): 217-233, 2022 06.
Artigo em Inglês | MEDLINE | ID: mdl-35438384

RESUMO

PURPOSE OF REVIEW: HIV rebound/remission after antiretroviral therapy (ART) interruption is likely influenced by (a) the size of the inducible replication-competent HIV reservoir and (b) factors in the host environment that influence immunological pressures on this reservoir. Identifying viral and/or host biomarkers of HIV rebound after ART cessation may improve the safety of treatment interruptions and our understanding of how the viral-host interplay results in post-treatment control. Here we review the predictive and functional significance of recently suggested viral and host biomarkers of time to viral rebound and post-treatment control following ART interruption. RECENT FINDINGS: There are currently no validated viral or host biomarkers of viral rebound; however, several biomarkers have been recently suggested. A combination of viral and host factors will likely be needed to predict viral rebound and to better understand the mechanisms contributing to post-treatment control of HIV, critical steps to developing a cure for HIV infection.


Assuntos
Antirretrovirais , Infecções por HIV , Antirretrovirais/uso terapêutico , Biomarcadores , Infecções por HIV/tratamento farmacológico , Humanos , Carga Viral
5.
AIDS Res Ther ; 19(1): 2, 2022 01 12.
Artigo em Inglês | MEDLINE | ID: mdl-35022035

RESUMO

BACKGROUND: We developed a personalized Monocyte-Derived Dendritic-cell Therapy (MDDCT) for HIV-infected individuals on suppressive antiretroviral treatment and evaluated HIV-specific T-cell responses. METHODS: PBMCs were obtained from 10 HIV+ individuals enrolled in trial NCT02961829. Monocytes were differentiated into DCs using IFN-α and GM-CSF. After sequencing each patient's HIV-1 Gag and determining HLA profiles, autologous Gag peptides were selected based on the predicted individual immunogenicity and used to pulse MDDCs. Three doses of the MDDCT were administered every 15 days. To assess immunogenicity, patients' cells were stimulated in vitro with autologous peptides, and intracellular IL-2, TNF, and interferon-gamma (IFN-γ) production were measured in CD4+ and CD8+ T-cells. RESULTS: The protocol of ex-vivo treatment with IFN-α and GM-CSF was able to induce maturation of MDDCs, as well as to preserve their viability for reinfusion. MDDCT administration was associated with increased expression of IL-2 in CD4+ and CD8+ T-cells at 15 and/or 30 days after the first MDDCT administration. Moreover, intracellular TNF and IFN-γ expression was significantly increased in CD4+ T-cells. The number of candidates that increased in vitro the cytokine levels in CD4+ and CD8+ T cells upon stimulation with Gag peptides from baseline to day 15 and from baseline to day 30 and day 120 after MDDCT was significant as compared to Gag unstimulated response. This was accompanied by an increasing trend in the frequency of polyfunctional T-cells over time, which was visible when considering both cells expressing two and three out of the three cytokines examined. CONCLUSIONS: MDDC had a mature profile, and this MDDCT promoted in-vitro T-cell immune responses in HIV-infected patients undergoing long-term suppressive antiretroviral treatment. Trial registration NCT02961829: (Multi Interventional Study Exploring HIV-1 Residual Replication: a Step Towards HIV-1 Eradication and Sterilizing Cure, https://www.clinicaltrials.gov/ct2/show/NCT02961829 , posted November 11th, 2016).


Assuntos
Infecções por HIV , HIV-1 , Linfócitos T CD4-Positivos , Linfócitos T CD8-Positivos , Terapia Baseada em Transplante de Células e Tecidos , Células Dendríticas , Infecções por HIV/tratamento farmacológico , Humanos
6.
J Biol Chem ; 295(41): 14084-14099, 2020 10 09.
Artigo em Inglês | MEDLINE | ID: mdl-32788215

RESUMO

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 Jurkat
7.
Curr HIV/AIDS Rep ; 16(2): 151-168, 2019 04.
Artigo em Inglês | MEDLINE | ID: mdl-30707400

RESUMO

PURPOSE OF REVIEW: Glycoimmunology is an emerging field focused on understanding how immune responses are mediated by glycans (carbohydrates) and their interaction with glycan-binding proteins called lectins. How glycans influence immunological functions is increasingly well understood. In a parallel way, in the HIV field, it is increasingly understood how the host immune system controls HIV persistence and immunopathogenesis. However, what has mostly been overlooked, despite its potential for therapeutic applications, is the role that the host glycosylation machinery plays in modulating the persistence and immunopathogenesis of HIV. Here, we will survey four areas in which the links between glycan-lectin interactions and immunology and between immunology and HIV are well described. For each area, we will describe these links and then delineate the opportunities for the HIV field in investigating potential interactions between glycoimmunology and HIV persistence/immunopathogenesis. RECENT FINDINGS: Recent studies show that the human glycome (the repertoire of human glycan structures) plays critical roles in driving or modulating several cellular processes and immunological functions that are central to maintaining HIV infection. Understanding the links between glycoimmunology and HIV infection may create a new paradigm for discovering novel glycan-based therapies that can lead to eradication, functional cure, or improved tolerance of lifelong infection.


Assuntos
Infecções por HIV/imunologia , HIV-1/imunologia , Polissacarídeos/imunologia , Latência Viral/imunologia , Glicosilação , Infecções por HIV/virologia , Humanos , Tolerância Imunológica/imunologia , Lectinas/imunologia
8.
Int J Mol Sci ; 20(20)2019 Oct 21.
Artigo em Inglês | MEDLINE | ID: mdl-31640124

RESUMO

Zika virus (ZIKV) is a global public health issue due to its association with severe developmental disorders in infants and neurological disorders in adults. ZIKV uses glycosylation of its envelope (E) protein to interact with host cell receptors to facilitate entry; these interactions could also be important for designing therapeutics and vaccines. Due to a lack of proper information about Asn-linked (N-glycans) on ZIKV E, we analyzed ZIKV E of various strains derived from different cells. We found ZIKV E proteins being extensively modified with oligomannose, hybrid and complex N-glycans of a highly heterogeneous nature. Host cell surface glycans correlated strongly with the glycomic features of ZIKV E. Mechanistically, we observed that ZIKV N-glycans might play a role in viral pathogenesis, as mannose-specific C-type lectins DC-SIGN and L-SIGN mediate host cell entry of ZIKV. Our findings represent the first detailed mapping of N-glycans on ZIKV E of various strains and their functional significance.


Assuntos
Proteínas do Envelope Viral/química , Infecção por Zika virus/virologia , Zika virus/fisiologia , Zika virus/patogenicidade , Animais , Chlorocebus aethiops , Glicosilação , Interações entre Hospedeiro e Microrganismos , Humanos , Oligossacarídeos/metabolismo , Polissacarídeos/metabolismo , Células THP-1 , Células Vero , Internalização do Vírus , Zika virus/metabolismo
9.
Curr Opin HIV AIDS ; 2024 Sep 26.
Artigo em Inglês | MEDLINE | ID: mdl-39392413

RESUMO

PURPOSE OF REVIEW: We focus on the different classes of biological molecules measurable in easily accessible bodily fluids that have the potential to serve as biomarkers for the HIV post-treatment controller (PTC) phenotype and/or the timing of viral rebound after stopping antiretroviral therapy (ART). RECENT FINDINGS: Various viral components and host factors measurable in body fluids can play crucial roles in understanding and predicting the PTC phenotype. We review recent findings linking viral components, the quantitative and qualitative features of antibodies (including autologous HIV-specific antibodies), markers of inflammation and tissue damage, other host proteins (including hormones such as sex hormones), as well as metabolites, extracellular vesicles, and cell-free DNA to HIV control post-ART interruption. Several of these molecules can or have the potential to predict the time and probability of viral rebound after stopping ART and are biologically active molecules that can directly or indirectly (by modulating immune pressures) impact the size and activity of HIV reservoirs during and post-ART interruption. SUMMARY: A comprehensive model combining multiple markers is needed to predict the PTC phenotype. This model can be leveraged to predict and understand the PTC phenotype, which can guide novel curative interventions to replicate this phenotype in post-treatment non-controllers.

10.
JCI Insight ; 9(3)2024 Feb 08.
Artigo em Inglês | MEDLINE | ID: mdl-38329130

RESUMO

BACKGROUNDIdentifying factors that predict the timing of HIV rebound after treatment interruption will be crucial for designing and evaluating interventions for HIV remission.METHODSWe performed a broad evaluation of viral and immune factors that predict viral rebound (AIDS Clinical Trials Group A5345). Participants initiated antiretroviral therapy (ART) during chronic (N = 33) or early (N = 12) HIV infection with ≥ 2 years of suppressive ART and restarted ART if they had 2 viral loads ≥ 1,000 copies/mL after treatment interruption.RESULTSCompared with chronic-treated participants, early-treated individuals had smaller and fewer transcriptionally active HIV reservoirs. A higher percentage of HIV Gag-specific CD8+ T cell cytotoxic response was associated with lower intact proviral DNA. Predictors of HIV rebound timing differed between early- versus chronic-treated participants, as the strongest reservoir predictor of time to HIV rebound was level of residual viremia in early-treated participants and intact DNA level in chronic-treated individuals. We also identified distinct sets of pre-treatment interruption viral, immune, and inflammatory markers that differentiated participants who had rapid versus slow rebound.CONCLUSIONThe results provide an in-depth overview of the complex interplay of viral, immunologic, and inflammatory predictors of viral rebound and demonstrate that the timing of ART initiation modifies the features of rapid and slow viral rebound.TRIAL REGISTRATIONClinicalTrials.gov NCT03001128FUNDINGNIH National Institute of Allergy and Infectious Diseases, Merck.


Assuntos
Infecções por HIV , Humanos , Provírus/genética , Linfócitos T CD8-Positivos , Carga Viral , DNA
11.
Microbiome ; 12(1): 31, 2024 Feb 22.
Artigo em Inglês | MEDLINE | ID: mdl-38383483

RESUMO

BACKGROUND: People living with HIV (PLWH), even when viral replication is controlled through antiretroviral therapy (ART), experience persistent inflammation. This inflammation is partly attributed to intestinal microbial dysbiosis and translocation, which may lead to non-AIDS-related aging-associated comorbidities. The extent to which living with HIV - influenced by the infection itself, ART usage, sexual orientation, or other associated factors - affects the biological age of the intestines is unclear. Furthermore, the role of microbial dysbiosis and translocation in the biological aging of PLWH remains to be elucidated. To investigate these uncertainties, we used a systems biology approach, analyzing colon and ileal biopsies, blood samples, and stool specimens from PLWH on ART and people living without HIV (PLWoH) as controls. RESULTS: PLWH exhibit accelerated biological aging in the colon, ileum, and blood, as measured by various epigenetic aging clocks, compared to PLWoH. Investigating the relationship between microbial translocation and biological aging, PLWH had decreased levels of tight junction proteins in the intestines, along with increased microbial translocation. This intestinal permeability correlated with faster biological aging and increased inflammation. When investigating the relationship between microbial dysbiosis and biological aging, the intestines of PLWH had higher abundance of specific pro-inflammatory bacteria, such as Catenibacterium and Prevotella. These bacteria correlated with accelerated biological aging. Conversely, the intestines of PLWH had lower abundance of bacteria known for producing the anti-inflammatory short-chain fatty acids, such as Subdoligranulum and Erysipelotrichaceae, and these bacteria were associated with slower biological aging. Correlation networks revealed significant links between specific microbial genera in the colon and ileum (but not in feces), increased aging, a rise in pro-inflammatory microbe-related metabolites (e.g., those in the tryptophan metabolism pathway), and a decrease in anti-inflammatory metabolites like hippuric acid. CONCLUSIONS: We identified specific microbial compositions and microbiota-related metabolic pathways that are intertwined with intestinal and systemic biological aging. This microbial signature of biological aging is likely reflecting various factors including the HIV infection itself, ART usage, sexual orientation, and other aspects associated with living with HIV. A deeper understanding of the mechanisms underlying these connections could offer potential strategies to mitigate accelerated aging and its associated health complications. Video Abstract.


Assuntos
Microbioma Gastrointestinal , Infecções por HIV , Humanos , Feminino , Masculino , Infecções por HIV/tratamento farmacológico , Disbiose/microbiologia , Microbioma Gastrointestinal/genética , Intestinos/microbiologia , Envelhecimento , Bactérias/genética , Inflamação/microbiologia , Anti-Inflamatórios
12.
Nat Commun ; 15(1): 3035, 2024 Apr 10.
Artigo em Inglês | MEDLINE | ID: mdl-38600088

RESUMO

People living with HIV (PLWH) experience increased vulnerability to premature aging and inflammation-associated comorbidities, even when HIV replication is suppressed by antiretroviral therapy (ART). However, the factors associated with this vulnerability remain uncertain. In the general population, alterations in the N-glycans on IgGs trigger inflammation and precede the onset of aging-associated diseases. Here, we investigate the IgG N-glycans in cross-sectional and longitudinal samples from 1214 women and men, living with and without HIV. PLWH exhibit an accelerated accumulation of pro-aging-associated glycan alterations and heightened expression of senescence-associated glycan-degrading enzymes compared to controls. These alterations correlate with elevated markers of inflammation and the severity of comorbidities, potentially preceding the development of such comorbidities. Mechanistically, HIV-specific antibodies glycoengineered with these alterations exhibit a reduced ability to elicit anti-HIV Fc-mediated immune activities. These findings hold potential for the development of biomarkers and tools to identify and prevent premature aging and comorbidities in PLWH.


Assuntos
Senilidade Prematura , Infecções por HIV , Masculino , Humanos , Feminino , Imunoglobulina G , Estudos Transversais , Envelhecimento , Inflamação/complicações , Polissacarídeos
13.
AIDS ; 37(4): 571-577, 2023 03 15.
Artigo em Inglês | MEDLINE | ID: mdl-36460646

RESUMO

OBJECTIVE: The human endogenous protein galectin-9 (Gal-9) reactivates latently HIV-infected cells in vitro and ex vivo , which may allow for immune-mediated clearance of these cells. However, Gal-9 also activates several immune cells, which could negatively affect HIV persistence by promoting chronic activation/exhaustion. This potential 'double-edged sword' effect of Gal-9 raises the question of the overall impact of Gal-9 on HIV persistence in vivo . DESIGN: We used the BLT (bone marrow, liver, thymus) humanized mouse model to evaluate the impact of Gal-9 on HIV persistence in vivo during antiretroviral therapy (ART). METHODS: Two independent cohorts of ART-suppressed HIV-infected BLT mice were treated with either recombinant Gal-9 or phosphate-buffered saline control. Plasma viral loads and levels of tissue-associated HIV DNA and RNA were measured by qPCR. Immunohistochemistry and HIV RNAscope were used to quantify CD4 + T, myeloid, and HIV RNA+ cells in tissues. T cell activation and exhaustion were measured by flow cytometry, and plasma markers of inflammation were measured by multiplex cytokine arrays. RESULTS: Gal-9 did not induce plasma markers of inflammation or T cell markers of activation/exhaustion in vivo . However, the treatment significantly increased levels of tissue-associated HIV DNA and RNA compared to controls ( P  = 0.0007 and P  = 0.011, respectively, for cohort I and P  = 0.002 and P  = 0.005, respectively, for cohort II). RNAscope validated the Gal-9 mediated induction of HIV RNA in tissue-associated myeloid cells, but not T cells. CONCLUSIONS: Our study highlights the overall adverse effects of Gal-9 on HIV persistence and the potential need to block Gal-9 interactions during ART-suppressed HIV infection.


Assuntos
Infecções por HIV , HIV-1 , Humanos , Camundongos , Animais , HIV-1/genética , RNA , Galectinas , Inflamação , Linfócitos T CD4-Positivos
14.
mBio ; 14(1): e0339322, 2023 02 28.
Artigo em Inglês | MEDLINE | ID: mdl-36728420

RESUMO

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection alters the immunological profiles of natural killer (NK) cells. However, whether NK antiviral functions are impaired during severe coronavirus disease 2019 (COVID-19) and what host factors modulate these functions remain unclear. We found that NK cells from hospitalized COVID-19 patients degranulate less against SARS-CoV-2 antigen-expressing cells (in direct cytolytic and antibody-dependent cell cytotoxicity [ADCC] assays) than NK cells from mild COVID-19 patients or negative controls. The lower NK degranulation was associated with higher plasma levels of SARS-CoV-2 nucleocapsid antigen. Phenotypic and functional analyses showed that NK cells expressing the glyco-immune checkpoint Siglec-9 elicited higher ADCC than Siglec-9- NK cells. Consistently, Siglec-9+ NK cells exhibit an activated and mature phenotype with higher expression of CD16 (FcγRIII; mediator of ADCC), CD57 (maturation marker), and NKG2C (activating receptor), along with lower expression of the inhibitory receptor NKG2A, than Siglec-9- CD56dim NK cells. These data are consistent with the concept that the NK cell subpopulation expressing Siglec-9 is highly activated and cytotoxic. However, the Siglec-9 molecule itself is an inhibitory receptor that restrains NK cytotoxicity during cancer and other viral infections. Indeed, blocking Siglec-9 significantly enhanced the ADCC-mediated NK degranulation and lysis of SARS-CoV-2-antigen-positive target cells. These data support a model in which the Siglec-9+ CD56dim NK subpopulation is cytotoxic even while it is restrained by the inhibitory effects of Siglec-9. Alleviating the Siglec-9-mediated restriction on NK cytotoxicity may further improve NK immune surveillance and presents an opportunity to develop novel immunotherapeutic tools against SARS-CoV-2 infected cells. IMPORTANCE One mechanism that cancer cells use to evade natural killer cell immune surveillance is by expressing high levels of sialoglycans, which bind to Siglec-9, a glyco-immune checkpoint molecule on NK cells. This binding inhibits NK cell cytotoxicity. Several viruses, such as hepatitis B virus (HBV) and HIV, also use a similar mechanism to evade NK surveillance. We found that NK cells from SARS-CoV-2-hospitalized patients are less able to function against cells expressing SARS-CoV-2 Spike protein than NK cells from SARS-CoV-2 mild patients or uninfected controls. We also found that the cytotoxicity of the Siglec-9+ NK subpopulation is indeed restrained by the inhibitory nature of the Siglec-9 molecule and that blocking Siglec-9 can enhance the ability of NK cells to target cells expressing SARS-CoV-2 antigens. Our results suggest that a targetable glyco-immune checkpoint mechanism, Siglec-9/sialoglycan interaction, may contribute to the ability of SARS-CoV-2 to evade NK immune surveillance.


Assuntos
COVID-19 , SARS-CoV-2 , Humanos , Anticorpos/metabolismo , Citotoxicidade Celular Dependente de Anticorpos , COVID-19/metabolismo , Células Matadoras Naturais , Lectinas Semelhantes a Imunoglobulina de Ligação ao Ácido Siálico/metabolismo
15.
Res Sq ; 2023 Oct 30.
Artigo em Inglês | MEDLINE | ID: mdl-37961645

RESUMO

Background: People with HIV (PWH), even with controlled viral replication through antiretroviral therapy (ART), experience persistent inflammation. This is partly due to intestinal microbial dysbiosis and translocation. Such ongoing inflammation may lead to the development of non-AIDS-related aging-associated comorbidities. However, there remains uncertainty regarding whether HIV affects the biological age of the intestines and whether microbial dysbiosis and translocation influence the biological aging process in PWH on ART. To fill this knowledge gap, we utilized a systems biology approach, analyzing colon and ileal biopsies, blood samples, and stool specimens from PWH on ART and their matched HIV-negative counterparts. Results: Despite having similar chronological ages, PWH on ART exhibit accelerated biological aging in the colon, ileum, and blood, as measured by various epigenetic aging clocks, compared to HIV-negative controls. Investigating the relationship between microbial translocation and biological aging, PWH on ART had decreased levels of tight junction proteins in the colon and ileum, along with increased microbial translocation. This increased intestinal permeability correlated with faster intestinal and systemic biological aging, as well as increased systemic inflammation. When investigating the relationship between microbial dysbiosis and biological aging, the intestines of PWH on ART had higher abundance of specific pro-inflammatory bacterial genera, such as Catenibacterium and Prevotella. These bacteria significantly correlated with accelerated local and systemic biological aging. Conversely, the intestines of PWH on ART had lower abundance of bacterial genera known for producing short-chain fatty acids and exhibiting anti-inflammatory properties, such as Subdoligranulum and Erysipelotrichaceae, and these bacteria taxa were associated with slower biological aging. Correlation networks revealed significant links between specific microbial genera in the colon and ileum (but not in feces), increased aging, a rise in pro-inflammatory microbial-related metabolites (e.g., those in the tryptophan metabolism pathway), and a decrease in anti-inflammatory metabolites like hippuric acid and oleic acid. Conclusions: We identified a specific microbial composition and microbiome-related metabolic pathways that are intertwined with both intestinal and systemic biological aging in PWH on ART. A deeper understanding of the mechanisms underlying these connections could potentially offer strategies to counteract premature aging and its associated health complications in PWH.

16.
bioRxiv ; 2023 Dec 31.
Artigo em Inglês | MEDLINE | ID: mdl-37609144

RESUMO

People with HIV (PWH) experience an increased vulnerability to premature aging and inflammation-associated comorbidities, even when HIV replication is suppressed by antiretroviral therapy (ART). However, the factors that contribute to or are associated with this vulnerability remain uncertain. In the general population, alterations in the glycomes of circulating IgGs trigger inflammation and precede the onset of aging-associated diseases. Here, we investigate the IgG glycomes of cross-sectional and longitudinal samples from 1,216 women and men, both living with virally suppressed HIV and those without HIV. Our glycan-based machine learning models indicate that living with chronic HIV significantly accelerates the accumulation of pro-aging-associated glycomic alterations. Consistently, PWH exhibit heightened expression of senescence-associated glycan-degrading enzymes compared to their controls. These glycomic alterations correlate with elevated markers of inflammatory aging and the severity of comorbidities, potentially preceding the development of such comorbidities. Mechanistically, HIV-specific antibodies glycoengineered with these alterations exhibit reduced anti-HIV IgG-mediated innate immune functions. These findings hold significant potential for the development of glycomic-based biomarkers and tools to identify and prevent premature aging and comorbidities in people living with chronic viral infections.

17.
J Clin Microbiol ; 50(1): 145-7, 2012 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-22012021

RESUMO

Ninety-six samples from hepatitis B virus (HBV)-infected individuals were used to compare ViveST samples to frozen samples in COBAS TaqMan, RealArt, and VERSANT. Correlation (r) between ViveST samples and frozen samples was 0.99 in all three platforms. Correlations among tests using frozen samples were 0.96 for COBAS and RealArt, 0.94 for COBAS and VERSANT, and 0.97 for VERSANT and RealArt. The results indicate that ViveST may be useful in clinical practice. Different HBV-VL platforms correlated well with one another.


Assuntos
Dessecação/métodos , Vírus da Hepatite B/isolamento & purificação , Hepatite B/diagnóstico , Hepatite B/virologia , Plasma/virologia , Manejo de Espécimes/métodos , Carga Viral/métodos , Congelamento , Vírus da Hepatite B/genética , Humanos
18.
Methods Mol Biol ; 2442: 463-474, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35320541

RESUMO

The ß-galactoside-binding protein Galectin-9 (Gal-9) functions as a double-edged sword during HIV infection. On the one hand, Gal-9 can reactivate HIV latently infected cells, the main barrier to achieving HIV eradication, making them visible to immune clearance. On the other hand, Gal-9 induces latent HIV transcription by activating T cell Receptor (TCR) signaling pathways. These signaling pathways induce undesirable pro-inflammatory responses. While these unwanted responses can be mitigated by rapamycin without impacting Gal-9-mediated latent HIV reactivation, this effect raises the concern that Gal-9 may play a role in the chronic immune activation/inflammation that persists in people living with HIV despite antiretroviral therapy. Together, these data highlight the need to understand the positive and negative impacts of galectin interactions on immunological functions during HIV infection. In this chapter, we describe methods that can be used to investigate the effects of galectins, in particular Gal-9, on latent HIV transcription in vitro and ex vivo.


Assuntos
Galectinas , Infecções por HIV , HIV-1 , Latência Viral , Galectinas/genética , Galectinas/fisiologia , Infecções por HIV/virologia , HIV-1/genética , HIV-1/fisiologia , Humanos , Transdução de Sinais , Transcrição Gênica , Latência Viral/genética
19.
J Leukoc Biol ; 112(4): 733-744, 2022 10.
Artigo em Inglês | MEDLINE | ID: mdl-35916053

RESUMO

Opioid use has negative effects on immune responses and may impair immune reconstitution in persons living with HIV (PLWH) infection undergoing antiretroviral treatment (ART). The effects of treatment with µ opioid receptor (MOR) agonists (e.g., methadone, MET) and antagonists (e.g., naltrexone, NTX) on immune reconstitution and immune activation in ART-suppressed PLWH have not been assessed in-depth. We studied the effects of methadone or naltrexone on measures of immune reconstitution and immune activation in a cross-sectional community cohort of 30 HIV-infected individuals receiving suppressive ART and medications for opioid use disorder (MOUD) (12 MET, 8 NTX and 10 controls). Plasma markers of inflammation and immune activation were measured using ELISA, Luminex, or Simoa. Plasma IgG glycosylation was assessed using capillary electrophoresis. Cell subsets and activation were studied using whole blood flow cytometry. Individuals in the MET group, but no in the NTX group, had higher plasma levels of inflammation and immune activation markers than controls. These markers include soluble CD14 (an independent predictor of morbidity and mortality during HIV infection), proinflammatory cytokines, and proinflammatory IgG glycans. This effect was independent of time on treatment. Our results indicate that methadone-based MOUD regimens may sustain immune activation and inflammation in ART-treated HIV-infected individuals. Our pilot study provides the foundation and rationale for future longitudinal functional studies of the impact of MOUD regimens on immune reconstitution and residual activation after ART-mediated suppression.


Assuntos
Infecções por HIV , Analgésicos Opioides/uso terapêutico , Estudos Transversais , Citocinas , Humanos , Imunoglobulina G , Inflamação/complicações , Receptores de Lipopolissacarídeos , Metadona/uso terapêutico , Naltrexona/uso terapêutico , Projetos Piloto , Receptores Opioides mu
20.
Front Immunol ; 13: 1033712, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36601110

RESUMO

Background: Neurocognitive impairment remains prevalent in people with HIV (PWH) despite long term virological suppression by antiretroviral therapy (ART) regimens. Systemic and neuro-inflammatory processes are suggested to contribute to the complex pathology leading to cognitive impairment in this population, yet the underlying mechanisms remain unresolved. Extracellular vesicles (EVs) play a central role in intracellular communication and have emerged as key modulators of immunological and inflammatory responses. In this report, we examined the impact of EVs in PWH experiencing cognitive deficits to determine their relevance in HIV associated neuropathology. Methods: EV phenotypes were measured in plasma samples from 108 PWH with either cognitive impairment (CI, n=92) or normal cognition (NC, n=16) by flow cytometry. Matched cerebrospinal fluid (CSF)-derived EVs were similarly profiled from a subgroup of 84 individuals who underwent a lumbar puncture. Peripheral blood mononuclear cells were assayed by flow cytometry to measure monocyte frequencies in a subset of 32 individuals. Results: Plasma-EVs expressing CD14, CD16, CD192, C195, and GFAP were significantly higher in HIV-infected individuals with cognitive impairment compared to individuals with normal cognition. Increased CSF-EVs expressing GFAP and CD200 were found in the cognitive impairment group compared to the normal cognition group. Frequencies of patrolling monocytes correlated with plasma-EVs expressing CD14, CD66b, MCSF, MAP2, and GFAP. Frequencies of CD195 expression on monocytes correlated positively with plasma-EVs expressing CD41a, CD62P, and CD63. Expression of CD163 on monocytes correlated positively with CSF-EVs expressing GFAP and CD200. Finally, the expression of CD192 on total monocytes correlated with CSF-EVs expressing CD200, CD62P, and CD63. Conclusions: EVs expressing monocyte activation and neuronal markers associated with HIV associated cognitive impairment, suggesting that distinct EV subsets may serve as novel biomarkers of neuronal injury in HIV infection. Further circulating platelet EV levels were linked to monocyte activation indicating a potential novel interaction in the pathogenesis of HIV-related cognitive impairment.


Assuntos
Transtornos Cognitivos , Vesículas Extracelulares , Infecções por HIV , Humanos , Infecções por HIV/complicações , Leucócitos Mononucleares , Encéfalo
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