Khader Ghneim

Emory University

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Rafick‐Pierre Sékaly

Emory University

Susan Pereira Ribeiro

Emory University

Ashish Sharma

Emory University

Robert Balderas

Becton Dickinson (United States)

Steven G. Deeks

University of California, San Francisco

Daria J. Hazuda

Quantitative BioSciences

Elias K. Haddad

Drexel University

Dan H. Barouch

Beth Israel Deaconess Medical Center

Daniel C. Douek

National Institutes of Health

Peter W. Hunt

University of California, San Francisco

Cooperative Institutions

Emory University

Vaccine & Gene Therapy Institute of Florida

National Institute of Allergy and Infectious Diseases

National Institutes of Health

Case Western Reserve University

Université de Montréal

Beth Israel Deaconess Medical Center

Harvard University

Ragon Institute of MGH, MIT and Harvard

McGill University

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Microbiome And Metabolome Driven Differentiation Of TGF-β Producing Tregs Leads to Senescence and HIV Latency

SSRN Electronic Journal (2021)

Khader Ghneim Ashish Sharma Susan Pereira Ribeiro Slim Fourati Jeffery Ahlers

Therapeutic interventions to eradicate latent HIV in ART-treated infection have yet to show efficacy. We used a systems biology approach to identify a subset of ART-treated individuals with immune-dysfunction that had the highest frequencies of cells with inducible HIV. Contrary to the prevailing notion that immune activation drives HIV persistence, blood from these individuals was enriched in senescence-inducing genes (high FOXO3, SMAD2 and IRF3), Treg frequencies and TGF-β signaling expression. In these "Senescent-INRs", high Firmicute phylum plasma nucleotides and butyrate/bile acids (like a-ketobutyrate) correlated with Treg frequencies and inducible HIV levels. Stimulation of naive CD4 T-cells with a-ketobutyrate led to TGF-β producing Treg differentiation, and PD-1 up-regulation on less differentiated cells. A dose dependent increase in latent HIV-infected memory CD4 T-cells was observed after TGF-β stimulation. Senescence cascades identified here can be targeted by PD-1/TGF-β specific interventions that have shown safety/efficacy in cancer, and can be crucial for HIV eradication.

Metabolome

Senescence

10.2139/ssrn.3822732

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Citations (0)

Dual blockade of IL-10 and PD-1 leads to control of SIV viral rebound following analytical treatment interruption

Nature Immunology (2024)

Susan Pereira Ribeiro Zachary Strongin Hugo Soudeyns Felipe ten-Caten Khader Ghneim

Human immunodeficiency virus (HIV) persistence during antiretroviral therapy (ART) is associated with heightened plasma interleukin-10 (IL-10) levels and PD-1 expression. We hypothesized that IL-10 and PD-1 blockade would lead to control of viral rebound following analytical treatment interruption (ATI). Twenty-eight ART-treated, simian immunodeficiency virus (SIV)mac

Simian immunodeficiency virus

Persistence (discontinuity)

10.1038/s41590-024-01952-4

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Citations (5)

Rapid Inflammasome Activation following Mucosal SIV Infection of Rhesus Monkeys

Cell (2016)

Dan H. Barouch Khader Ghneim William J. Bosche Yuan Li Brian Berkemeier

Simian immunodeficiency virus

Haplorhini

Mucosal Immunity

10.1016/j.cell.2016.03.021

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Citations (128)

IFN-α blockade during ART-treated SIV infection lowers tissue vDNA, rescues immune function, and improves overall health

JCI Insight (2022)

Louise Swainson Ashish Sharma Khader Ghneim Susan Pereira Ribeiro Peter Wilkinson

Type I IFNs (TI-IFNs) drive immune effector functions during acute viral infections and regulate cell cycling and systemic metabolism. That said, chronic TI-IFN signaling in the context of HIV infection treated with antiretroviral therapy (ART) also facilitates viral persistence, in part by promoting immunosuppressive responses and CD8+ T cell exhaustion. To determine whether inhibition of IFN-α might provide benefit in the setting of chronic, ART-treated SIV infection of rhesus macaques, we administered an anti-IFN-α antibody followed by an analytical treatment interruption (ATI). IFN-α blockade was well-tolerated and associated with lower expression of TI-IFN-inducible genes (including those that are antiviral) and reduced tissue viral DNA (vDNA). The reduction in vDNA was further accompanied by higher innate proinflammatory plasma cytokines, expression of monocyte activation genes, IL-12-induced effector CD8+ T cell genes, increased heme/metabolic activity, and lower plasma TGF-β levels. Upon ATI, SIV-infected, ART-suppressed nonhuman primates treated with anti-IFN-α displayed lower levels of weight loss and improved erythroid function relative to untreated controls. Overall, these data demonstrated that IFN-α blockade during ART-treated SIV infection was safe and associated with the induction of immune/erythroid pathways that reduced viral persistence during ART while mitigating the weight loss and anemia that typically ensue after ART interruption.

Proinflammatory cytokine

Chronic infection

Monocytosis

10.1172/jci.insight.153046

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Citations (13)

Systems Analysis of MVA-C Induced Immune Response Reveals Its Significance as a Vaccine Candidate against HIV/AIDS of Clade C

PLoS ONE (2012)

Carmen Gómez Beatriz Perdiguero Victoria Jiménez Abdelali Filali‐Mouhim Khader Ghneim

Based on the partial efficacy of the HIV/AIDS Thai trial (RV144) with a canarypox vector prime and protein boost, attenuated poxvirus recombinants expressing HIV-1 antigens are increasingly sought as vaccine candidates against HIV/AIDS. Here we describe using systems analysis the biological and immunological characteristics of the attenuated vaccinia virus Ankara strain expressing the HIV-1 antigens Env/Gag-Pol-Nef of HIV-1 of clade C (referred as MVA-C). MVA-C infection of human monocyte derived dendritic cells (moDCs) induced the expression of HIV-1 antigens at high levels from 2 to 8 hpi and triggered moDCs maturation as revealed by enhanced expression of HLA-DR, CD86, CD40, HLA-A2, and CD80 molecules. Infection ex vivo of purified mDC and pDC with MVA-C induced the expression of immunoregulatory pathways associated with antiviral responses, antigen presentation, T cell and B cell responses. Similarly, human whole blood or primary macrophages infected with MVA-C express high levels of proinflammatory cytokines and chemokines involved with T cell activation. The vector MVA-C has the ability to cross-present antigens to HIV-specific CD8 T cells in vitro and to increase CD8 T cell proliferation in a dose-dependent manner. The immunogenic profiling in mice after DNA-C prime/MVA-C boost combination revealed activation of HIV-1-specific CD4 and CD8 T cell memory responses that are polyfunctional and with effector memory phenotype. Env-specific IgG binding antibodies were also produced in animals receiving DNA-C prime/MVA-C boost. Our systems analysis of profiling immune response to MVA-C infection highlights the potential benefit of MVA-C as vaccine candidate against HIV/AIDS for clade C, the prevalent subtype virus in the most affected areas of the world.

Modified vaccinia Ankara

HIV vaccine

CD80

CD86

HIV Antigens

10.1371/journal.pone.0035485

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Citations (25)

Human follicular CD4 T cell function is defined by specific molecular, positional and TCR dynamic signatures

bioRxiv (Cold Spring Harbor Laboratory) (2020)

Kartika Padhan Eirini Moysi Alessandra Noto Alexander Chassiakos Khader Ghneim

Abstract The orchestrated interaction between follicular helper CD4 T cells (TFH) and germinal center (GC) B cells is crucial for optimal humoral immunity. However, the regulatory mechanisms behind spatial distribution and function of TFH is not well understood. Here, we studied human TFH cells and found that transitioning to a CD57 hi TFH status was associated with distinct positioning in the GC, phenotype, transcriptional signatures, function and downregulation of their T-cell receptor (TCR). Single cell TCR clonotype analysis indicated a unidirectional transition towards the CD57 hi TFH status, which was marked with drastic changes in the nature of immunological synapse formation where peripheral microclusters become dominant. Lack of central supra molecular activation cluster (cSMAC) formation in TFH synapse was associated with enhanced ubiquitination/proteasome activity in these cells. Our data reveal significant aspects of the tissue organization and heterogeneity of follicular adaptive immunity and suggest that CD57 hi TFH cells are endowed with distinctive programming and spatial positioning for optimal GC B cell help. One Sentence Summary human TFH cell heterogeneity

Immunological synapse

10.1101/2020.05.12.089706

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Citations (1)

Correction: Systems Analysis of MVA-C Induced Immune Response Reveals Its Significance as a Vaccine Candidate against HIV/AIDS of Clade C

PLoS ONE (2012)

Based on the partial efficacy of the HIV/AIDS Thai trial (RV144) with a canarypox vector prime and protein boost, attenuated poxvirus recombinants expressing HIV-1 antigens are increasingly sought as vaccine candidates against HIV/AIDS.Here we describe using systems analysis the biological and immunological characteristics of the attenuated vaccinia virus Ankara strain expressing the HIV-1 antigens Env/Gag-Pol-Nef of HIV-1 of clade C (referred as MVA-C).MVA-C infection of human monocyte derived dendritic cells (moDCs) induced the expression of HIV-1 antigens at high levels from 2 to 8 hpi and triggered moDCs maturation as revealed by enhanced expression of HLA-DR, CD86, CD40, HLA-A2, and CD80 molecules.Infection ex vivo of purified mDC and pDC with MVA-C induced the expression of immunoregulatory pathways associated with antiviral responses, antigen presentation, T cell and B cell responses.Similarly, human whole blood or primary macrophages infected with MVA-C express high levels of proinflammatory cytokines and chemokines involved with T cell activation.The vector MVA-C has the ability to cross-present antigens to HIV-specific CD8 T cells in vitro and to increase CD8 T cell proliferation in a dose-dependent manner.The immunogenic profiling in mice after DNA-C prime/MVA-C boost combination revealed activation of HIV-1-specific CD4 and CD8 T cell memory responses that are polyfunctional and with effector memory phenotype.Env-specific IgG binding antibodies were also produced in animals receiving DNA-C prime/ MVA-C boost.Our systems analysis of profiling immune response to MVA-C infection highlights the potential benefit of MVA-C as vaccine candidate against HIV/AIDS for clade C, the prevalent subtype virus in the most affected areas of the world.

HIV vaccine

AIDS Vaccines

10.1371/annotation/09c18b10-8433-4d64-be1c-61e578cc088b

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Citations (1)

TGF-β Signaling, Senescence and Impaired Metabolism in Central Memory CD4 T Cells Promotes HIV Persistence

SSRN Electronic Journal (2022)

Khader Ghneim Ashish Sharma Susan Pereira Ribeiro Slim Fourati Jeffery Ahlers

Therapeutic interventions to eradicate latent HIV and restore immune function in ART-treated infection have yet to show efficacy. We applied an integrated -omic approach to identify a distinct group of individuals with poor CD4 T-cell reconstitution (Senescent Immunologic non-responders, “Senescent-INRs”) and the highest frequencies of CD4 T cells with inducible HIV. Contrary to the notion that immune activation drives HIV persistence and immune dysfunction, leukocytes of these subjects expressed genes that regulate cellular senescence. Here, increased frequencies of Tregs and TGF-β signaling cascade expression coincided with downregulation of cell metabolism/cycling in PD1-expressing central memory CD4 T cells and with frequencies of cells with inducible HIV. This profile, driven by a β-hydroxybutyrate rich metabolic milieu, resulted in TGF-β associated latency establishment/maintenance. Our findings identify cellular senescence as a novel mechanism of HIV persistence, that can be targeted by PD-1 or TGF-β specific interventions that have shown safety and efficacy in cancer.

Senescence

Persistence (discontinuity)

10.2139/ssrn.4069031

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Citations (0)

Multi-omics analyses reveal that HIV-1 alters CD4+ T cell immunometabolism to fuel virus replication

Nature Immunology (2021)

Haitao Guo Qi Wang Khader Ghneim Li Wang Elena Rampanelli

10.1038/s41590-021-00898-1

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Citations (77)

Gut-derived bacterial toxins impair memory CD4+ T cell mitochondrial function in HIV-1 infection

Journal of Clinical Investigation (2022)

Brian Ferrari Amanda Cabral Da Silva Ken Liu Е. В. Сайдакова L. B. Korolevskaya

People living with HIV (PLWH) who are immune nonresponders (INRs) are at greater risk of comorbidity and mortality than are immune responders (IRs) who restore their CD4+ T cell count after antiretroviral therapy (ART). INRs have low CD4+ T cell counts (<350 c/μL), heightened systemic inflammation, and increased CD4+ T cell cycling (Ki67+). Here, we report the findings that memory CD4+ T cells and plasma samples of INRs from several cohorts are enriched in gut-derived bacterial solutes p-cresol sulfate (PCS) and indoxyl sulfate (IS) that both negatively correlated with CD4+ T cell counts. In vitro PCS or IS blocked CD4+ T cell proliferation, induced apoptosis, and diminished the expression of mitochondrial proteins. Electron microscopy imaging revealed perturbations of mitochondrial networks similar to those found in INRs following incubation of healthy memory CD4+ T cells with PCS. Using bacterial 16S rDNA, INR stool samples were found enriched in proteolytic bacterial genera that metabolize tyrosine and phenylalanine to produce PCS. We propose that toxic solutes from the gut bacterial flora may impair CD4+ T cell recovery during ART and may contribute to CD4+ T cell lymphopenia characteristic of INRs.

10.1172/jci149571

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Citations (18)