Document text
Principal Investigator: Elena Martinelli
Organization: NORTHWESTERN UNIVERSITY AT CHICAGO
Fiscal Year: 2024
Award: $1,180,430
Funding agency: National Institute of Allergy and Infectious Diseases
HIV persists in all treated individuals and in most cases viral rebound occurs promptly upon antiretroviral
treatment interruption (ATI). Tissues are major sites of HIV persistence during cART and, notably, the
gastrointestinal tract is the first site were rebound is detectable via SIV-end ImmunoPET/CT in a live SIV
infected animal upon ATI. However, a lot is still unknown about the mechanisms of viral persistence in tissues.
This is mostly because of logistical barriers in sampling deep tissues and the focal nature of HIV/SIV infection.
Our team has developed a sampling workflow based on ImmunoPET/CT signal that overcomes these
difficulties and allows sampling of areas of “rebound-competent reservoir” in tissues in a live animal. TGF-β is
an important immune suppressor factor, which orchestrates tissue immunity. Levels of TGF-β remain elevated
in HIV infected individuals even after years of fully suppressive cART and contribute to immune suppression as
well as to the development of non-AIDS-related, non-communicable disorders via pro-fibrotic mechanisms.
TGF-β inhibits TCR-driven T cell proliferation and the maturation and function of other immune cell subsets.
Importantly, TGF-β is currently being used to induce HIV latency in in vitro models with primary T cells. Our
preliminary data demonstrate that blocking TGF-β signaling in vivo favors HIV latency reversal especially in
tissues. Moreover, we found that TGF-β blockade stimulates SIV-specific immune responses and decreases
BCL-2 expression in memory T cells both in vivo and in vitro. These exciting new data support a view of TGF-β
as a critical factor in maintaining immune cells into a resting state mostly resistant to apoptosis. Hence, we
hypothesize that blocking TGF-β will not only increase the frequency of latency reversal events, but also
enhance the elimination of the viral reservoir by increasing its susceptibility to immune and viral-mediated cell
death. We will test this hypothesis by focusing on 3 specific aims. Aim 1 will be an investigation of the
mechanisms of TGF-β blockade in vivo. We will leverage PET/CT-guided sampling to obtain tissue areas
where virus reverses following TGF-β blockade and analyze the cells in these tissues for their transcriptomic
profiles in their own microenviroment. In Aim 2, we will dissect the mechanisms of TGF-β blockade ex vivo to
understand the pathways dependence of the effect of TGF-β blockade on HIV latency and on the survival
program of central memory T cells. Finally, in Aim 3, we will dissect the combination of TGF-β blockade and
PD-1 blockade on the differentiation program and apoptosis sensitivity of the cells harboring the viral reservoir
in vivo. In conclusion, we designed a comprehensive strategy that will help us understanding the potential of
this novel strategy to bring us closer to an HIV cure.
Terms: <AIDS Virus><Ablation><Acquired Immune Deficiency Syndrome Virus><Acquired Immunodeficiency Syndrome Virus><Alimentary Canal><Animals><Apoptosis><Apoptosis Pathway><Apoptotic><Area><Assay><Autopsy><B-Cell Chronic Lymphocytic Leukemia Associated Oncogene><B-cell Leukemia 1><BCL><BCL1 Oncogene><Beta 1 Receptor><Beta-1 Adrenoceptor><Beta-1 Adrenoreceptor><Binding><Bioassay><Biological Assay><Body Tissues><Bone-Derived Transforming Growth Factor><Bypass><CD28><CD28 gene><CD4 Cells><CD4 Positive T Lymphocytes><CD4 T cells><CD4 helper T cell><CD4 lymphocyte><CD4+ T-Lymphocyte><CD4-Positive Lymphocytes><Cell Body><Cell Communication and Signaling><Cell Death><Cell Isolation><Cell Segregation><Cell Separation><Cell Separation Technology><Cell Signaling><Cell model><Cells><Cellular Immune Function><Cellular Metabolic Process><Cellular model><Combined Modality Therapy><Control Groups><Critical Paths><Critical Pathways><DNA><Data><Deoxyribonucleic Acid><Dependence><Development><Digestive Tract><Disease><Disorder><Drugs><Effector Cell><Ensure><Event><Flow Cytofluorometries><Flow Cytofluorometry><Flow Cytometry><Flow Microfluorimetry><Flow Microfluorometry><Frequencies><GI Tract><Gastrointestinal Tract><Gastrointestinal tract structure><Gene Transcription><Genetic Transcription><HIV><HIV Infections><HTLV-III Infections><HTLV-III-LAV Infections><Heterogeneity><Human Immunodeficiency Viruses><Human T-Lymphotropic Virus Type III Infections><Immune><Immune response><Immunes><Immunity><Immuno-PET><ImmunoPET><Immunologic Suppressor Factors><Immunological response><Immunosuppression><Immunosuppression Effect><Immunosuppressive Effect><In Vitro><In vivo analysis><Individual><Infection><Interruption><Intracellular Communication and Signaling><Intrinsic factor><Investigation><Kinetics><LAV-HTLV-III><Lymph Node Reticuloendothelial System><Lymph node proper><Lymphadenopathy-Associated Virus><Lymphatic nodes><Macaca><Macaque><Maintenance><Measures><Mediating><Medication><Memory><Metabolic><Methods><Microscopy><Milk Growth Factor><Modeling><Molecular Interaction><Multimodal Therapy><Multimodal Treatment><Nature><Nivolumab><Noise><Opdivo><PD 1><PD-1><PD-1 blockade><PD1><PD1 blockade><PET><PET Scan><PET imaging><PET/CT><PET/CT scan><PETSCAN><PETT><Pathway interactions><Pharmaceutical Preparations><Phenotype><Platelet Transforming Growth Factor><Positron Emission Tomography Medical Imaging><Positron Emission Tomography Scan><Positron-Emission Tomography><Predisposition><Programmed Cell Death><Property><Proteomics><Proviruses><RNA Expression><Rad.-PET><Receptors, Adrenergic, beta-1><Resistance><Rest><Rhesus><SIV><Sampling><Signal Transduction><Signal Transduction Systems><Signaling><Simian Immunodeficiency Viruses><Site><Sleep><Stimulus><Suppressor T-Cell Factors><Susceptibility><Systems Biology><T memory cell><T-Cell Activation><T-Cell Proliferation><T-Cell Suppressive Factors><T-Cells><T-Lymphocyte><T-Suppressor Factors><T4 Cells><T4 Lymphocytes><T44><TGF B><TGF-beta><TGF-beta Receptors><TGF-β><TGF-β Receptors><TGFbeta><TGFβ><Techniques><Technology><Testing><Therapeutic><Tissue Sample><Tissues><Transcription><Transforming Growth Factor beta><Transforming Growth Factor beta Receptors><Transforming Growth Factor β Receptors><Transforming Growth Factor-Beta Family Gene><Viral><Viral reservoir><Virus><Virus reservoir><Virus-HIV><aPD-1><aPD1><activate T cells><alimentary tract><anti programmed cell death 1><anti-PD-1><anti-PD-1 blockade><anti-PD1><anti-PD1 blockade><anti-programmed cell death protein 1><antiPD-1><antiPD1><antiretroviral therapy><antiretroviral treatment><biological signal transduction><cell metabolism><cell sorting><cellular metabaolism><combination therapy><combined modality treatment><combined treatment><design><designing><developmental><digestive canal><drug/agent><falls><flow cytophotometry><host response><immune function><immune suppression><immune suppressive activity><immune suppressive function><immune system response><immune-PET><immunoresponse><immunosuppressive activity><immunosuppressive function><immunosuppressive response><in vitro Model><in vivo><in vivo evaluation><in vivo testing><inhibitor><innovate><innovation><innovative><latency/reactivation><long term memory><longterm memory><lymph gland><lymph nodes><lymphnodes><memory T lymphocyte><metabolism measurement><metabolomics><metabonomics><multi-modal therapy><multi-modal treatment><multidisciplinary><necrocytosis><necropsy><new approaches><novel><novel approaches><novel strategies><novel strategy><pathway><positron emission computed tomography><positron emission tomographic (PET) imaging><positron emission tomographic imaging><positron emitting tomography><postmortem><pro-apoptotic protein><programmed cell death 1><programmed cell death protein 1><programmed death 1><programs><reactivation from latency><resistant><response><sle2><small molecular inhibitor><small molecule inhibitor><spatiotemporal><systemic lupus erythematosus susceptibility 2><thymus derived lymphocyte><transcriptomics><viral rebound><virus rebound><αPD-1><αPD1>