Document text
Principal Investigator: Catherine A Blish
Organization: STANFORD UNIVERSITY
Fiscal Year: 2024
Award: $815,573
Funding agency: National Institute of Allergy and Infectious Diseases
ABSTRACT
Antiretroviral treatment (ART) for HIV infection effectively blocks viral replication, but fails to eradicate the virus,
which can be a source of persistent inflammation. The pathways by which chronic, treated HIV infection drives
inflammation are poorly defined, particularly in children and adolescents who acquire HIV perinatally. Perinatal
HIV infection occurs in the context of a developing immune system, requires life-long treatment, and even with
effective ART, treatment is associated with increased risks of metabolic, neurocognitive and cardiovascular
complications that result from this HIV-induced inflammation. Thus, to understand the mechanisms driving
inflammation in this vulnerable population that faces decades-long infection and treatment, we will study
HIV-induced inflammation in a unique cohort of perinatally infected adolescents in Kenya who have been
maintained on ART and followed clinically since their first year of life. To complement these valuable
longitudinal clinical samples, we have developed organoids of human secondary lymphoid tissues, a major HIV
reservoir site. The lymphoid organoids we are using are highly relevant to pediatric and adolescent infections
as they are derived from pediatric/adolescent tissue, contain all major immune cell types, infectable with HIV,
and are manipulable via gene editing, siRNA transfection, and antibody/small molecule inhibitors to probe
mechanisms driving HIV-induced inflammation. Our goal is to use these unique resources to identify
HIV-induced inflammatory networks in perinatally-infected adolescents on long-term ART and to define the viral
factors that drive HIV-induced inflammation. We will make use of single cell techniques, which to date have
only been applied to adult cohorts, to map the cell-intrinsic inflammatory networks induced during chronic
treated HIV infection and define the viral genes that initiate these cascades. In addition, to fill a gap that has
been missing in prior studies, we seek to understand how these rare infected cells initiate downstream
cascades of inflammation that drive pathology by studying communication networks using methods we recently
developed to infer cell-cell communication at the single cell level. This powerful combination of a long-term
pediatric treatment cohort coupled with mechanistic studies in a robust ex vivo lymphoid culture system will
provide a unique window into HIV-induced inflammation. Successful completion of this project will define
mechanisms by which residual HIV RNA expression during treated infection drives inflammation in perinatally
infected adolescents and establish models to test therapeutics.
Terms: <0-11 years old><21+ years old><3-D><3-D modeling><3-Dimensional><3D><3D modeling><AIDS Virus><AIDS test><AIDS/HIV test><Acquired Immune Deficiency Syndrome Virus><Acquired Immunodeficiency Syndrome Virus><Adolescent><Adolescent HIV><Adolescent Youth><Adult><Adult Human><Age><Algorithms><Antibodies><Automobile Driving><Body Tissues><CD4 Cells><CD4 Positive T Lymphocytes><CD4 T cells><CD4 helper T cell><CD4 lymphocyte><CD4+ T-Lymphocyte><CD4-Positive Lymphocytes><CRISPR approach><CRISPR based approach><CRISPR method><CRISPR methodology><CRISPR technique><CRISPR technology><CRISPR tools><CRISPR-CAS-9><CRISPR-based method><CRISPR-based technique><CRISPR-based technology><CRISPR-based tool><CRISPR/CAS approach><CRISPR/Cas method><CRISPR/Cas technology><CRISPR/Cas9><CRISPR/Cas9 technology><Cardiovascular><Cardiovascular Body System><Cardiovascular Organ System><Cardiovascular system><Cas nuclease technology><Cell Body><Cell Communication><Cell Communication and Signaling><Cell Interaction><Cell Signaling><Cell-to-Cell Interaction><Cells><Child><Child Youth><Childhood><Children (0-21)><Chronic><Clinical><Clustered Regularly Interspaced Short Palindromic Repeats approach><Clustered Regularly Interspaced Short Palindromic Repeats method><Clustered Regularly Interspaced Short Palindromic Repeats methodology><Clustered Regularly Interspaced Short Palindromic Repeats technique><Clustered Regularly Interspaced Short Palindromic Repeats technology><Communication><Complement><Complement Proteins><Coupled><Disease><Disease Progression><Disorder><Environment><Face><Gene Expression><Gene Transcription><Genes><Genetic Transcription><Goals><HIV><HIV Infections><HIV infection in adolescence><HIV infections in adolescents><HIV test><HIV-1 test><HIV-2 test><HIV-infected (HIV+) adolescents><HIV-infected adolescents><HTLV-III Infections><HTLV-III-LAV Infections><Heart Vascular><Human><Human Immunodeficiency Viruses><Human T-Lymphotropic Virus Type III Infections><Human immunodeficiency virus test><Immune><Immune Cell Activation><Immune Diseases><Immune Disorders><Immune Dysfunction><Immune System Diseases><Immune System Disorder><Immune System Dysfunction><Immune System and Related Disorders><Immune system><Immunes><Immunodeficiency and Immunosuppression Disorders><Immunologic Diseases><Immunological Diseases><Immunological Dysfunction><Immunological System Dysfunction><Individual><Infection><Inflammation><Inflammatory><Inflammatory Response><Intracellular Communication and Signaling><Kenya><LAV-HTLV-III><Life><Lymphadenopathy-Associated Virus><Lymphatic Tissue><Lymphoid><Lymphoid Tissue><Maps><Metabolic><Methods><Modeling><Modern Man><Neurocognitive><Non-Polyadenylated RNA><Organoids><PBMC><Pathology><Pathway interactions><Perinatal><Peripartum><Peripheral Blood Mononuclear Cell><Population><Proteins><Provirus Integration><RNA><RNA Expression><RNA Gene Products><Research Resources><Residual><Residual state><Resolution><Resources><Ribonucleic Acid><Risk><Role><Sampling><Short interfering RNA><Signal Transduction><Signal Transduction Systems><Signaling><Site><Small Interfering RNA><Source><Structure><System><T4 Cells><T4 Lymphocytes><Techniques><Testing><Tissues><Transcription><Transfection><Validation><Viral><Viral Burden><Viral Genes><Viral Load><Viral Load result><Virus><Virus Replication><Virus-HIV><Vulnerable Populations><adolescents living with HIV><adolescents with HIV><adulthood><ages><antiretroviral therapy><antiretroviral treatment><biological signal transduction><cell type><circulatory system><cohort><complementation><driving><faces><facial><immune activation><in vivo><inflammatory modulation><inhibitor><insight><juvenile><juvenile human><kids><latent HIV reservoir><latent HIV-1 reservoir><latent HIV1 reservoir><new drug treatments><new drugs><new pharmacological therapeutic><new therapeutics><new therapy><next generation therapeutics><novel><novel drug treatments><novel drugs><novel pharmaco-therapeutic><novel pharmacological therapeutic><novel therapeutics><novel therapy><pathway><pediatric><pediatric HIV disease><pediatric HIV infection><pediatric human immunodeficiency virus disease><pediatric human immunodeficiency virus infection><perinatal HIV><resolutions><scRNA-seq><secondary lymph organ><secondary lymphatic organ><secondary lymphoid organ><sex><siRNA><single cell RNA-seq><single cell RNAseq><single cell expression profiling><single cell transcriptomic profiling><single-cell RNA sequencing><small molecular inhibitor><small molecule><small molecule inhibitor><social role><therapeutic evaluation><therapeutic testing><three dimensional><three-dimensional modeling><validations><viral multiplication><viral replication><virus multiplication><vulnerable group><vulnerable individual><vulnerable people><youngster>