Document text
Principal Investigator: Timothy Jensen Henrich
Organization: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
Fiscal Year: 2024
Award: $191,388
Funding agency: National Institute of Allergy and Infectious Diseases
ABSTRACT/SUMMARY
The primary goals of this K24 award are to identify and cultivate diverse, highly motivated, young investigators
with a propensity for independent thinking, and increase their involvement in collaborative, patient-oriented HIV
pathogenesis and cure research. Specifically, junior investigators will be directed engaged in innovative
methods to characterize whole-body HIV persistence and determine mechanisms of host control of HIV
infection; research will foster their academic careers. One of the major barriers to the successful design and
implementation of HIV curative strategies is the limited ability to characterize the tissue-wide burden of HIV in
the setting of ART and monitor changes in HIV reservoirs relative to a therapeutic intervention. There is also a
paucity of data of how host immune and genetic responses in these microenvironments modulate HIV
persistence or exert immune control of virus without ART. Novel methods are urgently needed to address this
fundamental gap in knowledge and to develop tools to evaluate curative strategies. The goals of this proposal
are to: (1) determine relationships between residual HIV persistence and activity, T cell trafficking, and tissue
pharmacokinetics in PWH that exhibit exceptional elite control or post-treatment control following HIV curative
therapeutic intervention, (2) determine the relationship between longitudinal tissue PK of HIV bnAbs, ART and
viral dynamics using immunoPET imaging and lymph node microdialysis in the setting of cure interventions,
and, (3) determine the impact of HIV tissue burden and residual transcriptional activity on host cell factors in
study participants enrolled in unique clinical studies and from tissue from victims of sudden death with HIV on
ART. These aims involve innovative methods, such as magnetic resonance (MR) imaging studies of the HIV
envelope-specific tracer, 89Zr-VRC01, and [18F]F-AraG, which is selectively taken up by activated T cell, and in-
situ digital spatial profile analysis of tissue microenvironments which have customized to identify multiple HIV
transcripts representing various stages of the HIV lifecycle combined with unbiased human transcriptomic
analysis and targeted proteomics. Ultimately these studies will help direct interventional studies to purge HIV
reservoirs and maintain viral immune control following cessation of ART. These aims are representative of the
principal investigator's collaborative research program combining pathogenesis-based translational and
patient-oriented research to target latent HIV reservoirs and improve immune control of residual infection.
Furthermore, they expand on individually and collaboratively funded initiatives to enable long-term mentorship
and support opportunities to junior investigators to become involved in translational HIV cure research.
Terms: <AIDS Virus><Acquired Immune Deficiency Syndrome Virus><Acquired Immunodeficiency Syndrome Virus><Address><After Care><After-Treatment><Aftercare><Anatomic Sites><Anatomic structures><Anatomy><Atomic Medicine><Autopsy><Award><Body Burden><Body Tissues><CAR T cells><CAR modified T cells><CAR-T><CAR-Ts><CD30><CD4 Cells><CD4 Positive T Lymphocytes><CD4 T cells><CD4 helper T cell><CD4 lymphocyte><CD4+ T-Lymphocyte><CD4-Positive Lymphocytes><Cell Body><Cell Locomotion><Cell Migration><Cell Movement><Cell Therapy><Cell surface><Cells><Cellular Migration><Cellular Motility><Clinical><Clinical Research><Clinical Study><Combination immunotherapy><Custom><DNA><Data><Deoxyribonucleic Acid><Development><Discipline of Nuclear Medicine><Disease remission><Drug Kinetics><Drugs><Environment><Exhibits><Fostering><Funding><Gene Modified><Gene Transcription><Genetic><Genetic Transcription><Genomic approach><Genomics><Goals><Grant><HIV><HIV Infections><HIV envelope><HIV envelope protein><HTLV-III Infections><HTLV-III-LAV Infections><Human><Human Immunodeficiency Viruses><Human T-Lymphotropic Virus Type III Infections><Image><Immune><Immune mediated therapy><Immune response><Immunes><Immuno-PET><ImmunoPET><Immunofluorescence><Immunofluorescence Immunologic><Immunohistochemistry><Immunohistochemistry Cell/Tissue><Immunohistochemistry Staining Method><Immunological response><Immunologically Directed Therapy><Immunology><Immunotherapeutic agent><Immunotherapy><In Situ><In Situ Hybridization><Individual><Infection><Infection Control><Inflammation><Interdisciplinary Research><Interdisciplinary Study><Intervention><Intervention Strategies><Intervention Studies><Investigators><K24 Award><KI-1><Kinetics><Knowledge><LAV-HTLV-III><Life Cycle><Life Cycle Stages><Location><Lymph Node Reticuloendothelial System><Lymph Node Tissue><Lymph node proper><Lymphadenopathy-Associated Virus><Lymphatic Tissue><Lymphatic nodes><Lymphoid Tissue><MR Imaging><MR Tomography><MRI><MRIs><Magnetic Resonance Imaging><Measures><Medical Imaging, Magnetic Resonance / Nuclear Magnetic Resonance><Medication><Mentors><Mentorship><Methods><Microdialysis><Mid-Career Clinical Scientist Award (K24)><Modeling><Modern Man><Monitor><Multidisciplinary Collaboration><Multidisciplinary Research><NMR Imaging><NMR Tomography><Non-Polyadenylated RNA><Nuclear Magnetic Resonance Imaging><Nuclear Medicine><Outcome><PET><PET Scan><PET imaging><PETSCAN><PETT><Participant><Pathogenesis><Persons><Pharmaceutical Preparations><Pharmacokinetics><Pharmacology><Pilot Projects><Play><Population><Positron Emission Tomography Medical Imaging><Positron Emission Tomography Scan><Positron-Emission Tomography><Principal Investigator><Proliferating><Proteomics><Publications><RNA><RNA Expression><RNA Gene Products><Rad.-PET><Radiology / Radiation Biology / Nuclear Medicine><Regional Anatomy><Remission><Research><Research Personnel><Researchers><Residual><Residual state><Ribonucleic Acid><Role><Sampling><Scientific Publication><Scientist><Site><Sudden Death><T cells for CAR><T-Cell Activation><T-Cells><T-Lymphocyte><T4 Cells><T4 Lymphocytes><TM-MKR><TNFRSF8><TNFRSF8 gene><Techniques><Technology><Therapeutic><Therapeutic Intervention><Thinking><Time><Tissues><Tracer><Training><Transcript><Transcription><Tumor Markers><Viral><Viral Activity><Viral Function><Viral Physiology><Virus><Virus-HIV><Zeugmatography><activate T cells><biomarker discovery><career><cell mediated therapies><cell motility><cell-based therapeutic><cell-based therapy><cellular therapeutic><cellular therapy><chimeric antigen T cell receptor><chimeric antigen receptor (CAR) T cells><chimeric antigen receptor T cells><chimeric antigen receptor fusion protein T-cells><chimeric antigen receptor modified T cells><clinical translation><clinically translatable><cohort><collaboratory><combinatorial immunotherapy><curative intervention><curative therapeutic><curative therapy><curative treatments><customs><design><designing><developmental><digital><drug/agent><dual immunotherapy><experience><first in man><first-in-human><gene modification><genetically modified><genomic effort><genomic strategy><host response><image-based method><imaging><imaging method><imaging modality><imaging study><immune drugs><immune system response><immune therapeutic approach><immune therapeutic interventions><immune therapeutic regimens><immune therapeutic strategy><immune therapy><immune-PET><immune-based therapeutics><immune-based therapies><immune-based treatments><immuno therapy><immunologic therapeutics><immunoresponse><immunotherapeutics><immunotherapy agent><improved><in situ Hybridization Genetics><in situ Hybridization Staining Method><in vivo><innate immune pathways><innovate><innovation><innovative><insight><intervention research><intervention therapy><interventional research><interventional strategy><interventional study><interventions research><latent HIV reservoir><latent HIV-1 reservoir><latent HIV1 reservoir><life course><lymph gland><lymph nodes><lymphnodes><minimally invasive><multidisciplinary><nano-string><nanostring><necropsy><new technology><novel><novel technologies><nuclear imaging><participant enrollment><patient centered><patient enrollment><patient oriented><patient oriented research><patient oriented study><pilot study><positron emission tomographic (PET) imaging><positron emission tomographic imaging><positron emitting tomography><post treatment><postmortem><programs><purge><purges><purging><response><social role><thoughts><thymus derived lymphocyte><tool><trafficking><transcriptomics><tumor biomarker><tumor specific biomarker><viral genomics><viral rebound><virus genomics><virus rebound>