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Principal Investigator: Amelia N Deitchman
Organization: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
Fiscal Year: 2024
Award: $201,150
Funding agency: National Institute of Allergy and Infectious Diseases
Project Summary/Abstract
For the nearly 37 million people living with HIV (PLWH), functional cure, or antiretroviral (ART)-free remission,
is rapidly becoming an attainable target. While extensive research on the mechanisms underlying immune
dysfunction and viral persistence present promising opportunities for novel therapeutic modalities, a modest
understanding of how pharmacology (pharmacokinetics, PK, and pharmacodynamics, PD) contributes to clinical
variability in reservoir reduction and immune modulation has frequently resulted in marginal clinical trial
outcomes. This career development award will provide Dr. Amelia Deitchman, a pharmacist-researcher with a
PhD in PK/PD, with the essential mentorship and training to develop her independent research program to bridge
this gap in translational HIV cure research by harnessing heterogeneity in drug response and mismatched clinical
translation to further the HIV cure agenda and develop robust and targeted treatments for all patients.
Numerous novel therapeutic approaches are being investigated as components of durable HIV cure,
including immunosuppressants targeting chronic immune dysfunction and inflammation associated with HIV
persistence, as well as broadly neutralizing antibodies (bNAbs) that clear virus and HIV-infected cells. This
research investigates the use of sirolimus alone and with Shingrix (recombinant varicella zoster virus, rVZV
vaccine) in two clinical trials, and two bNAbs in a combination clinical trial. Using data and samples from these
trials in PLWH on virally suppressive ART, and state-of-the-art viral, immune, and pharmacological approaches,
the candidate will 1) establish exposure-response of sirolimus and rVZV vaccine on HIV reservoirs, immune
function and safety, 2) define predictors of sirolimus and rVZV vaccine response variability attributable to PK and
PD heterogeneity, and 3) determine if systemic bNAb levels can predict time to viral rebound after ART
interruption in the context of other curative strategies. We hypothesize that changes in outcomes (reservoir size,
immune phenotype, inflammatory markers, and for bNAbs, reservoir size and time to viral rebound post ART
interruption) are directly related to drug exposure. For sirolimus, these PK/PD relationships may be entirely
distinct from those used for other therapeutic indications. Furthermore, we hypothesize that drug-drug
interactions, and differences in immune genetics, and patient demographic, clinical, and disease-related traits
account for observed variability in clinical drug exposure and response.
Ultimately, this award will be the cornerstone for a career in HIV cure clinical pharmacology research
through hands-on and didactic training in HIV pharmacology, immunology and virology, clinical trials, and grant
writing by an expert team of mentors. These mentors will foster the candidate's development of an independent
academic research career answering clinical pharmacology questions in the setting of HIV cure. The research
performed as part of this award will support a future R01 submission investigating PK/PD relationships to
accelerate drug development, identify novel therapeutic approaches, and deliver precision care to patients.
Terms: <AIDS Virus><Acceleration><Acquired Immune Deficiency Syndrome Virus><Acquired Immunodeficiency Syndrome Virus><Address><Adverse Experience><Adverse event><Age><Agonist><Anti-Retroviral Agents><Award><CD4 Cells><CD4 Positive T Lymphocytes><CD4 T cells><CD4 helper T cell><CD4 lymphocyte><CD4+ T-Lymphocyte><CD4-Positive Lymphocytes><Career Development Awards><Career Development Awards and Programs><Career Development Programs K-Series><Cell Body><Cell Cycle><Cell Division Cycle><Cells><Cellular Immune Function><Characteristics><Chicken Pox><Chickenpox><Chickenpox Virus><Chronic><Clinical><Clinical Pharmacology><Clinical Research><Clinical Study><Clinical Trials><Complex><DNA><DNA Vaccines><Data><Deoxyribonucleic Acid><Development><Disease><Disease remission><Disorder><Doctor of Philosophy><Dose><Down-Regulation><Drug Exposure><Drug Interactions><Drug Kinetics><Drugs><Exposure to><FK506 Binding Protein 12-Rapamycin Associated Protein 1><FKBP12 Rapamycin Complex Associated Protein 1><FRAP1><FRAP1 gene><FRAP2><Fostering><Funding><Future><Genetic><Grant><HHV-3><HHV3><HIV><HIV Infections><HTLV-III Infections><HTLV-III-LAV Infections><Hematology><Herpes zoster Virus><Herpesvirus Type 3><Herpesvirus varicellae><Heterogeneity><Human Immunodeficiency Viruses><Human T-Lymphotropic Virus Type III Infections><Immune><Immune Cell Activation><Immune Diseases><Immune Disorders><Immune Dysfunction><Immune Markers><Immune Modulation Therapy><Immune System Diseases><Immune System Disorder><Immune System Dysfunction><Immune System and Related Disorders><Immune Targeting><Immune response><Immunes><Immunity><Immunochemical Immunologic><Immunodeficiency and Immunosuppression Disorders><Immunologic><Immunologic Diseases><Immunologic Markers><Immunological><Immunological Diseases><Immunological Dysfunction><Immunological System Dysfunction><Immunological response><Immunologically><Immunologics><Immunology><Immunomodulation><Immunosuppressants><Immunosuppressive Agents><Immunosuppressive drug><Immunosuppressive treatment><Immunotherapeutic agent><Individual><Inflammation><Inflammatory><Interruption><Investigation><Investigators><K-Awards><K-Series Research Career Programs><Knowledge><LAV-HTLV-III><Lymphadenopathy-Associated Virus><Mechanistic Target of Rapamycin><Medication><Mentors><Mentorship><Metabolic Marker><Modality><Naked DNA Vaccines><Non-Polyadenylated RNA><Ocular Herpes zoster Virus><Outcome><PK/PD><Participant><Pathway interactions><Patients><Persons><Ph.D.><PhD><Pharmaceutical Preparations><Pharmacists><Pharmacodynamics><Pharmacokinetics><Pharmacological Study><Pharmacology><Pharmacology Study><Phenotype><Precision care><Proliferating><RAFT1><RNA><RNA Gene Products><Race><Races><Rapamune><Rapamycin><Recombinant DNA Vaccines><Recombinants><Regimen><Remission><Research><Research Career Program><Research Personnel><Researchers><Ribonucleic Acid><SDZ RAD><Safety><Sampling><Sirolimus><T-Cell Activation><T-Cells><T-Lymphocyte><T4 Cells><T4 Lymphocytes><Therapeutic><Time><Training><Transplant Recipients><Up-Regulation><Upregulation><VZ Virus><VZV vaccine><Vaccines><Varicella><Varicella-Zoster Virus><Viral><Viral Markers><Virus><Virus-HIV><Weight><Writing><Zoster Vaccine><activate T cells><ages><anti-retroviral><antiretroviral therapy><antiretroviral treatment><career><chronic infection><clinical translation><clinically translatable><developmental><drug development><drug/agent><everolimus><host response><immune activation><immune drugs><immune function><immune modulating therapies><immune modulation><immune modulatory therapies><immune regulation><immune suppressive agent><immune suppressor><immune system response><immune-based biomarkers><immune-based therapeutics><immune-modulation treatment><immunologic reactivity control><immunologic therapeutics><immunological biomarkers><immunological markers><immunomodulation therapy><immunomodulation treatment><immunomodulator therapies><immunomodulator treatment><immunomodulator-based therapies><immunomodulatory><immunomodulatory therapies><immunomodulatory therapy><immunomodulatory treatment><immunoregulation><immunoregulatory><immunoresponse><immunosuppressive substance><immunosuppressor><immunotherapeutics><immunotherapy agent><improved><individualized care><individualized patient care><inflammation marker><inflammatory marker><inhibitor><mTOR><mammalian target of rapamycin><neutralizing antibody><new drug treatments><new drugs><new pharmacological therapeutic><new therapeutic approach><new therapeutic intervention><new therapeutic strategies><new therapeutics><new therapy><new therapy approaches><new treatment approach><new treatment strategy><next generation therapeutics><novel><novel drug treatments><novel drugs><novel pharmaco-therapeutic><novel pharmacological therapeutic><novel therapeutic approach><novel therapeutic intervention><novel therapeutic strategies><novel therapeutics><novel therapy><novel therapy approach><pathway><persistent infection><personalized care><personalized patient care><pharmacodynamic model><pharmacokinetics and pharmacodynamics><pharmacologic><predict responsiveness><predicting response><preservation><programs><racial><racial background><racial origin><response><sex><thymus derived lymphocyte><trait><transplant patient><treatment risk><trial design><vaccine response><vaccine responsiveness><vaccine-induced response><varicella zoster virus vaccine><viral rebound><virology><virus rebound><weights>