Document text
Principal Investigator: R. Brad Jones
Organization: WEILL MEDICAL COLL OF CORNELL UNIV
Fiscal Year: 2023
Award: $211,875
Funding agency: National Institute of Allergy and Infectious Diseases
PROJECT SUMMARY/ABSTRACT
Although modern therapies have dramatically improved the outlooks for people living with HIV they are unable
to cure infection, leaving these individuals burdened by a lifelong commitment to antiretroviral (ARV) medication.
For any given individual, maintaining lifelong adherence to medication can present substantial challenges.
Moreover, many people do not have access to these expensive medications - in particular those living in
resource-limited settings. Furthermore, efforts to end the HIV epidemic have suffered from the lack of effective
preventative or therapeutic vaccines – biomedical tools which have played critical roles in the elimination of other
epidemics, such as smallpox. Recent years have seen important advances in harnessing the antibody arm of
the immune system towards these aims, though substantial challenges still exist. The T-cell arm of the immune
system, which specializes in the recognition and elimination of virus infected cells, holds great promise to
contribute to these efforts, but has lagged behind in development. This can be attributed – in part – to substantial
limitations in the suitability of currently available pre-clinical animal models for the study of T-cell responses. For
example, the property of major histocompatibility (MHC) restriction means that the ways in which the virus-
infected cells of a rhesus macaque will recognize a virus-infected cell differ from the way they would be
recognized by a given human. The current proposal aims to build upon compelling preliminary results, in which
we have observed that a relatively simple, but powerful, modification of a humanized mouse model solves many
of the key issues that have limited utility to date. Namely, we present a mouse model that can be stably engrafted
with immune cells (PBMC) from HIV-infected or uninfected adults, without inducing graft versus host disease
(GvHD). The use of adult cells both avoids the need for fetal tissue. In this project, we will test whether HIV-
specific T-cell responses arise naturally in this mouse model, and whether these play a role in suppressing viral
replication. We will then test whether we are able to induce HIV-specific T-cell responses in uninfected animals
using an mRNA vaccine technology, similar to that employed against COVID-19. Finally, we will test whether
vaccine-induced responses can control viral replication. If successful, this will result in a novel small animal
model in which we can rapidly test and optimize HIV vaccination strategies using a mRNA platform. We believe
that this will facilitate the translation of optimal approaches to clinical trials.
Terms: <21+ years old><AIDS Virus><Acceleration><Acquired Immune Deficiency Syndrome Virus><Acquired Immunodeficiency Syndrome Virus><Address><Adherence><Adult><Adult Human><Animal Model><Animal Models and Related Studies><Animals><Anti-Retroviral Agents><Antibodies><Antigen-Presenting Cells><Antiretroviral Agents><Binding><Blood Plasma><CD8 Cell><CD8 T cells><CD8 lymphocyte><CD8+ T cell><CD8+ T-Lymphocyte><CD8-Positive Lymphocytes><CD8-Positive T-Lymphocytes><COVID-19><COVID19><CV-19><CV19><Cell Body><Cells><Cellular Assay><Clinical Trials><Complex><Data><Development><Drugs><Engraftment><Epidemic><Equipment><Evaluation><Fetal Tissues><Foundations><Genetic Alteration><Genetic Change><Genetic defect><GvHD><HIV><HIV Infections><HTLV-III Infections><HTLV-III-LAV Infections><Heterograft><Heterologous Transplantation><Histocompatibility><Homologous Wasting Disease><Human><Human Immunodeficiency Viruses><Human T-Lymphotropic Virus Type III Infections><Immune><Immune system><Immunes><Immunization><Immunodeficiency Disorder><Immunodeficiency Syndrome><Immunologic Deficiency Syndromes><Immunological Deficiency Syndromes><Immunotherapeutic agent><Individual><Infection><KO mice><Knock-out Mice><Knockout Mice><LAV-HTLV-III><Low-resource area><Low-resource community><Low-resource environment><Low-resource region><Low-resource setting><Lymphadenopathy-Associated Virus><M mulatta><M. mulatta><Macaca mulatta><Mediating><Medication><Messenger RNA><Methods><Mice><Mice Mammals><Modeling><Modern Man><Modernization><Modification><Molecular Interaction><Murine><Mus><Mutation><Null Mouse><Operative Procedures><Operative Surgical Procedures><PBMC><Participant><Peripheral Blood Mononuclear Cell><Persons><Pharmaceutic Preparations><Pharmaceutical Preparations><Plasma><Plasma Serum><Play><Preventative vaccine><Preventive vaccine><Property><Prophylactic vaccine><Publications><RNA immunization><RNA vaccination><RNA vaccine><RNA-based vaccine><Reporting><Resource-constrained area><Resource-constrained community><Resource-constrained environment><Resource-constrained region><Resource-constrained setting><Resource-limited area><Resource-limited community><Resource-limited environment><Resource-limited region><Resource-limited setting><Resource-poor area><Resource-poor community><Resource-poor environment><Resource-poor region><Resource-poor setting><Reticuloendothelial System, Serum, Plasma><Rhesus Macaque><Rhesus Monkey><Robotics><Role><Runt Disease><Scientific Publication><Smallpox><Study models><Surgical><Surgical Interventions><Surgical Procedure><T cell based therapeutics><T cell based therapy><T cell directed therapies><T cell response><T cell targeted therapeutics><T cell therapy><T-Cells><T-Lymphocyte><T8 Cells><T8 Lymphocytes><Technical Expertise><Technology><Testing><Tissue Compatibility><Translations><Vaccination><Vaccines><Variola><Viral><Viral Activity><Viral Burden><Viral Function><Viral Load><Viral Load result><Viral Physiology><Viral load measurement><Viremia><Virus><Virus Replication><Virus-HIV><Work><Xenograft><Xenograft Model><Xenograft procedure><Xenotransplantation><accessory cell><adoptive T cell transfer><adoptive T-cell therapy><adulthood><anti-retroviral><anti-retroviral therapy><anti-retroviral treatment><anti-viral efficacy><antiretroviral><antiretroviral therapy><antiretroviral treatment><antiviral efficacy><arm><cell assay><corona virus disease 2019><coronavirus disease 2019><coronavirus disease-19><coronavirus infectious disease-19><cost effectiveness><developmental><drug/agent><experience><experiment><experimental research><experimental study><experiments><fetus tissue><flexibility><flexible><gene product><genome mutation><graft versus host disease><graft versus host disease induction><graft vs host disease><graft vs. host disease><humanized mice><humanized mouse><hypoimmunity><immune deficiency disorder><immune drugs><immune-based therapeutics><immunization strategy><immunodeficiency><immunogenicity><immunologic therapeutics><immunotherapeutics><immunotherapy agent><improved><in vivo><lipid based nanoparticle><lipid nanoparticle><mRNA><mRNA immunization><mRNA vaccination><mRNA vaccine><mRNA-based vaccine><memory CD4 T cell><memory CD4 T lymphocyte><model of animal><mouse model><murine model><next generation><novel><pre-clinical><preclinical><response><small pox><social role><surgery><technical skills><therapeutic T-cell platform><therapeutic agent development><therapeutic development><therapeutic vaccine><thymus derived lymphocyte><tool><translation><treatment vaccines><vaccination strategy><vaccine for the treatment><vaccine for treatment><vaccine response><vaccine responsiveness><vaccine strategy><vaccine-induced response><variola major><viraemia><viral multiplication><viral replication><viral sepsis><virus load><virus multiplication><virusemia><xeno-transplant><xeno-transplantation><xenograft transplant model><xenotransplant model>