Document text
Principal Investigator: Mary Rose D'Angelo
Organization: STATE UNIVERSITY OF NEW YORK AT BUFFALO
Fiscal Year: 2024
Award: $36,070
Funding agency: National Institute of Allergy and Infectious Diseases
PROJECT SUMMARY/ABSTRACT
Human Immunodeficiency Virus 1 (HIV-1) is the causative agent behind acquired immunodeficiency syndrome
(AIDS) and the resulting pandemic. Antiretroviral therapies are effective in controlling infections, however
patients require lifelong treatment and can have severe side effects, resulting in the constant need for novel
therapeutics. Therefore, a better understanding of the interaction between host cells and HIV-1 can unmask
novel targets for therapeutics. Recent reports identified that MARCH1, 2 and 8, members of a family of host E3
ubiquitin ligases known as Membrane Associated RING-CH (MARCH) proteins, whose physiological functions
involve immune receptor homeostasis, restrict HIV-1 by blocking the incorporation of viral envelope glycoproteins
in nascent virions. Another member of the MARCH protein family, MARCH9, reduces HIV-1 infectivity, however,
its mechanism of restriction is unknown and different from that of MARCH1, 2 and 8. MARCH9 targets immune
cell receptors for ubiquitin and subsequential lysosomal degradation as a means of maintaining homeostasis
including MHC-1 and ICAM-1. Preliminary data shown in this proposal demonstrate that MARCH9 reduces the
cellular levels of all HIV-1 structural proteins thereby resulting in reduced viral particle production, which is quite
different from what has been shown with MARCH1, 2 and 8. Additional data show that MARCH9 does not affect
cell viability. The goal of this proposal is to determine the mechanism by which MARCH9 restricts HIV-1 infection.
The experiments outlined here will characterize the step in the HIV-1 life cycle that MARCH9 acts on to inhibit
HIV-1 particle production and the mechanism it utilizes to do so. Additionally, we will determine the role of
endogenous MARCH9 through shRNA knockdown on CD4+ T cells and Monocyte derived Macrophages
(MDMs) to better elucidate its antiviral mechanism. The proposed work will determine the role of MARCH9 in
HIV-1 infection. In doing so, this proposal will provide new insights into the role of the MARCH protein family
during retrovirus infection. Finally, the findings of this proposal have the potential to provide new therapeutic
targets for the development of novel antiretrovirals.
Terms: <AIDS><APF-1><ATP-Dependent Proteolysis Factor 1><Acquired Immune Deficiency><Acquired Immune Deficiency Syndrome><Acquired Immunodeficiency Syndrome><Address><Anti-Retroviral Agents><Assay><Autoregulation><Bioassay><Biological Assay><Blood monocyte><CD4 Cells><CD4 Positive T Lymphocytes><CD4 T cells><CD4 helper T cell><CD4 lymphocyte><CD4+ T-Lymphocyte><CD4-Positive Lymphocytes><CD54 Antigens><Cell Body><Cell Survival><Cell Viability><Cell membrane><Cell surface><Cells><Charge><Co-Immunoprecipitations><Cytoplasmic Domain><Cytoplasmic Membrane><Cytoplasmic Tail><Data><Development><Disease Progression><Down-Regulation><E3 Ligase><E3 Ubiquitin Ligase><ELISA><Enzyme-Linked Immunosorbent Assay><Family><Family member><Gene Transcription><Genes><Genetic Transcription><Glycoproteins><Goals><HIV-1><HIV-I><HIV1><HMG-20><High Mobility Protein 20><Homeostasis><Homo><Human><Human Immunodeficiency Virus Type 1><Human immunodeficiency virus 1><Humanities><ICAM-1><Immune Targeting><Immune response><Immune system><Immunoblot Analysis><Immunoblotting><Immunofluorescence><Immunofluorescence Immunologic><Immunologic Receptors><Immunological Receptors><Immunological response><Immunomodulation><Infection><Infection Control><Intercellular adhesion molecule 1><Invaded><Isoforms><Length><Life Cycle><Life Cycle Stages><Macrophage><Marrow monocyte><Mediating><Membrane><Modeling><Modern Man><Mφ><Patients><Physiologic><Physiological><Physiological Homeostasis><Plasma Membrane><Production><Protein Family><Protein Isoforms><Proteins><RNA Expression><RNA Splicing><RT-PCR><RTPCR><Receptor Cell><Receptor Protein><Reporting><Retroviridae Infections><Retroviridae disease><Retrovirus Infections><Reverse Transcriptase Polymerase Chain Reaction><Role><Splicing><Structural Protein><T-Cells><T-Lymphocyte><T4 Cells><T4 Lymphocytes><Techniques><Transcription><Translations><Ubiquitilation><Ubiquitin><Ubiquitin Protein Ligase><Ubiquitin-Protein Ligase Complexes><Ubiquitin-Protein Ligase E3><Ubiquitination><Ubiquitinoylation><Viral><Viral Activity><Viral Diseases><Viral Function><Viral Physiology><Virion><Virus><Virus Diseases><Virus Particle><Virus Replication><Western Blotting><Western Immunoblotting><Work><anti-retroviral><antiretroviral therapy><antiretroviral treatment><developmental><enzyme linked immunoassay><experiment><experimental research><experimental study><experiments><global health><host response><immune modulation><immune receptor><immune regulation><immune system response><immunologic reactivity control><immunomodulatory><immunoregulation><immunoregulatory><immunoresponse><improved><insight><knock-down><knockdown><life course><member><membrane activity><membrane structure><monocyte><mutant><new drug target><new drug treatments><new druggable target><new drugs><new pharmacological therapeutic><new pharmacotherapy target><new therapeutic target><new therapeutics><new therapy><new therapy target><next generation therapeutics><novel><novel drug target><novel drug treatments><novel druggable target><novel drugs><novel pharmaco-therapeutic><novel pharmacological therapeutic><novel pharmacotherapy target><novel therapeutic target><novel therapeutics><novel therapy><novel therapy target><opportunistic pathogen><overexpress><overexpression><pandemic><pandemic disease><particle><pathogen><plasmalemma><protein blotting><receptor><reverse transcriptase PCR><shRNA><short hairpin RNA><side effect><small hairpin RNA><social role><therapeutic agent development><therapeutic development><thymus derived lymphocyte><trans-Golgi Network><translation><ubiquination><ubiquitin conjugation><ubiquitin-protein ligase><viral infection><viral multiplication><viral replication><virus infection><virus multiplication><virus-induced disease>