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Principal Investigator: JAMES R FUCHS
Organization: UNIVERSITY OF COLORADO DENVER
Fiscal Year: 2024
Award: $847,141
Funding agency: National Institute of Allergy and Infectious Diseases
Abstract
New therapeutic options are needed to treat people infected with multi-drug resistant HIV-1 phenotypes. Here
we propose to both investigate and exploit the non-catalytic, essential function of HIV-1 integrase (IN) during
virion morphogenesis as a novel therapeutic target. Our highly collaborative research team has already made
important contributions toward these goals. Specifically, our studies have revealed that IN binds the viral RNA
genome (vRNA) in virions and that these interactions enable formation of properly matured, infectious HIV-1
particles. Moreover, we found that IN tetramers bind with high affinity to select vRNA elements. These findings
have begun to uncover mechanistic details behind the non-catalytic function of IN. We have been also
investigating the mode of action of a promising class of novel antiretroviral agents termed allosteric HIV-1
inhibitors or ALLINIs. Our studies have demonstrated that ALLINIs inhibit IN-vRNA interactions in virions by
inducing aberrant IN multimerization. Consequently, ALLINI treatments yield inactive virus particles with
ribonucleoprotein complexes mislocalized outside of the protective capsid. Our more recent studies have
focused on characterizing the antiviral mechanism of action of a lead clinical candidate ALLINI pirmitegravir (PIR,
STP0404) discovered by ST Pharm, Republic of Korea. This highly safe and potent HIV-1 inhibitor has recently
advanced into Phase 2 clinical trials in the USA. Here we propose to build on our highly successful research and
have set out the following two multidisciplinary and complementary specific aims. In aim1, we will continue our
investigation into the non-catalytic role of IN during virion morphogenesis. For this, we will use biochemical
assays to delineate sequence and structural features of vRNA preferentially recognized by HIV-1 IN.
Furthermore, we will determine cryo-EM structures of IN tetramers bound to cognate vRNA segments. In
addition, we’ll develop a novel and powerful in vitro model system for assembly of mature virus like particles by
using IN mediated encapsulation of vRNA inside capsid like particles. Taken together, these studies will markedly
advance our understanding of the non-catalytic function of IN during virion morphogenesis and the underlying
mechanisms for assembly of mature virions. In Aim 2, we will continue our investigation into a highly promising
investigational drug PIR. Specifically, we will delineate the mechanism for how PIR impairs IN-vRNA interactions.
Furthermore, our structural, biochemistry and virology experiments will uncover the underlying mechanisms for
drug-resistance to PIR. In turn, the findings from these studies will inform our medicinal chemistry efforts to
rationally develop improved chemotypes with an enhanced barrier to resistance. Collectively, the two specific
aims will elucidate key aspects of the HIV-1 IN biology and will exploit these insights to advance novel therapies
to treat people living with HIV-1.
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Terms: <AIDS Virus><Acquired Immune Deficiency Syndrome Virus><Acquired Immunodeficiency Syndrome Virus><Address><Affinity><Anti-Retroviral Agents><Assay><Binding><Bioassay><Biochemical><Biochemistry><Biologic Models><Biological Assay><Biological Chemistry><Biological Models><Biology><CLIP-Seq><Capsid><Chemicals><Clinical><Complex><Cryo-electron Microscopy><Cryoelectron Microscopy><DNA Molecular Biology><Drug Industry><Drug resistance><Drug resistant viral><Electron Cryomicroscopy><Elements><Encapsulated><Evolution><Exhibits><Generations><Genetic Alteration><Genetic Change><Genetic defect><Genome><Genomic Segment><Goals><Grant><HITS-CLIP><HIV><HIV 1 drug resistance><HIV-1><HIV-1 drug resistance><HIV-1 drug resistant><HIV-1 integrase><HIV-I><HIV1><HIV1 drug resistance><HIV1 drug resistant><High-throughput sequencing of CLIP cDNA library><Human Immunodeficiency Virus Type 1><Human Immunodeficiency Viruses><Human immunodeficiency virus 1><Impairment><In Vitro><Integrase><Integrase Inhibitors><Investigation><Investigational Drugs><Investigational New Drugs><Knowledge><LAV-HTLV-III><Laboratories><Lead><Life Cycle><Life Cycle Stages><Lymphadenopathy-Associated Virus><Mediating><Medicinal Chemistry><Model System><Molecular Biology><Molecular Interaction><Morphogenesis><Multi-Drug Resistance><Multidrug Resistance><Multiple Drug Resistance><Multiple Drug Resistant><Mutation><Non-Polyadenylated RNA><Pb element><Peer Review><Persons><Pharmaceutic Chemistry><Pharmaceutic Industry><Pharmaceutical Chemistry><Pharmaceutical Industry><Phase 2 Clinical Trials><Phase II Clinical Trials><Phenotype><Play><Publications><RNA><RNA Gene Products><Recombinants><Republic of Korea><Research><Resistance><Resistance to Multi-drug><Resistance to Multidrug><Resistance to Multiple Drug><Resistant to Multiple Drug><Resistant to multi-drug><Resistant to multidrug><Ribonucleic Acid><Ribonucleoproteins><Role><Scientific Publication><Scientist><Seminal><Single Crystal Diffraction><South Korea><Structure><Time><Viral><Virion><Virus Particle><Virus Replication><Virus-HIV><Virus-like particle><X Ray Crystallographies><X-Ray Crystallography><X-Ray Diffraction Crystallography><X-Ray/Neutron Crystallography><Xray Crystallography><analog><anti-retroviral><antiretroviral therapy><antiretroviral treatment><base><bases><clinical candidate><cost effective><crosslinking and immunoprecipitation sequencing><cryo-EM><cryoEM><cryogenic electron microscopy><drug resistance in HIV 1><drug resistance in HIV-1><drug resistant><drug resistant HIV 1><drug resistant HIV-1><drug resistant virus><experience><experiment><experimental research><experimental study><experiments><genome mutation><genome segment><genomic region><heavy metal Pb><heavy metal lead><improved><in vitro Model><inhibitor><insight><interest><life course><morphogenetic process><multi-drug resistant><multidisciplinary><multidrug resistant><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><particle><phase II protocol><preference><resistance to Drug><resistance to HIV-1 drug><resistance to HIV1 drug><resistant><resistant to Drug><resistant to HIV-1 drug><resistant to HIV1 drug><social role><structural biology><therapeutic target><viral RNA><viral multiplication><viral replication><virology><virus RNA><virus multiplication><virus-like nanoparticles><viruslike particle>