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Principal Investigator: Leor S Weinberger
Organization: J. DAVID GLADSTONE INSTITUTES
Fiscal Year: 2022
Award: $189,000
Funding agency: National Institute on Drug Abuse
ABSTRACT
Substantial evidence now indicates that HIV-infected individuals are at a significantly elevated risk for severe
COVID-19 disease when infected with SARS-CoV-2. Moreover, persons who use and inject drugs (PWUD and
PWID) have a high-risk of HIV infection and exposure to SARS-CoV-2 and face major barriers to accessing
antiviral therapies (i.e., are often immunocompromised). The problem is further exacerbated by the emergence
of SARS-CoV-2 variants that escape vaccine-mediated immunity—it is now evident that immunocompromised
individuals promote the evolution of SARS-CoV-2 escape variants and HIV-infected PWUD/PWID with barriers
to treatment represent such a population. Consequently, there is a critical unmet medical need for new
therapeutics that could treat HIV as well as SARS-CoV-2—particularly the emerging variants of concern’—and
could be effectively deployed in difficult-to-reach, high-risk populations (e.g., PWUD/PWID). The long-term goal
of this work is to develop single-administration therapies for HIV-1 and SARS-CoV-2 variants to effectively reach
PWID/PWUD populations. The specific objective of this supplement proposal is to test efficacy of our recently
developed Gene Drive Therapies (GDT) against HIV and SARS-CoV-2 variants in patient cells from HIV+ PWID.
This effort will build heavily off our recent success in engineering GDTs for HIV-1 (see Parent Award) and Zika
Virus (ZIKV), as well as our extensive preliminary in vitro data showing efficacy of GDTs against SARS-CoV-2
variants. The central hypothesis—based on our extensive preliminary in vitro studies—is that our engineered
GDT candidates will have the capacity to reduce both SARS-CoV-2 viral load and pathogenesis, including of
SARS-CoV-2 variants of concern, and HIV viral load, thereby serving as a single-administration, combination
therapeutic for HIV-1 and SARS-CoV-2. The rationale for a GDT for SARS-CoV-2 is based on our preliminary
data showing that GDTs significantly reduce SARS-CoV-2 replication in cell culture, are equally effective against
CoV-2 variants and from extensive studies on HIV-1 in humanized mice and positive FDA meetings. We will
achieve our objectives via two specific aims: (i) Quantify in vivo efficacy of the recently developed GDT in
reducing SARS-CoV-2 viral replication and pathogenesis in hamsters; and (ii) Develop a lung-organoid co-
culture to test efficacy of GDTs against HIV-1 and SARS-CoV-2 in patient-derived cells from HIV+ PWIDs. While
the GDT approach carries inherent risks, single-administration therapeutics active against both SARS-CoV-2
variants and HIV would be highly beneficial, particularly for treating difficult-to-reach, high-risk PWID populations.
The studies proposed here will also have broad fundamental significance by establishing a novel culture model
and tool to assay how SARS-CoV-2 and HIV infections interact in the PWUD/PWID setting (i.e., in the context
of Substance Use Disorders (SUDs) in at-risk populations) and will provide in vivo validation of a novel medical
countermeasure with therapeutic efficacy against emerging SARS-CoV-2 variants.
Terms: <2019 novel corona virus><2019 novel coronavirus><2019-nCoV><2019-nCoV variant><2019-nCoV variant forms><2019-nCoV variant strains><AIDS Virus><Acquired Immune Deficiency Syndrome Virus><Acquired Immunodeficiency Syndrome Virus><Antiviral Therapy><Award><Body Weight decreased><COVID-19><COVID-19 assay><COVID-19 exposure><COVID-19 infection><COVID-19 therapy><COVID-19 treatment><COVID-19 variant><COVID-19 variant forms><COVID-19 variant strains><COVID-19 virus><COVID19><COVID19 assay><COVID19 infection><COVID19 therapy><COVID19 treatment><COVID19 virus><CV-19><CV19><Cell Body><Cell Culture Techniques><Cells><Co-culture><CoV-2><CoV2><Cocultivation><Coculture><Coculture Techniques><Cricetinae><Culicidae><Data><Disease><Disorder><Drug Therapy><Drug user><Drugs><Engineered Gene><Evolution><Exposure to><Face><Formulation><Genes><Genetic Alteration><Genetic Change><Genetic defect><Goals><Golden Hamsters><Golden Syrian Hamsters><HIV><HIV Infections><HIV therapy><HIV-1><HIV-I><HIV1><HTLV-III Infections><HTLV-III-LAV Infections><Hamsters><Hamsters Mammals><Homelessness><Human Immunodeficiency Virus Type 1><Human Immunodeficiency Viruses><Human T-Lymphotropic Virus Type III Infections><Human immunodeficiency virus 1><Immunity><Immunocompromised><Immunocompromised Host><Immunocompromised Patient><Immunosuppressed Host><Imprisonment><In Vitro><Individual><Injecting drug user><Injection Drug User><Intervention><Intervention Strategies><LAV-HTLV-III><Lung><Lung Respiratory System><Lymphadenopathy-Associated Virus><Mediating><Medical><Medication><Mesocricetus auratus><Mexico><Mice><Mice Mammals><Modeling><Mosquitoes><Murine><Mus><Mutation><Organoids><Outcome><PWID><PWUD><Parents><Pathogenesis><Pathogenicity><Patients><Persons><Pharmaceutic Preparations><Pharmaceutical Preparations><Pharmacotherapy><Population><Populations at Risk><Predisposition><RNA vaccine><RNA-based vaccine><Risk><SARS><SARS corona virus 2><SARS coronavirus disease><SARS-CO-V2><SARS-COVID-2><SARS-CoV disease><SARS-CoV-2><SARS-CoV-2 assay><SARS-CoV-2 exposure><SARS-CoV-2 infection><SARS-CoV-2 pathogenesis><SARS-CoV-2 therapy><SARS-CoV-2 treatment><SARS-CoV-2 variant><SARS-CoV-2 variant forms><SARS-CoV-2 variant strains><SARS-CoV2><SARS-CoV2 exposure><SARS-CoV2 infection><SARS-associated corona virus 2><SARS-associated coronavirus 2><SARS-coronavirus-2><SARS-related corona virus 2><SARS-related coronavirus 2><SARSCoV2><Severe Acute Respiratory Coronavirus 2><Severe Acute Respiratory Distress Syndrome CoV 2><Severe Acute Respiratory Distress Syndrome Corona Virus 2><Severe Acute Respiratory Distress Syndrome Coronavirus 2><Severe Acute Respiratory Syndrome><Severe Acute Respiratory Syndrome CoV 2><Severe Acute Respiratory Syndrome CoV disease><Severe Acute Respiratory Syndrome coronavirus disease><Severe Acute Respiratory Syndrome-associated coronavirus 2><Severe Acute Respiratory Syndrome-related coronavirus 2><Severe acute respiratory syndrome associated corona virus 2><Severe acute respiratory syndrome corona virus 2><Severe acute respiratory syndrome coronavirus 2><Severe acute respiratory syndrome coronavirus 2 exposure><Severe acute respiratory syndrome coronavirus 2 infection><Severe acute respiratory syndrome related corona virus 2><South Africa><Substance Use Disorder><Susceptibility><Syrian Hamsters><System><T-Cell Depletion><T-Cells><T-Lymphocyte><T-cell depletion therapy><T-lymphocyte depletion therapy><Testing><Therapeutic><Treatment Efficacy><Vaccines><Validation><Variant><Variation><Viral Burden><Viral Load><Viral Load result><Viral Pathogenesis><Viremia><Virus><Virus Replication><Virus-HIV><Weight Loss><Weight Reduction><Work><Wuhan coronavirus><ZIKV><Zika Virus><anti-viral therapy><barrier to care><barrier to health care><barrier to healthcare><barrier to treatment><base><body weight loss><cell culture><cell cultures><co-infection><cohort><coinfection><corona virus disease 2019><coronavirus disease 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respiratory syndrome coronavirus 2><intervention efficacy><interventional strategy><life-threatening COVID><life-threatening COVID-19><life-threatening SARS-CoV-2><life-threatening coronavirus disease><life-threatening coronavirus disease 2019><life-threatening severe acute respiratory syndrome coronavirus 2><lipid based nanoparticle><lipid nanoparticle><mRNA vaccine><mRNA-based vaccine><medical countermeasure><meetings><nCoV2><new drug treatments><new drugs><new therapeutics><new therapy><next generation therapeutics><novel><novel drug treatments><novel drugs><novel therapeutics><novel therapy><obstacle to care><obstacle to healthcare><people who inject drugs><people who inject illicit drugs><people who use drugs><people who use illicit drugs><persons who inject drugs><persons who use drugs><pulmonary><serious COVID><serious COVID-19><serious SARS-CoV-2><serious coronavirus disease><serious coronavirus disease 2019><serious severe acute respiratory syndrome coronavirus 2><severe 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