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Principal Investigator: Ivona Vasile Pandrea
Organization: UNIVERSITY OF PITTSBURGH AT PITTSBURGH
Fiscal Year: 2024
Award: $793,137
Funding agency: National Heart Lung and Blood Institute
Antiretroviral therapy (ART) has dramatically changed the landscape of chronic HIV infection and massively
reduced mortality in persons living with HIV (PWH). Yet, many PWH present with intestinal dysfunction, residual
immune activation and inflammation, incomplete immune restoration and a hypercoagulable state, all of which
drive a poor prognosis and development of non-AIDS comorbidities, such as the cardiovascular disease (CVD).
The pathways involved in the development of CVD in PWH and SIV-infected macaques are not completely
elucidated. We recently reported that neutrophil dysfunction may be a key driver of this process, through
overwhelming activation and excessive production of neutrophil extracellular traps (NETs). By studying the
dynamics and functions of NETs in SIV infection, we showed that they may contribute to disease progression
and comorbidities: (a) proinflammatory NETosis increases throughout untreated SIV infection, and is only
partially reduced by ART, (b) NETs may be a determinant of the indiscriminate depletion of immune cells that
are not virus targets, and of the incomplete CD4+ T cell restoration observed in PWH on ART, and (c) NETosis
may promote thrombosis in the thrombocytopenic environment of HIV/SIV infections by capturing platelets and
expressing tissue factor. We thus propose a project to assess the role of NETosis in HIV disease progression
and response to ART through a direct intervention in vivo. We will use an SIVsab/PTM model developed in our
laboratory that faithfully reproduce both key aspects of SIV pathogenesis on ART and the CV disease. We will
also use a NET inhibitor that has been validated in vivo by numerous studies in murine animal models. In
preliminary studies, we demonstrated that this drug has the ability to inhibit ex vivo production of NETs by
neutrophils isolated from our SIV-infected PTMs. We will first test the hypothesis that NETosis is involved in
driving SIV pathogenesis and disease progression. To this goal, we will administer the NET inhibitor during
chronic infection to untreated SIV-infected PTMs and assess its impact on the natural history of SIV infection,
including CV comorbidities. These experiments are designed to model those PWH who either do not receive
ART or do not achieve complete virus suppression on ART. Second, we will test the hypothesis that NETosis
is involved in driving the response to ART and development of CV comorbidities. To this goal, we will
administer a NET inhibitor to ART-treated SIV-infected PTMs and assess the consequences of this intervention
on the CD4+ T cell restoration, inflammation, coagulation and CV disease development. These experiments are
designed to model PWH, who receive ART. This highly innovative project will improve our understanding of HIV
pathogenesis and mechanisms of HIV-related comorbidities, particularly the CVD, a major cause of death in
PWH, and thus may have a critical impact on the clinical management and survival of the PWH.
Terms: <AIDS><AIDS Virus><AIDS/HIV><AT III-protease complex><Acceleration><Acquired Immune Deficiency><Acquired Immune Deficiency Syndrome><Acquired Immune Deficiency Syndrome Virus><Acquired Immunodeficiency Syndrome><Acquired Immunodeficiency Syndrome Virus><Address><Adjuvant><Age><Animal Model><Animal Models and Related Studies><Automobile Driving><Biological Markers><Blood Coagulation Factor III><Blood Neutrophil><Blood Platelet Count><Blood Platelet Number><Blood Platelets><Blood Polymorphonuclear Neutrophil><Body Tissues><CD142 Antigens><CD4 Cells><CD4 Positive T Lymphocytes><CD4 T cells><CD4 helper T cell><CD4 lymphocyte><CD4+ T-Lymphocyte><CD4-Positive Lymphocytes><COVID-19><CV-19><Cardiovascular Diseases><Cause of Death><Cell Body><Cells><Cessation of life><Chronic><Clinical Management><Clotting><Coagulation><Coagulation Factor III><Coagulation Process><Coagulin><Coronavirus Infectious Disease 2019><D-dimer><D-dimer fibrin><D-dimer fragments><Data><Death><Development><Disease><Disease Progression><Disorder><Drugs><Dysfunction><Environment><Experimental Designs><Factor III><Fibrin fragment D><Frequencies><Functional disorder><Glomerular Procoagulant Activity><Goals><HIV><HIV Infections><HIV/AIDS><HTLV-III Infections><HTLV-III-LAV Infections><Human Immunodeficiency Viruses><Human T-Lymphotropic Virus Type III Infections><Hypercoagulability><Immune><Immune Cell Activation><Immunes><Individual><Infection><Inflammation><Inflammatory><Intervention><Intervention Strategies><Intestinal><Intestines><Knowledge><LAV-HTLV-III><Laboratories><Lymphadenopathy-Associated Virus><M nemestrina><M. nemestrina><Macaca><Macaca nemestrina><Macaque><Marrow Neutrophil><Marrow platelet><Medication><Mice><Mice Mammals><Modeling><Morbidity><Morbidity - disease rate><Mucosa><Mucosal Tissue><Mucous Membrane><Murine><Mus><Natural History><Neutrophilic Granulocyte><Neutrophilic Leukocyte><Organ><Pathogenesis><Pathogenicity><Pathway interactions><Patients><Persons><Pharmaceutical Preparations><Physiopathology><Pigtail Macaque><Pigtail Monkey><Platelet Count><Platelet Count measurement><Platelet Number><Platelets><Polymorphonuclear Cell><Polymorphonuclear Leukocytes><Polymorphonuclear Neutrophils><Population><Process><Production><Prognosis><Prothrombinase><Recovery><Reporting><Research><Residual><Residual state><Role><SIV><Simian Immunodeficiency Viruses><T4 Cells><T4 Lymphocytes><Testing><Thrombin-Antithrombin Complex><Thrombocytes><Thrombophilia><Thromboplastin><Thrombosis><Tissue Factor><Tissue Factor Procoagulant><Tissue Thromboplastin><Tissues><Urothromboplastin><Virus><Virus Replication><Virus-HIV><ages><antiretroviral therapy><antiretroviral treatment><antithrombin III-protease complex><bio-markers><biologic marker><biomarker><bowel><cardiovascular disorder><chronic infection><co-morbid><co-morbidity><comorbidity><coronavirus disease 2019><coronavirus disease-19><coronavirus infectious disease-19><cytokine><design><designing><developmental><driving><drug/agent><experiment><experimental research><experimental study><experiments><extracellular><fibrin fragment D-dimer><fibrin fragment D1 dimer><fibrin fragment DD><gut health><immune activation><improved><in vivo><inhibitor><innovate><innovation><innovative><interventional strategy><model of animal><mortality><neutrophil><new drug treatments><new drugs><new pharmacological therapeutic><new therapeutics><new therapy><next generation therapeutics><non-human primate><nonhuman primate><novel drug treatments><novel drugs><novel pharmaco-therapeutic><novel pharmacological therapeutic><novel therapeutics><novel therapy><pandemic concern><pandemic potential><pandemic risk><pandemic threat><pathophysiology><pathway><persistent infection><pig-tailed macaque><response><response to therapy><response to treatment><restoration><social role><therapeutic response><therapy response><thrombin-antithrombin III complex><thrombotic disease><thrombotic disorder><treatment response><treatment responsiveness><viral multiplication><viral replication><virus multiplication>