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Principal Investigator: CRISTIAN APETREI
Organization: UNIVERSITY OF PITTSBURGH AT PITTSBURGH
Fiscal Year: 2021
Award: $690,235
Funding agency: National Institute of Diabetes and Digestive and Kidney Diseases
Abstract
A coronavirus pandemic is currently in progress and a tremendous effort for developing effective vaccines to curb
it is currently being made. Adenovirus (Ad)-based vaccines are in the lead in the clinical trials, and it is to be
expected that at least one vaccine formulation will comprise of an Ad vector. These vectors are known for inducing
massive activation of the immune responses at the mucosal sites. The gastrointestinal (GI) tract is the primary site
of HIV replication and CD4+ T cell depletion. HIV induces major alterations at the mucosal sites, which impact their
barrier function, permitting transfer of microbial products from the intestinal lumen into the surrounding tissues and
general circulation. Microbial translocation is a key driver of the chronic immune activation and inflammation
(IA/INFL) that are responsible for HIV disease progression. IA/INFL have a tremendous impact on the outcome of
HIV infection and persist even in subjects on antiretroviral therapy (ART), preventing a proper recovery of the CD4+
T cells and thus being responsible for comorbidities and accelerated aging. Improving gut health and controlling
chronic IA/INFL is thus one of the major goals both for prevention of HIV-associated comorbidities and for cure
strategies. It is conceivable that the use of Ad-based vaccines for the SARS-CoV-2 in people living with HIV may
result in high levels of IA/INFL at the mucosal sites, which may reverse HIV control provided by ART. Therefore,
we teamedwith Dr. Andrea Gambotto from the University of Pittsburgh, who produced a recombinant type 5 Ad
vector encoding the transgene for the antigen SARS-CoV-2 S1 subunit (Ad5.SARS-CoV-2-S1). We will use this
vaccine in SIV-infected, ART-suppressed rhesus macaques (RMs) to induce effective mucosal immune responses
to SARS-CoV2, and we will monitor the impact of these responses on the key pathogenic features of HIV infection:
(a) T-cell immune activation, with particular attention given to the mucosal sites; (b) mucosal inflammation and gut
integrity; (c) microbial translocation; (d) microbiome; (e) hypercoagulability; (f) impact on the drug metabolism and
viral suppression; (g) impact on the viral reservoirs. Since severe SARS-CoV-2 infection disproportionately target
older individuals, both young and old RMs will be included. Our specific aim is to test the impact of a SARS-CoV-
2 vaccine on the gut dysfunction and its consequences, systemic immune activation and inflammation and
on the response to ART and viral reservoirs in ART-suppressed SIV infection of young versus old RMs.
By directly probing the impact of an Ad5.SARS-CoV-2 S1 vaccine on key parameters of HIV infection, our
approach will assess whether the planned COVID-19 vaccination has the potential of being deleterious to HIV-
infected subjects. We will also assess the importance of a healthy gastrointestinal mucosa to the efficacy of the
SARS-CoV-2 vaccine, which goes beyond the HIV infection field, covering all the inflammatory bowel disease
pathology.
Terms: <2019 novel corona virus><2019 novel coronavirus><2019-nCoV><2019-nCoV vaccine><AIDS><AIDS Virus><AIDS prevention><Acquired Immune Deficiency><Acquired Immune Deficiency Syndrome><Acquired Immune Deficiency Syndrome Virus><Acquired Immuno-Deficiency Syndrome><Acquired Immunodeficiency Syndrome><Acquired Immunodeficiency Syndrome Virus><Acquired Immunologic Deficiency Syndrome><Ad vector><Address><Adenoviral Vector><Adenoviridae><Adenovirus Vector><Adenoviruses><African American><Afro American><Afroamerican><Age><Aging><Alimentary Canal><Animals><Attention><Black Populations><Blood Circulation><Bloodstream><Body Tissues><CD4 Cells><CD4 Positive T Lymphocytes><CD4 T cells><CD4 helper T cell><CD4 lymphocyte><CD4+ T-Lymphocyte><CD4-Positive Lymphocytes><COVID crisis><COVID disease severity><COVID epidemic><COVID pandemic><COVID severity><COVID-19><COVID-19 antigen><COVID-19 crisis><COVID-19 disease severity><COVID-19 epidemic><COVID-19 global health crisis><COVID-19 global pandemic><COVID-19 health crisis><COVID-19 infection><COVID-19 pandemic><COVID-19 public health crisis><COVID-19 severity><COVID-19 vaccination><COVID-19 vaccine><COVID-19 virus><COVID19><COVID19 crisis><COVID19 disease severity><COVID19 epidemic><COVID19 global health crisis><COVID19 global pandemic><COVID19 health crisis><COVID19 infection><COVID19 pandemic><COVID19 public health crisis><COVID19 severity><COVID19 vaccination><COVID19 vaccine><COVID19 virus><CV-19><CV19><California><Cardiovascular Diseases><Cessation of life><Characteristics><Chronic><Circulation><Clinical><Clinical Trials><Clotting><CoV emergence><CoV-2><CoV2><Coagulation><Coagulation Process><Communities><Control Groups><Coronaviridae><Coronavirus><D-dimer><D-dimer fibrin><D-dimer fragments><Death><Digestive Tract><Disease><Disease Progression><Disorder><Dysfunction><Educational Mainstreaming><Elderly><Epidemic><Excess Mortality><Exposure to><Fibrin fragment D><Functional disorder><GI Tract><Gastrointestinal Tract><Gastrointestinal tract structure><Goals><HIV><HIV Infections><HIV Prevention><HIV/AIDS prevention><HTLV-III Infections><HTLV-III-LAV Infections><Health><Herd Immunity><Human><Human Immunodeficiency Viruses><Human T-Lymphotropic Virus Type III Infections><Hypercoagulability><Immune Cell Activation><Immune response><Immune system><Immunity><Immunochemical Immunologic><Immunologic><Immunological><Immunological response><Immunologically><Immunologics><Impairment><Individual><Infection><Inflammation><Inflammatory><Inflammatory Bowel Diseases><Inflammatory Bowel Disorder><Intestinal><Intestines><LAV-HTLV-III><Lead><Lesion><Lymphadenopathy-Associated Virus><M mulatta><M. mulatta><Macaca mulatta><Mainstreaming><Michigan><Modern Man><Monitor><Mucosa><Mucosal Immune Responses><Mucosal Immunity><Mucosal Inflammation><Mucosal Tissue><Mucositis><Mucous Membrane><NIDDK><National Institute of Diabetes and Digestive and Kidney Diseases><New York><Outcome><Pathogenesis><Pathogenicity><Pathology><Patients><Pb element><Persons><Physiopathology><Population><Population Group><Procedures><Process><Prognosis><Race><Racial Group><Racial Stocks><Recombinants><Recovery><Research><Rhesus Macaque><Rhesus Monkey><Risk><Route><SARS corona virus 2><SARS-CoV-2><SARS-CoV-2 antigen><SARS-CoV-2 disease severity><SARS-CoV-2 epidemic><SARS-CoV-2 global health crisis><SARS-CoV-2 global pandemic><SARS-CoV-2 infection><SARS-CoV-2 pandemic><SARS-CoV-2 severity><SARS-CoV-2 vaccination><SARS-CoV-2 vaccine><SARS-CoV2><SARS-CoV2 antigen><SARS-CoV2 epidemic><SARS-CoV2 infection><SARS-CoV2 pandemic><SARS-CoV2 vaccine><SARS-associated corona virus 2><SARS-associated coronavirus 2><SARS-coronavirus-2><SARS-coronavirus-2 epidemic><SARS-coronavirus-2 pandemic><SARS-coronavirus-2 vaccine><SARS-related corona virus 2><SARS-related coronavirus 2><SARSCoV2><SIV><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 CoV 2><Severe Acute Respiratory Syndrome CoV 2 epidemic><Severe Acute Respiratory Syndrome CoV 2 pandemic><Severe Acute Respiratory Syndrome CoV 2 vaccine><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 epidemic><Severe acute respiratory syndrome coronavirus 2 infection><Severe acute respiratory syndrome coronavirus 2 pandemic><Severe acute respiratory syndrome coronavirus 2 vaccination><Severe acute respiratory syndrome coronavirus 2 vaccine><Severe acute respiratory syndrome related corona virus 2><Simian Immunodeficiency Viruses><Site><T-Cell Activation><T-Cell Depletion><T-Cells><T-Lymphocyte><T-cell depletion therapy><T-lymphocyte depletion therapy><T4 Cells><T4 Lymphocytes><Testing><Thrombophilia><Time><Tissues><Transgenes><Treatment Efficacy><Tropism><United States><Universities><Vaccines><Viral><Viral reservoir><Virus><Virus reservoir><Virus-HIV><Wuhan coronavirus><achievement Mainstream Education><adeno vector><adenovector><advanced age><age group><aged><aged population><ages><aging population><alimentary tract><allergic/immunologic body system><allergic/immunologic organ system><anti-retroviral therapy><anti-retroviral treatment><antiretroviral therapy><antiretroviral treatment><base><black American><bowel><cardiovascular disorder><co-morbid><co-morbidity><comorbidity><corona virus><corona virus disease 2019><corona virus disease 2019 epidemic><corona virus disease 2019 pandemic><corona virus disease 2019 vaccine><corona virus emergence><coronavirus disease 2019><coronavirus disease 2019 antigen><coronavirus disease 2019 crisis><coronavirus disease 2019 disease severity><coronavirus 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response><immune activation><immune system response><immunoresponse><improved><infected with COVID-19><infected with COVID19><infected with SARS-CoV-2><infected with SARS-CoV2><infected with coronavirus disease 2019><infected with severe acute respiratory syndrome coronavirus 2><intervention efficacy><late life><later life><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><microbial><microbiome><mucosal site><nCoV><nCoV2><new CoV><new corona virus><new coronavirus><novel CoV><novel corona virus><novel coronavirus><older adult><older person><pandemic><pandemic disease><pathophysiology><population aging><prevent><preventing><response><senior citizen><serious COVID><serious COVID-19><serious SARS-CoV-2><serious coronavirus disease><serious coronavirus disease 2019><serious severe acute respiratory syndrome 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coronavirus disease 2019><vaccine against 2019-nCov><vaccine against SARS-CoV-2><vaccine against SARS-CoV2><vaccine against SARS-coronavirus-2><vaccine against Severe Acute Respiratory Syndrome CoV 2><vaccine against Severe acute respiratory syndrome coronavirus 2><vaccine development><vaccine for novel coronavirus><vaccine formulation><vector><virtual>