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Principal Investigator: CRISTIAN APETREI
Organization: UNIVERSITY OF PITTSBURGH AT PITTSBURGH
Fiscal Year: 2020
Award: $705,280
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 coronavirus><2019-nCoV><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><Antigens><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-19><COVID19><California><Cardiovascular Diseases><Cessation of life><Characteristics><Chronic><Circulation><Clinical><Clinical Trials><Clotting><CoV emergence><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><Inflammatory Intestinal Disease><Inflammatory Intestinal 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-CoV-2><SARS-CoV2><SARS-associated coronavirus 2><SARS-coronavirus-2><SARS-related coronavirus 2><SIV><Severe acute respiratory syndrome coronavirus 2><Severities><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><Vaccination><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><coronavirus disease 2019><coronavirus emergence><cytokine><cytokine release syndrome><cytokine storm><design><designing><develop a vaccine><development of a vaccine><digestive canal><dosage><drug metabolism><elders><emergent CoV><emergent coronavirus><emerging CoV><emerging coronavirus><fibrin fragment D-dimer><fibrin fragment D1 dimer><fibrin fragment DD><gastrointestinal><geriatric><heavy metal Pb><heavy metal lead><host response><immune activation><immunogen><immunoresponse><improved><intervention efficacy><late life><later life><microbial><microbiome><mucosal site><nCoV><new CoV><new coronavirus><novel CoV><novel coronavirus><older adult><older person><outcome forecast><pandemic><pandemic disease><pathophysiology><population aging><prevent><preventing><response><senior citizen><side effect><therapeutic efficacy><therapeutically effective><therapy efficacy><thymus derived lymphocyte><vaccine development><vaccine formulation><vector><virtual>