This $3,356,188 Project Grant awarded by the National Institute of Allergy and Infectious Diseases (CFDA 93.855 Allergy and Infectious Diseases Research) aims to characterize the HIV-1 proviral reservoir in neonates and infants receiving very early antiretroviral therapy (ART) and combination ART with broadly neutralizing antibodies (bNAbs) towards achieving ART-free remission. The key objectives are to: (1) quantify and characterize the intact proviral pool, (2) evaluate HIV integration...
This $1,376,850 federal Project Grant award from the National Institute of Child Health and Human Development (CFDA 93.865 - Child Health and Human Development Extramural Research) supports research to understand and address the increased risk of severe infections, hospitalizations, and death in the first 1-2 years of life that HIV-exposed uninfected (HEU) infants face compared to HIV-unexposed infants. The project aims to define the relationships between the infant gut microbiome, immune system...
This $756,077 Project Grant was awarded by the National Institute of Child Health and Human Development (NICHD) under the Child Health and Human Development Extramural Research program (CFDA 93.865). The grant supports a 5-year research study to investigate the long-term immunologic, cardiovascular, metabolic, and neurocognitive outcomes in children and adolescents with perinatal HIV infection who have achieved viral suppression on long-term antiretroviral therapy. The research will assess...
This Project Grant award from the National Institute of Child Health and Human Development (NICHD), under the Child Health and Human Development Extramural Research program (CFDA 93.865), provides $273,424 to Weill Medical College of Cornell University to study the ability of broadly neutralizing antibodies (bNAbs) to prevent HIV-1 transmission in HIV-1 exposed infants. The key objectives are to: 1) define the serum antiviral functional profile of HIV-1 exposed infants passively administered...
This federal Project Grant award from the National Institute of Child Health and Human Development (CFDA 93.865 - Child Health and Human Development Extramural Research) provides $534,721 to Oregon Health & Science University to study the impact of antiretroviral therapy (ART) on fetal immune system development in a rhesus macaque model of simian immunodeficiency virus (SIV) infection. The research aims to determine the effects of maternal SIV/ART or ART alone on fetal immune system function...
This $232,500 Project Grant awarded by the National Institute of Child Health and Human Development (NICHD) under the Child Health and Human Development Extramural Research program (CFDA 93.865) will fund research to investigate the virologic determinants that lead to long-term, antiretroviral therapy-free control in infants with in utero HIV-1 infection. The research will create and analyze infectious molecular clones from the HIV-1 genomes of participants in the IMPAACT P1115 clinical trial,...
This Project Grant award from the National Institute of Allergy and Infectious Diseases (NIAID) under the Allergy and Infectious Diseases Research program (CFDA 93.855) provides $1,332,155 to Emory University to conduct research on developing virus and host-directed immunotherapies for curing HIV infection in an infant macaque model. The key objectives are to: Determine how activating the non-canonical NF-kB pathway with broadly neutralizing antibody (bNAb) administration during early...
This Project Grant award from the National Institute of Child Health and Human Development (NICHD), under the Child Health and Human Development Extramural Research program (CFDA 93.865), will provide $498,000 to the Regents of the University of California at Riverside to conduct research on the interactions between the enteric virome, bacterial microbiota, and cellular immune responses in HIV-exposed but uninfected infants. The study aims to longitudinally identify how the altered gut...
This Project Grant award from the National Institute of Allergy and Infectious Diseases (NIAID), under the Allergy and Infectious Diseases Research program (CFDA 93.855), provides $489,500 to The Children's Hospital of Philadelphia (CHOP) Research Institute to conduct research on the cellular identity of the intact HIV reservoir. The key objectives of this 2-year research project are to: 1) Investigate whether CD4+ T cells with provirus in closed chromatin are transcriptionally distinct from...
The National Institute of Allergy and Infectious Diseases (NIAID) awarded a Project Grant totaling $244,328 to The General Hospital Corporation, doing business as Massachusetts General Hospital (MGH), under the Allergy and Infectious Diseases Research program (CFDA 93.855). The grant aims to elucidate the independent effects of HIV and antiretroviral (ARV) exposure on the placenta and birth weight of children born to women with HIV or uninfected women taking ARVs as pre-exposure prophylaxis...
DECIPHERING HEMATOPOIETIC STEM CELL DEFECTS IN HIV EXPOSED, UNINFECTED INFANTS BORN TO ART-TREATED MOTHERS - PROJECT SUMMARY: INTENSIVE RESEARCH OF THE PAST FEW DECADES DEMONSTRATED THAT HUMAN IMMUNODEFICIENCY VIRUS (HIV)- INFECTED INDIVIDUALS DEVELOP SEVERE HEMATOPATHOLOGIES, INCLUDING ANEMIA, THROMBOCYTOPENIA, PANCYTOPENIA, AND BONE MARROW FAILURE. EVEN THOUGH A GREAT DEAL OF INFORMATION IS AVAILABLE ON HIV- INDUCED HEMATOPOIETIC DEFECTS IN PEOPLE LIVING WITH HIV, HEMATOPATHOLOGIES CAUSED BY IN-UTERO EXPOSURE OF HIV IN HIV-EXPOSED UNINFECTED (HEU) CHILDREN REMAINS LARGELY UNKNOWN. PARTICULARLY, PHYSIOLOGICAL IMPACT OF MATERNAL EXPOSURE OF HIV ON HEMATOPOIETIC STEM CELLS (HSCS) OF HEU INFANTS REMAIN COMPLETELY UNKNOWN. A VAST MAJORITY OF HEU CHILDREN HAVE HIGHER RISK OF OPPORTUNISTIC INFECTIONS WITHIN THE FIRST 6 MONTHS OF LIFE. INDEED, HEU INFANTS HAVE 2- TO 4- FOLD HIGHER MORTALITY RATE, LARGELY DUE TO RESPIRATORY INFECTIONS AND BACTERIAL SEPSIS, WHEN COMPARED WITH HIV-UNEXPOSED UNINFECTED (HU) INFANTS. EMERGING EVIDENCE ESTABLISH A STRONG LINK BETWEEN HIV-1 AND HSCS OF THE BONE MARROW. MORE IMPORTANTLY, ANTIRETROVIRAL TREATMENTS RESULT IN INCOMPLETE RESCUE OF HEMATOPOIESIS AND IMMUNE FUNCTIONS IN PATIENTS LIVING WITH HIV INFECTION. OVERALL, THESE STUDIES PROVIDE A COMPELLING RATIONALE FOR FURTHER INVESTIGATIONS INTO CELLULAR AND MOLECULAR MECHANISMS THAT CONTRIBUTE TO IMMUNE DYSFUNCTIONS AND INCREASED SUSCEPTIBILITIES TO MICROBIAL INFECTIONS IN HEU CHILDREN. TO THIS END, RESEARCH PROPOSED HERE AIMS TO UNRAVEL THE PHYSIOLOGIC IMPACT OF IN-UTERO HIV EXPOSURE ON HSC MAINTENANCE AND MYELOID DIFFERENTIATION AND TO IDENTIFY THE UPSTREAM MECHANISMS THROUGH WHICH HIV EXPOSURE IMPAIRS HSCS IN HEU CHILDREN. THE MAJOR HYPOTHESIS OF THIS STUDY IS THAT SELF-RENEWAL AND DIFFERENTIATION OF HSCS ARE COMPROMISED IN HEU CHILDREN, MOST LIKELY DUE TO HIV-ASSOCIATED CHRONIC INFLAMMATION, WHICH EVENTUALLY RESULTS IN DEFECTIVE PERIPHERAL IMMUNE FUNCTIONS. TO TEST OUR HYPOTHESIS, WE WILL USE A COMBINATION OF XENOTRANSPLANTATION, IN-VITRO CULTURE, MOLECULAR CELL BIOLOGY, BIOCHEMICAL AND SPECTRAL FLOW CYTOMETRY STUDIES. IN THE FIRST SPECIFIC AIM, WE WOULD INVESTIGATE THE PHYSIOLOGICAL AND MOLECULAR ALTERATIONS CAUSED BY HIV-EXPOSURE ON HSCS. IN THE SECOND SPECIFIC AIM, WE WOULD ASSESS MYELOID DIFFERENTIATION CAPACITIES OF HEU-HSCS AND EVALUATE THE FUNCTIONS OF HEU-HSC-DERIVED DCS AND MACROPHAGES TO MOUNT EFFECTIVE IMMUNE RESPONSES AGAINST RESPIRATORY INFECTIONS. IN THE THIRD SPECIFIC AIM, WE WOULD IDENTIFY THE CELLULAR SOURCE OF INFLAMMATION AND EVALUATE THE THERAPEUTIC BENEFIT OF INHIBITING INFLAMMATORY CIRCUITS IN HEU INFANTS. STUDIES PROPOSED IN AIMS 1, 2 & 3 ARE COMPLIMENTARY AND INFORMED BY THE DATA OF EACH OTHER, BUT NOT DEPENDENT ON THE OUTCOME OF THE OTHER AIMS. WE BELIEVE THAT STUDIES DESCRIBED HERE WOULD BE OF MAJOR CLINICAL RELEVANCE AS IT ATTEMPTS TO UNRAVEL THE CELLULAR AND MOLECULAR MECHANISMS THAT MAY BE RESPONSIBLE FOR INCREASED MORBIDITIES AND MORTALITIES IN HEU CHILDREN.