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Principal Investigator: Mathias Lichterfeld
Organization: HARVARD UNIVERSITY D/B/A HARVARD SCHOOL OF PUBLIC HEALTH
Fiscal Year: 2023
Award: $82,537
Funding agency: Eunice Kennedy Shriver National Institute of Child Health and Human Development
Project Summary/Abstract, Immune Control (Project 4)
Finding a cure for HIV-1 infection is of particular importance for the growing number of HIV-1-infected infants,
children and teenagers who will have to take lifelong antiretroviral therapy if curative treatment options will not
be available. Recent advances suggest that achieving a functional cure of HIV-1 infection may not require
complete elimination of all intact HIV-1 proviruses; instead, it may be sufficient to target intact proviruses
integrated in permissive chromatin positions that support HIV-1 transcription and are more susceptible to viral
reactivation signals. This model for a cure of HIV-1 infection seems to be exemplified by elite controllers, in whom
we documented a highly distinct chromosomal integration site landscape characterized by location of intact
proviruses in heterochromatin regions. Notably, such a “blocked and locked” pattern of proviral integration sites
likely represents the consequence of cellular immune selection forces that have successfully eliminated
proviruses in accessible chromatin locations, while proviruses in heterochromatin positions can persist long term.
This concept raises the possibility that immune-mediated selection mechanisms can be intensified or accelerated
through therapeutic vaccination, and may be preferentially inducible in HIV-1-infected infants starting ART at
early stages of infection. Here, we propose to conduct a detailed analysis of viral reservoir dynamics in infants
undergoing dolutegravir-containing antiretroviral therapy (ART), with the ultimate aim of informing future clinical
trials designed to induce a “blocked and locked” viral reservoir structure through personalized therapeutic mRNA
vaccines incorporating autologous proviral sequences. In specific aim 1, we will investigate viral sequences
near birth and determine the frequency of intact proviruses in infants started on dolutegravir-containing ART,
relative to existing corresponding data from infants undergoing lopinavir/ritonavir-containing ART; these studies
will allow us to track the natural evolution of intact and defective proviruses, and generate an atlas of intact
proviruses that can be considered for inclusion into personalized therapeutic mRNA vaccines to be tested in
future proof-of-principle studies. In specific aim 2, we will longitudinally evaluate the chromosomal positioning
of intact proviruses during continuous ART in these infants; we hypothesize that immune-mediated selection
mechanisms can at least in some infants promote and facilitate a proviral integration site landscape that
approximates the “blocked and locked” proviral architecture observed in elite controllers; such selection
mechanisms may then be further intensified through planned personalized mRNA vaccination in future studies.
In specific aim 3, we will conduct pioneering studies to characterize the quantity and functionality of cellular and
humoral immune responses induced by the licensed SARS-CoV2 mRNA vaccine in HIV-1-infected pediatric
patients from Botswana; such studies will be highly informative for all future HIV-1-specific therapeutic
vaccination approaches on the mRNA platform.
Terms: <0-11 years old><2019 novel corona virus><2019 novel coronavirus><2019-nCoV><AIDS Virus><Acceleration><Acquired Immune Deficiency Syndrome Virus><Acquired Immunodeficiency Syndrome Virus><Adolescent><Adolescent Youth><Architecture><Atlases><Autologous><Bechuanaland><Binding><Biotech><Biotechnology><Birth><Botswana><COVID-19 vaccination><COVID-19 virus><COVID19 vaccination><COVID19 virus><Cell Body><Cell Communication and Signaling><Cell Signaling><Cells><Child><Child Youth><Children (0-21)><Chromatin><Chromosome 19><Clinical Trials Design><CoV-2><CoV2><Country><Data><Development><Disease><Disorder><Drugs><Early treatment><Engineering / Architecture><Evolution><Frequencies><Future><Gene Transcription><Genes><Genetic Transcription><HIV><HIV vaccine><HIV-1><HIV-I><HIV/AIDS Vaccines><HIV1><Heterochromatin><Human Genome><Human Immunodeficiency Virus Type 1><Human Immunodeficiency Viruses><Human immunodeficiency virus 1><Immune><Immune Cell Activation><Immune response><Immunes><Immunochemical Immunologic><Immunologic><Immunological><Immunological response><Immunologically><Immunologics><Infant><Infection><Intracellular Communication and Signaling><Kaletra><LAV-HTLV-III><Length><Licensing><Location><Lopinavir/Ritonavir><Lymphadenopathy-Associated Virus><Mass Vaccinations><Mediating><Medication><Memory><Memory B Cell><Memory B-Lymphocyte><Messenger RNA><Methodology><Modeling><Molecular Interaction><NGS Method><NGS system><Non-Polyadenylated RNA><Parturition><Patients><Pattern><Persons><Pharmaceutic Preparations><Pharmaceutical Preparations><Position><Positioning Attribute><Predisposition><Pregnant Women><Probability><Provirus Integration><Proviruses><RNA><RNA Expression><RNA Gene Products><RNA immunization><RNA vaccination><RNA vaccine><RNA-based vaccine><Research><Research Resources><Resources><Ribonucleic Acid><SARS corona virus 2><SARS-CO-V2><SARS-COVID-2><SARS-CoV-2><SARS-CoV-2 vaccination><SARS-CoV2><SARS-associated corona virus 2><SARS-associated coronavirus 2><SARS-coronavirus-2><SARS-related corona virus 2><SARS-related coronavirus 2><SARSCoV2><Satellite DNA><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 CoV 2><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 coronavirus 2><Severe acute respiratory syndrome coronavirus 2 vaccination><Severe acute respiratory syndrome related corona virus 2><Signal Transduction><Signal Transduction Systems><Signaling><Structure><Susceptibility><T cell response><Techniques><Teen><Teenagers><Testing><Therapeutic><Transcription><VAC-TX><Vaccination><Vaccine Design><Vaccine Research><Vaccine Therapy><Vaccines><Viral><Viral reservoir><Viremia><Virus reservoir><Virus-HIV><Work><Wuhan coronavirus><ZNFs><Zn-finger nuclease><anti-retroviral therapy><anti-retroviral treatment><antiretroviral therapy><antiretroviral treatment><biological signal transduction><child patients><chromosomal location><chromosomal position><chromosome location><clinical significance><clinically significant><coronavirus disease 2019 vaccination><coronavirus disease 2019 virus><coronavirus disease-19 virus><curative intervention><curative therapeutic><curative therapy><curative treatments><design><designing><developmental><drug/agent><early therapy><expectant mother><expecting mother><hCoV19><host response><human immunodeficiency virus vaccine><human whole genome><immune activation><immune system response><immunogenicity><immunoresponse><improved><infant infection><infected infant><infected neonate><infected newborn><integration site><juvenile><juvenile human><kids><mRNA><mRNA immunization><mRNA vaccination><mRNA vaccine><mRNA-based vaccine><nCoV2><neonatal infection><new approaches><newborn infection><next gen sequencing><next generation sequencing><nextgen sequencing><novel><novel approaches><novel strategies><novel strategy><patient population><pediatric HIV><pediatric human immunodeficiency virus><pediatric patients><permissiveness><personalized therapeutic><precision medicine><precision-based medicine><pregnant mothers><response><sequencing platform><technology platform><technology system><teen years><teenage><theories><therapeutic vaccination><therapeutic vaccine><treatment vaccines><vaccinate against COVID-19><vaccinate against COVID19><vaccinate against SARS-CoV-2><vaccinate against coronavirus disease 2019><vaccinate against severe acute respiratory syndrome coronavirus 2><vaccination against COVID-19><vaccination against COVID19><vaccination against SARS-CoV-2><vaccination against Severe acute respiratory syndrome coronavirus 2><vaccination against coronavirus disease 2019><vaccine for the treatment><vaccine for treatment><vaccine-related research><viraemia><viral sepsis><virusemia><youngster><zinc finger nuclease><zinc finger nucleases>