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Principal Investigator: Grace C. John-Stewart
Organization: UNIVERSITY OF WASHINGTON
Fiscal Year: 2024
Award: $755,327
Funding agency: Eunice Kennedy Shriver National Institute of Child Health and Human Development
Abstract
Antiretroviral treatment (ART) has dramatically improved outcomes for children living with HIV (CHIV) but
poses challenges including poor adherence, side-effects, stigma, and drug resistance. An HIV cure would
address these challenges but has been elusive due to the latent HIV reservoir that persists despite ART. To
advance pediatric HIV cure, it is important to identify determinants and consequences of the pediatric HIV
reservoir. Recent adult studies have shown differences in the decline of total versus intact HIV reservoir and
have demonstrated antigen-related clonal proliferation of the reservoir, with enriched HIV provirus in memory T-
cells responding to CMV, EBV, HIV, influenza, or tetanus antigens. Acute CMV frequently occurs concurrent with
HIV infection in infancy and elicits a substantial immune response; this may result in increased HIV-proviral
infection of CMV-responsive immune cells. Indeed, we recently found that earlier and cumulative CMV viremia
were associated with increased HIV total reservoir size in CHIV. There are few epidemiologic studies to estimate
population-level impact of antigen-specific proliferation; and scant data from pediatric cohorts on intact HIV
reservoir. In addition to impeding eradication of HIV, the HIV reservoir may also influence neurocognitive
outcomes due to the trafficking between systemic and CNS compartments potentially via HIV reservoir-
containing immune cells.
We have had 4 cycles of a renewed NIH R01 (NICHD R01-023412). Cycle 3 of the R01 involved a cohort of
early-treated Kenyan infants (OPH cohort) which we have continued to follow-up to examine HIV reservoir. Our
team has optimized a novel intact proviral DNA assay (IPDA) for Kenyan subtypes which provides quantitative
estimates of intact and defective virus. Building on this work, we propose a competitive renewal of our R01 to
examine the influence of cumulative and episodic CMV/EBV activation on the intact HIV reservoir and the
relationship between HIV reservoir and long-term neurocognitive outcomes. Aim 1. Compare reservoir clonal
dynamics in children who initiated ART during concurrent acute HIV/ acute CMV infection (early-ART) to children
who initiated ART during chronic HIV/CMV (late-ART) and to mothers who initiated ART during chronic HIV/CMV.
Aim 2. Quantify the influence of CMV/EBV antigenic stimulation on HIV intact/defective reservoir size in
longitudinal molecular epidemiologic studies over >15-year follow-up. Aim 3. Determine influence of total and
intact HIV reservoir on long-term neurocognitive outcomes. These aims will provide novel data on the pediatric
HIV reservoir that will inform strategies for HIV cure and to optimize neurocognitive outcomes in CHIV.
Terms: <0-11 years old><12-20 years old><21+ years old><8 year old><8 years of age><AIDS Virus><Acceleration><Acquired Immune Deficiency Syndrome Virus><Acquired Immunodeficiency Syndrome Virus><Active Follow-up><Acute><Address><Adherence><Adolescence><Adult><Adult Human><Africa South of the Sahara><Age><Antigens><Assay><Bioassay><Biological Assay><Blood monocyte><Burkitt Herpesvirus><Burkitt Lymphoma Virus><CD4 Cells><CD4 Positive T Lymphocytes><CD4 T cells><CD4 helper T cell><CD4 lymphocyte><CD4+ T-Lymphocyte><CD4-Positive Lymphocytes><CMV><CMV infection><Cell Body><Cells><Child><Child Health><Child Youth><Childhood><Children (0-21)><Chronic><Clonality><Cytomegalic Inclusion Disease><Cytomegalovirus><Cytomegalovirus Infections><DNA><Data><Defective Hybrids><Defective Interfering Particles><Defective Interfering Viruses><Defective Viruses><Deoxyribonucleic Acid><Development><Drug resistance><EB virus><EBV><EBV Infections><Economic Income><Economical Income><Epidemiologic Research><Epidemiologic Studies><Epidemiological Studies><Epidemiology Research><Epstein Barr Virus><Epstein-Barr Virus Infections><Epstein-Barr viral infections><Evaluation><Freedom><Frequencies><Grippe><HCMV><HHV-4><HHV4><HIV><HIV Infections><HTLV-III Infections><HTLV-III-LAV Infections><Human Herpesvirus 4><Human Immunodeficiency Viruses><Human T-Lymphotropic Virus Type III Infections><Immune><Immune response><Immunes><Immunological response><Inclusion Disease><Income><Incomplete Viruses><Infant><Infection><Infectious Mononucleosis Virus><Influenza><LAV-HTLV-III><Liberty><Life><Lymphadenopathy-Associated Virus><Marrow monocyte><Molecular Epidemiology><Mothers><NICHD><NIH><National Institute of Child Health and Human Development><National Institute of Children's Health and Human Development><National Institutes of Health><Neurocognition><Neurocognitive><Outcome><Pediatric cohort><Phenotype><Population><Productivity><Proliferating><Proviruses><Recurrence><Recurrent><Resistance><Role><Salivary Gland Virus Disease><Salivary Gland Viruses><Sampling><Sub-Saharan Africa><Subsaharan Africa><T memory cell><T-Cells><T-Lymphocyte><T4 Cells><T4 Lymphocytes><Tetanus><Time><United States National Institutes of Health><Viral><Viremia><Virus><Virus Activation><Virus Induction><Virus-HIV><Work><active followup><adolescence (12-20)><adulthood><adverse consequence><adverse outcome><age 8 years><ages><antigen-specific T cells><antiretroviral therapy><antiretroviral treatment><clostridial tetanus><cohort><cost><cytomegalovirus group><design><designing><developmental><drug resistant><eight year old><eight years of age><epidemiologic investigation><epidemiology study><executive control><executive function><follow up><follow-up><followed up><followup><host response><immune system response><immunogen><immunoresponse><improved><improved outcome><incomes><infancy><infantile><integration site><kids><latent HIV reservoir><latent HIV-1 reservoir><latent HIV1 reservoir><memory T lymphocyte><monocyte><novel><pediatric><pediatric HIV><pediatric HIV disease><pediatric HIV infection><pediatric human immunodeficiency virus><pediatric human immunodeficiency virus disease><pediatric human immunodeficiency virus infection><resistance to Drug><resistant><resistant to Drug><response><side effect><social role><social stigma><stigma><thymus derived lymphocyte><trafficking><viraemia><viral activation><viral induction><viral sepsis><virusemia><youngster>