The overall goal of this application is to understand whether distinctive features of the neonatal immune system, combined with prompt initiation of combination antiretroviral therapy (cART) in perinatally-infected infants, can sufficiently alter te size and distribution of proviral reservoirs to facilitate viral remission, where cART can be stopped without viremic rebound. A major barrier to HIV-1 remission is the early establishment of latent cellular reservoirs that permit lifelong persistence of replication-competent virus. The opportunity to start cART promptly in infants may severely restrict or abort the formation of these long-lived HIV-1 reservoirs. This concept is exemplified in the recent case of the Mississippi Child in whom cART started by 31 hours of age led to HIV-1 remission. We specifically hypothesize that early or very early cART in the context of HIV-1 infection of a predominantly fetal immune system restricts the size, distribution, and replication-competence of the HIV-1 reservoirs in long-lived central memory CD4+ T cells, eventually permitting HIV-1 remission. In three different cohorts of perinatally-infected children spanning the neonatal period through adolescents, including in a planned clinical trial sponsored by the International Maternal Pediatric Adolescent AIDS Clinical Trials (IMPAACT) Network, we will use ultrasensitive molecular, immunology and virus culture assays to: 1) Confirm ongoing decay of and identify where HIV-1 proviral reservoirs reside under long-term effective cART in perinatal HIV-1 infection, 2) identify a virologic and immunologic profile of HIV-1 near-remission that indicates the appropriate timing of cART cessation after very early or early cART initiation, 3) determine if infection of neonatal CD4+ T cells is associated with diminished HIV-1 integration events and replication-deficient genomes that permit clearance of HIV-1 in neonates initiating very early cART and 4) determine whether a predominance of fetal T and/or myeloid cells at birth is associated with and predictive of rapid decay of a restricted viral reservoir. The proposed project will improve scientific knowledge on the long-term virologic and immunologic effects of early/very early HAART for infants who are now likely to survive to young adulthood. It will also provide insights into the early infection events leading up to HIV-1 reservoir formation and whether prompt antiretroviral therapy will lead to HIV-1 remission or cure, thus sparing HIV- 1 infected children a lifetime of therapy. The studies have direct relevance to the research mission of the National Institutes of Health where finding ways to achieve viral remission or cure is a top research priority area.

Public Health Relevance

Remission of HIV-1 where antiretroviral therapy may be discontinued without viremic rebound remains elusive for the 33 million infected persons living with HIV-1/AIDS, 2.5 million of whom are children younger than 13 years. A single case of HIV-1 remission in a perinatally infected child has provided optimism that prompt antiretroviral therapy of an infected neonate may be sufficient to achieve HIV-1 remission in perinatal HIV-1 infection. Work outlined in this proposal will provide insights into whether distinctive features of the neonatal immune system, combined with prompt initiation of combination antiretroviral therapy (cART) in perinatally-infected infants, can sufficiently alter proviral reservoirs to facilitate vial remission, allowing discontinuation of cART without viral rebound.

Agency
National Institute of Health (NIH)
Institute
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
Type
Research Project (R01)
Project #
5R01HD080474-04
Application #
9258459
Study Section
Special Emphasis Panel (ZHD1-DSR-A (50))
Program Officer
Lorenzo, Eric
Project Start
2014-05-01
Project End
2019-04-30
Budget Start
2017-05-01
Budget End
2018-04-30
Support Year
4
Fiscal Year
2017
Total Cost
$1,050,501
Indirect Cost
$162,629
Name
Johns Hopkins University
Department
Pediatrics
Type
Schools of Medicine
DUNS #
001910777
City
Baltimore
State
MD
Country
United States
Zip Code
21205
Rainwater-Lovett, Kaitlin; Ziemniak, Carrie; Watson, Douglas et al. (2017) Paucity of Intact Non-Induced Provirus with Early, Long-Term Antiretroviral Therapy of Perinatal HIV Infection. PLoS One 12:e0170548
Uprety, Priyanka; Lindsey, Jane C; Levin, Myron J et al. (2017) Inflammation and Immune Activation in Antiretroviral-Treated Human Immunodeficiency Virus Type 1-Infected African Infants and Rotavirus Vaccine Responses. J Infect Dis 215:928-932
Uprety, Priyanka; Lindsey, Jane C; Levin, Myron J et al. (2017) Inflammation and Immune Activation in Antiretroviral-Treated HIV-1-Infected African Infants and Rotavirus Vaccine Responses. J Infect Dis :
Uprety, Priyanka; Patel, Kunjal; Karalius, Brad et al. (2017) Human Immunodeficiency Virus Type 1 DNA Decay Dynamics With Early, Long-term Virologic Control of Perinatal Infection. Clin Infect Dis 64:1471-1478
Rainwater-Lovett, Kaitlin; Uprety, Priyanka; Persaud, Deborah (2016) Advances and hope for perinatal HIV remission and cure in children and adolescents. Curr Opin Pediatr 28:86-92
Luzuriaga, Katherine (2016) Early Combination Antiretroviral Therapy Limits HIV-1 Persistence in Children. Annu Rev Med 67:201-13
Uprety, Priyanka; Chadwick, Ellen G; Rainwater-Lovett, Kaitlin et al. (2015) Cell-Associated HIV-1 DNA and RNA Decay Dynamics During Early Combination Antiretroviral Therapy in HIV-1-Infected Infants. Clin Infect Dis 61:1862-70
Rainwater-Lovett, Kaitlin; Luzuriaga, Katherine; Persaud, Deborah (2015) Very early combination antiretroviral therapy in infants: prospects for cure. Curr Opin HIV AIDS 10:4-11
King, Caroline C; Kourtis, Athena P; Persaud, Deborah et al. (2015) Delayed HIV detection among infants exposed to postnatal antiretroviral prophylaxis during breastfeeding. AIDS 29:1953-61
Luzuriaga, Katherine; Gay, Hannah; Ziemniak, Carrie et al. (2015) Viremic relapse after HIV-1 remission in a perinatally infected child. N Engl J Med 372:786-8

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