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)
Type
Research Project (R01)
Project #
1R01HD080474-01
Application #
8729134
Study Section
Special Emphasis Panel (ZHD1)
Program Officer
Hazra, Rohan
Project Start
Project End
Budget Start
Budget End
Support Year
1
Fiscal Year
2014
Total Cost
Indirect Cost
Name
Johns Hopkins University
Department
Pediatrics
Type
Schools of Medicine
DUNS #
City
Baltimore
State
MD
Country
United States
Zip Code
21218
Luzuriaga, Katherine (2016) Early Combination Antiretroviral Therapy Limits HIV-1 Persistence in Children. Annu Rev Med 67:201-13
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
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
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
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
Persaud, Deborah; Patel, Kunjal; Karalius, Brad et al. (2014) Influence of age at virologic control on peripheral blood human immunodeficiency virus reservoir size and serostatus in perinatally infected adolescents. JAMA Pediatr 168:1138-46
Persaud, Deborah; Luzuriaga, Katherine (2014) Absence of HIV-1 after treatment cessation in an infant. N Engl J Med 370:678