Emerging Perspectives on Perinatal HIV: Intact Proviral Dynamics and Cure Strategies
Overview
Children with perinatal HIV who initiate antiretroviral therapy (ART) early exhibit significantly lower levels of intact HIV proviruses compared to those who start ART later. This difference is associated with a more rapid decline in intact proviral DNA during the first five years of ART, highlighting the importance of early treatment in reducing HIV reservoirs and informing cure strategies.
Background
Perinatal HIV infection affects millions of children worldwide, with challenges in maintaining sustained virologic suppression due to adherence issues. HIV persists in long-lived reservoirs of infected cells harboring proviral DNA, of which only intact proviruses can cause viral rebound after ART cessation. Recent advances have enabled differentiation between intact and defective proviruses, providing new insights into HIV persistence and reservoir dynamics in both adults and children. Understanding these dynamics is critical for developing interventions aimed at ART-free remission or cure.
Data Highlights
Group
Intact Proviral DNA Copies/million PBMC (Year 5)
% Samples Below Detection
Early Suppressive ART (≤1 year)
2.0
~66%
Late Suppressive ART (1–5 years)
6.6
11%–31%
Key Findings
Early ART initiation (by 1 year of age) leads to significantly lower intact proviral DNA levels compared to later ART initiation (1–5 years).
Two-thirds of samples from early ART-treated children had undetectable intact proviruses, whereas only 11%–31% of late ART-treated samples were below detection.
Intact proviral DNA declines biphasically, with a rapid initial decrease followed by a slower decay phase, consistent with adult data.
Smaller HIV reservoirs in early treated children may be due to more effective immune clearance and/or starting with a smaller reservoir at ART initiation.
Naive and memory CD4+ T cells in children treated as infants both harbor intact proviruses and can clonally expand, influenced by the developing immune system.
Cases of ART-free remission have been reported in children who received very early ART and achieved undetectable HIV DNA, supporting early treatment as a key strategy.
Clinical Implications
Early initiation of ART in children with perinatal HIV is crucial to minimize the size of the intact proviral reservoir, which is associated with better prospects for achieving ART-free remission. Clinicians should prioritize early diagnosis and prompt treatment initiation. Additionally, future cure strategies may benefit from combining early ART with interventions that accelerate clearance of replication-competent proviruses.
Conclusion
The evidence underscores the importance of early ART initiation in reducing intact HIV reservoirs in children with perinatal infection, providing a foundation for developing effective cure strategies. Continued research into reservoir dynamics and immune responses in this population is essential to advance towards HIV remission and cure.
References
Khetan et al. -- Characterization of Intact and Defective HIV Proviruses in Perinatal Infection
IMPAACT P1115 Trial -- ART-Free Remission in Early Treated Children
Tatelo Study -- HIV DNA and Plasma RNA Suppression with Broadly Neutralizing Antibodies
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