Understanding the extent to which early antiretroviral therapy (ART) can limit the establishment and persistence of the HIV reservoir is an important step to designing interventions aimed at achieving HIV cure. We measured the markers of HIV persistence and HIV-specific immunity in early treated children.
This is a cross-sectional study that enrolled 15 children older than 2 years of age who initiated ART before 6 months of age and had sustained viral suppression. Quantification of total and integrated HIV DNA, and 2-LTR circles in CD4 T cells, fourth generation HIV enzyme immunoassay, and CD4 and CD8 T-cell responses to gag/env peptides by intracellular cytokine staining of CD4 and CD8 T cells were performed.
The median current age was 6.3 years and age at ART initiation was 17 weeks. The median duration of viral suppression was 6 years, and all had HIV RNA less than 50 copies/ml. The median CD4 was 44%. The median total HIV DNA was 132 copies/10 CD4 T cells (range 11-1804) and integrated HIV DNA was 17 copies/10 CD4 T cells (range 0-516), and no one had detectable 2-LTR circles. Nine of the 15 children (60%) had undetectable or extremely low integrated HIV DNA (<20 copies/10 CD4 T cells). All except one (93%) had undetectable HIV-specific CD4/CD8 cell responses and seven (47%) had nonreactive enzyme immunoassay.
Early ART resulted in very low levels of markers of HIV persistence and undetectable HIV-specific immune responses in the majority of HIV-infected children who started ART before 6 months of age.
"The frequency of latently infected CD4 T cells in children strongly depends on early initiation of ART and the time to achieve virologic suppression (192). A cross-sectional study found low to undetectable levels of integrated pro-viral DNA in CD4 cells of children starting treatment before 6 months of age after more than 3 years of follow-up (193). A recent longitudinal study compared perinatally infected youth initiating treatment before or after 3 months of age (194). "
[Show abstract][Hide abstract] ABSTRACT: The developing immune system is adapted to the exposure to a plethora of pathogenic and non-pathogenic antigens encountered in utero and after birth, requiring a fine balance between protective immunity and immune tolerance. In early stages of life, this tolerogenic state of the innate and adaptive immune system and the lack of immunological memory render the host more susceptible to infectious pathogens like HIV. HIV pathogenesis is different in children, compared to adults, with more rapid disease progression and a substantial lack of control of viremia compared to adults. Plasma viral load remains high during infancy and only declines gradually over several years in line with immune maturation, even in rare cases where children maintain normal CD4 T-lymphocyte counts for several years without antiretroviral therapy (ART). These pediatric slow progressors also typically show low levels of immune activation despite persistently high viremia, resembling the phenotype of natural hosts of SIV infection. The lack of immunological memory places the fetus and the newborn at higher risk of infections; however, it may also provide an opportunity for unique interventions. Frequencies of central memory CD4+ T-lymphocytes, one of the main cellular reservoirs of HIV, are very low in the newborn child, so immediate ART could prevent the establishment of persistent viral reservoirs and result in "functional cure." However, as recently demonstrated in the case report of the "Mississippi child" who experienced viral rebound after more than 2 years off ART, additional immunomodulatory strategies might be required for sustained viral suppression after ART cessation. In this review, we discuss the interactions between HIV and the developing immune system in children and the potential implications for therapeutic and prophylactic interventions.
Frontiers in Immunology 08/2014; 5:391. DOI:10.3389/fimmu.2014.00391
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