Factors Influencing T Cell Activation and Programmed Death 1 Expression in HIV-Infected Children
ABSTRACT Immune activation is the best marker of HIV disease progression in both adults and children. However, the factors that drive immune activation in HIV-infected children remain incompletely understood and may differ from those in adults. Immune activation was investigated in a cohort of 93 untreated HIV-infected children, of median age 10.8 years, and 37 HIV-uninfected children. CD8(+) T cell activation, which was higher in HIV-infected than HIV-uninfected children (p<0.001), did not correlate with viral load (R=-0.03, p=0.838). Similarly, programmed death 1 (PD-1) expression on CD8(+) T cells, which was higher in HIV-infected children than HIV-uninfected children (p<0.001), was not associated with viral load (R=0.11, p=0.40), but correlated with CD8 activation (R=0.41, p=0.002). Both CD8 activation and PD-1 expression were partially driven by the magnitude of the HIV-specific CD8(+) T cell response. CD3(+)CD4(+)CD25(hi)FoxP3(+) regulatory T cells (Tregs) were depleted in HIV-infected, compared to HIV-uninfected, children [median 1.0% (IQR 0.6, 1.9) vs. 2.6% (IQR 1.7, 3.2) CD3 cells; p<0.001]. Depletion was associated with increased CD8 activation (R=-0.27, p=0.068), suggesting that the decline in Tregs may allow immune activation to increase. Taken together, immune activation and PD-1 upregulation in children are not directly driven by viral load but may be influenced by the magnitude of the immune response to HIV itself, and to the depletion of Tregs that occurs during HIV infection. Further understanding of the factors that drive immune activation in children is critical to developing future therapeutic strategies in this population.
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ABSTRACT: IntroductionThe mechanisms sustaining the absence of complete immune recovery in HIV-infected patients upon long-term effective highly active antiretroviral therapy remain elusive. Immune activation, regulatory T cells (Tregs) or very low-level viremia (VLLV) have been alternatively suspected, but rarely investigated simultaneously. Materials and Methods We performed a cross sectional study in HIV-infected aviremic subjects (mean duration of HAART: 12 years) to concomitantly assess parameters independently associated with inadequate immunological response. Patients were classified as complete immunological responders (cIR, n = 48) and inadequate immunological responders (iIR, n = 39) depending on CD4+ T cell count (> or < 500/mm3). Clinical and virological data (including very low level viremia) were collected. In parallel, immunophenotyping of CD4+ lymphocytes, including Tregs subsets, and CD8+ T cells was performed. ResultsPercentages of activated CD4+ T cells, Tregs, effector Tregs and terminal effector Tregs were found to be significantly elevated in iIR. Neither the percentage of activated CD8+ T cells nor VLLV were found to be associated with iIR. In the multivariate analysis, nadir of CD4+ T cell count and percentage of Tregs were the only two parameters independently associated with iIR (OR=2.339, p=0.001, and OR=0.803, p=0.041). Conclusion We present here the largest study investigating simultaneously immune response to long-term HAART, activation of CD4+ and CD8+ T cells, Tregs percentages and very low-level viremia. Causative interactions between Tregs and CD4+ T cells should now be prospectively explored in a large cohort of patients.Clinical & Experimental Immunology 06/2014; 176(3). DOI:10.1111/cei.12278 · 3.28 Impact Factor
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ABSTRACT: To evaluate the immunological and viral consequences of planned treatment interruptions (PTI) in children with HIV. This was an immunological and virological sub-study of the Paediatric European Network for Treatment of AIDS (PENTA) 11 trial, which compared CD4-guided PTI of antiretroviral therapy (ART) with continuous therapy (CT) in children. HIV-1 RNA and lymphocyte subsets, including CD4 and CD8 cells, were quantified on fresh samples collected during the study; CD45RA, CD45RO and CD31 subpopulations were evaluated in some centres. For 36 (18 PTI, 18 CT) children, immunophenotyping was performed and cell-associated HIV-1 DNA analysed on stored samples to 48 weeks. In the PTI group, CD4 cell count fell rapidly in the first 12 weeks off ART, with decreases in both naïve and memory cells. However, the proportion of CD4 cells expressing CD45RA and CD45RO remained constant in both groups. The increase in CD8 cells in the first 12 weeks off ART in the PTI group was predominantly due to increases in RO-expressing cells. PTI was associated with a rapid and sustained increase in CD4 cells expressing Ki67 and HLA-DR, and increased levels of HIV-1 DNA. PTI in children is associated with rapid changes in CD4 and CD8 cells, likely due to increased cell turnover and immune activation. However, children off treatment may be able to maintain stable levels of naïve CD4 cells, at least in proportion to the memory cell pool, which may in part explain the observed excellent CD4 cell recovery with re-introduction of ART.PLoS ONE 10/2013; 8(10):e76582. DOI:10.1371/journal.pone.0076582 · 3.53 Impact Factor
Article: Immunity to HIV in Early Life[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