Impact of antiretroviral protocols on dynamics of AIDS progression markers

Aims: To assess the "real life" effectiveness of different antiretroviral therapies (ART). Methods: A retrospective multicentre observational study in 150 HIV-1 vertically infected children on the progression to AIDS (study A), and in 61 HIV-1 infected children on the evolution of the most relevant markers of progression (study B). All children were categorised into four groups: untreated (NT); on monotherapy (MT); on combination therapy (dual-ART); and on potent ART (HAART). Results: No child in the HAART group progressed to AIDS, whereas 14 children in the NT and seven in the MT groups progressed to AIDS, respectively, the differences being statistically significant. There was a mean increase of 8 units of %CD4+ per year; this was greater in the HAART group than in the other groups. The mean decrease in viral load was 0.65 log(10) copies/ml per year; this was greater in the HAART group than in the NT and MT groups. The HAART group had the lowest probability of returning to baseline %CD4+ and viral load. Conclusion: Potent ART had the greatest protective effect against progression to AIDS in this observational study

Naïve and memory CD4+ T cells and T cell activation markers in HIV-1 infected children on HAART

The objective of this study was to investigate the relationship between peripheral blood CD4+ T cell subsets and routine viro-immunological markers in vertically HIV-1-infected children undergoing highly active antiretroviral therapy (HAART). CD4+ and CD8+ T cell subsets were examined by three-colour flow cytometry. Plasma viraemia was quantified by a standardized molecular assay. A negative correlation between the %CD4+ T cells and both viral load and the %CD8+ T cells was observed. A strong positive correlation between the %CD4 T cells and naïve, CD38+ and non-activated CD4+ T cell subsets was found, whereas the %CD4 T cells correlated negatively with the numbers of memory, activated and memory-activated CD4+ T cell subsets. Elevated percentages of CD8 T cells were associated with increased memory and CD4+ CD62L-T cell subsets, whereas the naïve and CD4+ HLA-DRCD38+ subsets negatively correlated with the CD8%. Co-expression of CD62L on memory CD4+ cells and high expression of HLA-DR (but not of CD38) were associated with high viral load. No association between viral load and naïve CD4+ T cells was observed. Specific CD4+ T cell subsets may be more informative than routine surrogate markers in defining the evolution of HIV infection and immune reconstitution in children

A leaky mutation in CD3D differentially affects αβ and γδ T cells and leads to a Tαβ^-Tγδ⁺B⁺NK⁺ human SCID

T cells recognize antigens via their cell surface TCR and are classified as either αβ or γδ depending on the variable chains in their TCR, α and β or γ and δ, respectively. Both αβ and γδ TCRs also contain several invariant chains, including CD3δ, which support surface TCR expression and transduce the TCR signal. Mutations in variable chains would be expected to affect a single T cell lineage, while mutations in the invariant chains would affect all T cells. Consistent with this, all CD3δ-deficient patients described to date showed a complete block in T cell development. However, CD3δ-KO mice have an αβ T cell-specific defect. Here, we report 2 unrelated cases of SCID with a selective block in αβ but not in γδ T cell development, associated with a new splicing mutation in the CD3D gene. The patients' T cells showed reduced CD3D transcripts, CD3δ proteins, surface TCR, and early TCR signaling. Their lymph nodes showed severe T cell depletion, recent thymus emigrants in peripheral blood were strongly decreased, and the scant αβ T cells were oligoclonal. T cell-dependent B cell functions were also impaired, despite the presence of normal B cell numbers. Strikingly, despite the specific loss of αβ T cells, surface TCR expression was more reduced in γδ than in αβ T cells. Analysis of individuals with this CD3D mutation thus demonstrates the contrasting CD3δ requirements for αβ versus γδ T cell development and TCR expression in humans and highlights the diagnostic and clinical relevance of studying both TCR isotypes when a T cell defect is suspected

The immunological and virological consequences of planned treatment interruptions in children with HIV infection

Contains fulltext : 126098.pdf (publisher's version ) (Open Access)OBJECTIVES: To evaluate the immunological and viral consequences of planned treatment interruptions (PTI) in children with HIV. DESIGN: 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. METHODS: 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. RESULTS: In the PTI group, CD4 cell count fell rapidly in the first 12 weeks off ART, with decreases in both naive 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. CONCLUSIONS: 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 naive 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