Paradoxical CD4 decline on ART: a novel, rare and perplexing immunologic outcome
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ABSTRACT:
PROVIDER: PRJNA515603 | ENA |
REPOSITORIES: ENA
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Project description:With the increasing use of Assisted Reproductive Technologies (ART) for treatment of human infertility, there is an increasing requirement for embryo culture conditions that perform as similar to nature as possible. How good the match, however, cannot be tested experimentally in human. We solved the central question of how well ART culture protocols prepare embryos for postimplantation development, under the provisions of the 'mouse embryo assay' (MEA). Our side-by-side comparison of 8 conditions [i.e., 3 culture conditions (KSOM, HTF and ISDM1) plus the in vivo system in two different mouse strains (B6 and CD1)] shows that mouse embryos cultured under ART conditions are differentially primed for postimplantation development, and that certain ART protocols outperform the oviduct. The distinct performances of blastocysts formed in ART vs. oviduct do not correlate with any significant transcriptome changes, whereas protein analysis by immunoconfocal microscopy reveals differences in the allocation of embryonic cells to the three germ layers of blastocysts. We conclude that in vitro technology is not always a defective copy of nature, and that the choice of ART protocol primes the embryos for subsequent development. 22 samples were analyzed. B6KSOM: Mouse B6 background, E3.5 blastocysts in KSOM medium, 3 biological rep B6HTF: Mouse B6 background, E3.5 blastocysts in HTF medium, 3 biological rep B6ISM1: Mouse B6 background, E3.5 blastocysts in ISM1 medium, 3 biological rep B6vivo: Mouse B6 background, E3.5 blastocysts in vivo, 3 biological rep CD1KSOM: Mouse CD1 background, E3.5 blastocysts in KSOM medium, 1 biological rep CD1HTF: Mouse CD1 background, E3.5 blastocysts in HTF medium, 3 biological rep CD1ISM1: Mouse CD1 background, E3.5 blastocysts in ISM1 medium, 3 biological rep CD1vivo: Mouse CD1 background, E3.5 blastocysts in vivo, 3 biological rep
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Project description:In study NCT00594880, we successfully administered weekly doses of pegylated interferon-α-2a (Peg-IFN-α2a) with antiretroviral therapy (ART) for 5 weeks, before continued Peg-IFN-α2a monotherapy to 12 weeks (primary endpoint) in chronic HIV-infected subjects. Subjects maintaining HIV viral load <400 copies/ml by primary endpoint were defined as responders. We now describe innate immune correlates and transcriptional profiles associated with viral control and decrease in integrated HIV DNA after Peg-IFN-α2a immunotherapy. Peripheral blood samples were obtained prior to Peg-IFN-α2a administration (ART), after 5 weeks of ART+Peg-IFN-α2a dual treatment, and after 12 weeks of Peg-IFN-α2a monotherapy. Cell subset modulation, natural killer cell (NK) function and signaling, as well as inflammatory mediators and gene expression were assessed. Results were analyzed using R.2.5.1 or MATLAB 7.10.0. Five weeks of ART+Peg-IFN-α2a preserved the frequency of immune subsets and NK cytotoxicity, while increased the levels of inflammatory mediators, and decreased cell-responsiveness to in vitro IFN-α re-stimulation. Gene expression analysis showed that induction of host restriction factors after ART+Peg-IFN-α2a was not solely predictive of a virologic response, and revealed a 108 gene signature that identified subjects who did not modulate genes after ART+Peg-IFN-α2a. A 29 gene signature along with higher NK cell activation and IFN-γ-induced protein 10 (IP-10) levels on ART, as well as higher in vitro responses to IFN-γ-induced NK cytotoxicity, and decrease in the frequency of NK bearing inhibitory receptors [i.e. killer cell immunoglobulin-like receptor, two domains, long cytoplasmic tail 1 (KIR2DL1) or KIR2DL2/DL3] and C-C chemokine receptor type 7+ (CCR7) myeloid dendritic cells after ART+Peg-IFN-α2a distinguished responders from non-responders. Reductions in integrated HIV DNA after immunotherapy were associated with expression patterns of genes that are associated with activated cell-mediated response and NK cytotoxicity. In summary, innate activation and NK cell cytotoxicity are identified as correlates of HIV control and reduction after Peg-IFN-α2a immunotherapy in ART-suppressed subjects.
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