The origin of T cells after highly active antiretroviral therapy (HAART) in patients infected with human immunodeficiency virus 1 (HIV-1) is now under discussion. The possibility of renewed lymphopoiesis in aged thymuses is still controversial. In this work we combine the analysis of naïve T cells, T-cell receptor excision circles (TRECs), and computed tomography scanning of thymic tissue to further assess whether the thymus is involved in immune reconstitution. Fifteen antiretroviral-naïve HIV-1-infected patients were evaluated during 48 weeks of HAART. At baseline, significant correlation was present among age and both thymic volume and TRECs, and between naïve T cells and TRECs. After starting HAART, there was a significant increase at week 12 in naïve CD4 ؉ and CD8 ؉ T cells, TRECs, and thymic volume. The initial net increases in naïve T cells and TREC counts were significantly correlated. Changes in thymic volume and TRECs were also indirectly related; splitting the population into 2 groups of high and low baseline TREC levels, only the group with low TREC levels had significant increases in both TRECs and thymic volume. Thus, the increase in thymic volume might be functional, in response to depleted TREC levels. Taken IntroductionInfection by human immunodeficiency virus 1 (HIV-1) is characterized by a progressive depletion of not only naïve and memory CD4 ϩ T-cell subsets, but also the naïve subset of CD8 ϩ T cells. 1,2 These alterations can be partially corrected after inhibition of HIV-1 replication by highly active antiretroviral therapy (HAART), although the mechanism for which T-cell counts increase thereafter is still controversial. In fact, more than one mechanism might be involved. Soon after starting HAART, a rapid increase in peripheral blood CD4 ϩ T-cell counts probably reflects a redistribution from lymph node-sequestered memory T cells, 3,4 which ends after a few weeks. On the other hand, naïve CD4 ϩ and CD8 ϩ T-cell increases are slower but maintained for a longer period. 5 An especially interesting issue is whether the thymus contributes to the repopulation of naïve T cells or whether they are derived from other sources. In the setting of pediatric HIV-1 infection, naïve T-cell repopulation after antiretroviral treatment is early 6 and correlated with enlarged thymic volumes. 7 However, the thymic role in immune reconstitution of adults remains a controversial issue, due to the accepted thymic involution in adulthood. Thymic evaluation by computed tomography (CT) scans has shown a higher initial increase in naïve T-cell counts in patients with abundant thymic tissue after 48 weeks of HAART. 8 However, early increases in naïve T cells after starting HAART have been also reported in some thymectomized HIV-1-infected patients. 9 In addition, the determination of thymic output by quantification of T-cell receptor excision circles (TRECs) has been recently described. TRECs are byproducts of T-cell receptor (TCR) gene rearrangements, generated during lymphocyte maturation in the thymus. 10,11 Th...

Magnetic resonance based molecular imaging has emerged as a very promising technique for early detection and treatment of a wide variety of diseases, including cancer, neurodegenerative disorders, and vascular diseases. The limited sensitivity and specificity of conventional MRI are being overcome by the development of a new generation of contrast agents, using nanotechnology approaches, with improved magnetic and biological properties. In particular, for molecular imaging, high specificity, high sensitivity, and long blood circulation times are required. Furthermore, the lack of toxicity and immunogenicity together with low-cost scalable production are also necessary to get them into the clinics. In this work, we describe a facile, robust and cost-effective ligand-exchange method to synthesize dual T1 and T2 MRI contrast agents with long circulation times. These contrast agents are based on manganese ferrite nanoparticles (MNPs) between 6 and 14 nm in size covered by a 3 kDa polyethylene glycol (PEG) shell that leads to a great stability in aqueous media with high crystallinity and magnetization values, thus retaining the magnetic properties of the uncovered MNPs. Moreover, the PEGylated MNPs have shown different relaxivities depending on their size and the magnetic field applied. Thus, the 6 nm PEGylated MNPs are characterized by a low r2/r1 ratio of 4.9 at 1.5 T, hence resulting in good dual T1 and T2 contrast agents under low magnetic fields, whereas the 14 nm MNPs behave as excellent T2 contrast agents under high magnetic fields (r2 = 335.6 mM(-1) s(-1)). The polymer core shell of the PEGylated MNPs minimizes their cytotoxicity, and allows long blood circulation times. This combination of cellular compatibility and excellent T2 and r2/r1 values under low magnetic fields, together with long circulation times, make these nanomaterials very promising contrast agents for molecular imaging.

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