R us se ll -L od ri gue, C hr is to ph er Monjure,

Cytosine-phosphate-guanine class C (CpG-C) immunostimulatory sequence oligodeoxynucleotides (ISS-ODNs) activate human B cells and dendritic cells (DCs), properties that suggest potential use as a novel adjuvant to enhance vaccine efficacy. After demonstrating that the CpG-C ISS-ODN C274 activates macaque DCs, we examined in vitro activation of macaque B cells by C274 as a prelude to evaluation of this molecule as an adjuvant in the testing of candidate human immunodeficiency virus vaccines in the rhesus macaque-simian immunodeficiency virus (SIV) model. C274 induced macaque CD20(+) B cells to proliferate more strongly than CD40 ligand or CpG-B ISS-ODN. C274 enhanced B cell survival; increased viability was most evident after 3-7 days of culture. Increased expression of CD40, CD80, and CD86 by B cells was apparent within 24 h of exposure to C274 and persisted for up to 1 week. C274-stimulated, B cell-enriched and peripheral blood mononuclear cell suspensions from naïve and immunodeficiency virus-infected monkeys secreted several cytokines [e.g., interleukin (IL)-3, IL-6, IL-12, interferon-alpha] and chemokines [e.g., monocyte chemoattractant protein-1/CC chemokine ligand 2 (CCL2), macrophage-inflammatory protein-1alpha/CCL3, IL-8/CXC chemokine ligand 8]. In comparison, exposure of macaque B cells to SIV had minimal impact on surface phenotype, despite inducing cytokine and chemokine production in cells from infected and uninfected animals. These observations emphasize the need to identify strategies to optimally boost immune function, as immunodeficiency viruses themselves only partially activate B cells and DCs. The ability of C274 to stimulate B cells and DCs in healthy and infected monkeys suggests its possible use as a broad-acting adjuvant to be applied in the rhesus macaque model for the development of preventative and therapeutic vaccines.

No abstract

The goal of this study was to define, by surgical removal of the thymus in juvenile rhesus macaques, the role of the thymus in peripheral T cell homeostasis and to assess the significance of thymic output in SIV infection. By monitoring the changes in phenotypic T cell markers as well as in the numbers of TCR excisional circles -a recently described marker for recent thymic emigrants -following thymectomy, we present evidence that surgical thymectomy in juvenile macaques results in a faster decay of peripheral CD4 + cells, but does not cause a substantial shift in CD45RA + and CD45RA -populations. We were able to measure a thymic output of 0.32% and 0.21% per day of CD4 + and CD8 + cells, respectively. No compensatory extra-thymic source was detected in lymphoid tissues, although there was a small compensatory increase in T cell proliferation in the peripheral T cell pool. After SIV infection, thymectomized animals did not have higher viral loads, greater T cell decay, or faster disease progression. We therefore conclude that peripheral destructive processes, rather than a loss of thymic output, appear to be the main causes of T cell depletion in SIV infection.