In this study, we examined the effect of in vivo treatment of acutely SIV-infected Mamu-A*01+ rhesus macaques with IL-15. IL-15 treatment during acute infection increased viral set point by 3 logs and accelerated the development of simian AIDS in two of six animals with one developing early minimal lesion SIV meningoencephalitis. Although IL-15 induced a 2- to 3-fold increase in SIV-specific CD8+ T cell and NK cell numbers at peak viremia and reduced lymph node (LN) SIV-infected cells, this had no impact on peak viremia and did not lower viral set point. At viral set point, however, activated SIV-specific CD8+ T cells and NK cells were reduced in the blood of IL-15-treated animals and LN SIV-infected cells were increased. Week 30 LN from IL-15-treated animals had significantly increased Gag-specific CD8+ T cell numbers, whereas total cell, lymphocyte, and CD4+ T cell numbers were reduced. IL-15 treatment significantly reduced anti-SIV Ab concentrations at week 3 and viral set point. IL-15 increased Ki-67+CD4+ T cells at week 1 of treatment and reduced blood CCR5+ and CD45RA−CD62L− CD4+ T cells. The frequency of day 7 Ki-67+CD4+ T cells strongly correlated with viral set point. These findings suggest that CD4+ T cell activation during acute infection determines subsequent viral set point and IL-15 treatment by increasing such activation elevates viral set point. Finally, IL-15-treated acutely SIV-infected primates may serve as a useful model to investigate the poorly understood mechanisms that control viral set point and disease progression in HIV infection.

What governs the increased apoptosis sensitivity of HIV-specific CD8 ؉ T cells is poorly understood. Here, we examined the involvement of mitochondria in this apoptosis. Remarkably higher mitochondrial mass (MM) was found in HIV-specific compared with CMV-specific CD8 ؉ T cells from HIV ؉ patients and this could not be attributed to their different differentiation status. MM High phenotype characterized those CD8 ؉ T cells from HIV ؉ patients that are sensitive to spontaneous and CD95/Fas-induced apoptosis. CD38 expression did not correlate with high MM, whereas Bcl-2 levels were significantly reduced in both CD38 ؉ and CD38 ؊ HIVspecific CD8 ؉ T cells. Although CD38 ؉ HIV-specific CD8 ؉ T cells were more susceptible to apoptosis, CD38 expression does not explain on its own the selective apoptosis sensitivity of HIV-specific CD8 ؉ T cells, as CD38 ؊ HIV-specific CD8 ؉ T cells were more apoptotic than CD38 ؉ CMV-specific ones. Proapoptotic HIVspecific CD8 ؉ T cells were CD38 ؉ Bcl-2 Low MM High . Copolarization of mitochondria with CD95/Fas capping, very early in CD95/Fas-induced apoptosis of HIV-specific CD8 ؉ T cells, suggests that mitochondria act as an amplification step for this apoptosis. Thus, an extensive mitochondrial network contributes to apoptosis sensitivity of CD8 ؉ T cells and, when this occurs together with reduced levels of Bcl-2 and chronic activation, determines the proapoptotic state of HIV-specific CD8 ؉ T cells. IntroductionCD8 ϩ T-cell response is a critical player for controlling HIV infection and AIDS progression. 1,2 However, HIV-specific CD8 ϩ T cells ultimately fail to control the virus. Various mechanisms related either to HIV-infected cells or to intrinsic defects in CD8 ϩ T cells themselves have been proposed to explain this failure. [3][4][5] Among others, apoptosis of HIV-specific CD8 ϩ T cells has been suggested as a strategy employed by HIV to evade the immune system. 6,7 What governs this apoptosis sensitivity, however, remains to be elucidated.CD8 ϩ T cells from HIV-infected patients are susceptible to spontaneous and CD95/Fas-induced apoptosis. [8][9][10] We recently found HIVspecific CD8 ϩ T cells to be highly sensitive to apoptosis 11 whereas this is not the case for CMV-specific CD8 ϩ T cells from HIV ϩ individuals. 11 This sensitivity is associated with a remarkable down-regulation of Bcl-2 and Bcl-xL antiapoptotic molecules, 12 suggesting a role of mitochondria in this apoptotic process. Several studies have revealed a mitochondrial dysfunction in T cells during HIV infection. 13,14 CD95/ Fas cross-linking initiates a complex signaling process involving CD95/Fas capping and formation of death-inducing signaling complex (DISC), 15,16 ultimately leading to activation of the executor caspase-3 directly by caspase-8 or through mitochondrial-secreted proapoptotic factors. 17 The cross-talk of these 2 pathways in apoptosis of primary T cells, particularly in CD8 ϩ T cells from HIV ϩ patients, is currently unknown. Furthermore, no studies have addressed the role and impact of ...

Differentiation and survival defects of human immunodeficiency virus (HIV)-specific CD8؉ T cells may contribute to the failure of HIV-specific CD8 ؉ T cells to control HIV replication. It is not known, however, whether simian immunodeficiency virus (SIV)-infected rhesus macaques show comparable defects in these virus-specific CD8 ؉ T cells or when such defects are established during infection. Peripheral blood cells from acutely and chronically infected rhesus macaques were stained ex vivo for memory subpopulations and examined by in vitro assays for apoptosis sensitivity. We show here that SIV-specific CD8 ؉ T cells from chronically SIV infected rhesus macaques show defects comparable to those observed in HIV infection, namely, a skewed CD45RA ؊ CD62L ؊ effector memory phenotype, reduced Bcl-2 levels, and increased levels of spontaneous and CD95-induced apoptosis of SIV-specific CD8 ؉ T cells. Longitudinal studies showed that the survival defects and phenotype are established early in the first few weeks of SIV infection. Most importantly, they appear to be antigen driven, since most probably the loss of epitope recognition due to viral escape results in the reversal of the phenotype and reduced apoptosis sensitivity, something we observed also for animals treated with antiretroviral therapy. These findings further support the use of SIV-infected rhesus macaques to investigate the phenotypic changes and apoptotic defects of HIV-specific CD8 ؉ T cells and indicate that such defects of HIV-specific CD8 ؉ T cells are the result of chronic antigen stimulation.

The authors investigated the bactericidal activity of high-chlorine-content nanoporous carbide-derived carbon (CDC) against the Gram-positive, spore-forming bacterium Bacillus anthracis and the common Gram-negative enteric bacterium Escherichia coli. Chlorine-loaded nanoporous CDC produced by thermochemical etching of metals and metalloids by chlorination of carbides can retain up to 40 wt % of chlorine. Etching temperature and the structure and composition of carbides allow tuning the porosity of CDC. The CDC chlorine content depends on the synthesis temperature, pore size, and metal carbide used during preparation. It was observed that chlorine-loaded CDC killed up to 100% of exposed E. coli and B. anthracis spores and vegetative cells in a dose and time-dependent manner. CDC containing higher concentrations of chlorine killed bacteria to a greater extent and faster than did CDC containing lesser concentrations of chlorine. The results suggest that chlorine-loaded CDC can be used in several commercial, defense, and industrial activities and processes to kill bacteria.