The cytokine network in HIV infection

Cytokines are major controller of HIV replication and represent, at the same time, a target for viral-induced immune dysregulation. This mutual relationship has profound implications for both active HIV replication and immune-mediated governance of latency; in addition, cytokines have therapeutic value in the perspective of immune reconstitution. In the current article we will review the most relevant aspects emerged in almost 20 years of research in this area with particular reference to the distinct, but interconnected contribution of the most simple (cell lines) to the most complex (animal) models of HIV infection.     

Disruption of the gamma c cytokine network in T cells during HIV infection

The common gamma chain (gammac)-sharing cytokines (IL's-2, 4, 7, 9, 15, and 21) play a vital role in the survival, proliferation, differentiation and function of T lymphocytes. As such, disruption of their signaling pathways would be expected to have severe consequences on the integrity of the immune system. Indeed, it appears that the signaling network of these cytokines is both disrupted and exploited by HIV at various stages of infection. IL-2 secretion and signaling downstream of its receptor are impaired in T cells from chronically-infected HIV+ patients. Elevated plasma IL-7 levels and decreased IL-7Ralpha expression in patient T cells results in significantly decreased responsiveness to this critical cytokine. Interestingly, IL-2 and IL-15 are also able to render CD4+ T cells permissive to HIV infection through their influence on the activity of the APOBEC3G deaminase enzyme. Herein, we describe the current state of knowledge on how the gammac cytokine network is affected during HIV infection, with a focus on how this impairs CD4+ and CD8+ T cell function while also benefiting the virus itself. We also address the use of cytokines as adjuncts to highly active antiretroviral therapy to bolster immune reconstitution in infected patients.     

Dissecting the cytokine network

Understanding the cytokine network is a very complex task. One way is the dissection of the network by the generation and analysis of mutant mice. As the technology advances more sophisticated approaches toward this goal become available and proof to disclose an even more complex picture of the cytokine network as we initially anticipated. This increase in complexity leads to fascinating challenges in the future.     

The effects of recombinant bovine interferon-alpha on fertility in ewes

Recombinant bovine interferon-alpha(I)1 (rBolFN-alpha) may be useful for enhancing fertility in sheep because it has extensive sequence homology with ovine trophoblast protein-1. To test the effectiveness of rBolFN-alpha, several experiments were performed in which bred females were given intramuscular injections of rBolFN-alpha around the time of maintenance of the corpus luteum. Treatment with rBolFN-alpha enhanced the fertility of ewes that were bred via natural service or embryo transfer of whole or demi-embryos. Interferon treatment was successful in enhancing lambing rate if injections were given twice daily from Days 11 to 18, 12 to 14, 12 to 15 or 12 to 16. Overall, the lambing rate for ewes bred via natural service was 94/126 (74.6%) for control ewes and 101/126 (80.2%) for rBolFN-alpha treated ewes. Litter size was not affected by treatment. Interferon treatment was not successful in increasing the lambing rate if given as a single injection on Day 12 or as a series of once-daily injections from Days 11 to 16. These results demonstrate that rBolFN-alpha can increase the lambing rate in ewes.     

Complex cytokine regulation of tissue fibrosis

Tissue fibrosis, a serious and even deadly complication of chronic inflammation and environmental exposures, is regulated by a host of factors including interactions with the extracellular matrix, surface of inflammatory cells, hormones, and an extremely complex and redundant network of profibrotic cytokines. The nature of mechanisms by which cytokines regulate fibrosis is dual - indirect, through attraction of inflammatory cells, and direct, through binding to specific receptors on fibroblasts and stimulating proliferation, collagen production and secretion of autocrine factors. This review focuses on systematizing the direct effects of cytokines on fibroblasts. Understanding of the complexity of the cytokine-driven mechanisms of fibrosis is important for identification of potential molecular targets for future pharmacological interventions in prevention and treatment of tissue fibrosis.     

Mutational effects on O(6)-methylguanine-DNA methyltransferase from hyperthermophile: contribution of ion-pair network to protein thermostability

Ion pairs have been considered to be general stabilizing factors in hyperthermophilic proteins, but the present experimental data cannot fully explain how ion pairs and ion-pair networks contribute to the stability. In this paper, we show experimental evidence that not all of the internal ion pairs contribute to the thermal and thermodynamic stability, using O(6)-methylguanine-DNA methyltransferase from Thermococcus kodakaraensis KOD1 (Tk-MGMT) as a model protein. Of three mutants in which an inter-helical ion pair was disrupted, only one mutant (E93A) was shown to be destabilized. Delta G of E93A was lower by approximately 4 kJ mol(-1) than that of the wild type, and E93A unfolded one order of magnitude faster than did the wild type and other variants. Glu 93 has unique properties in forming an ion-pair network that bridges the N- and C-terminal domains and connects three helices in the protein interior.     

Dosing schedule-dependent change in the disruptive effects of interferon-alpha on the circadian clock function

Altered homeostatic regulation, including the disturbance of circadian rhythms, is often observed in patients undergoing interferon (IFN) therapy. We reported previously that IFN-alpha has the ability to modulate the circadian clock function at the molecular level and that the alteration of clock function could be overcome by changing the dosing schedule. In this study, we investigated the influence of IFN-alpha on the intrinsic biological rhythms in mice by comparing two dosing schedules, continuous administration and repetitive injection. Continuous administration of IFN-alpha to mice decreased the rhythm amplitude of locomotor activity, body temperature, leukocyte counts, and plasma corticosterone levels. The treatment also suppressed the oscillation in the expression of clock genes in the liver. On the other hand, modulation effects were scarcely observed in mice treated with repetitive injection of IFN-alpha. These results indicate that treatment with IFN-alpha does not always modulate the circadian clock function. This notion was also supported by in vitro findings that the inhibitory action of IFN-alpha on the expression of clock genes was dependent on its exposure time to cells. The alteration of clock function induced by IFN-alpha could be avoided by optimizing the dosing schedule.     

The breakdown of the cytokine network subsequent to human immunodeficiency virus infection

The acquired immunodeflciency syndrome (AIDS) is a clinically multifaceted disease induced by infection with the human immunodeficiency virus (HIV). HIV infection results in a complex pattern of immunologic alterations that leads to the development of AIDS in the majority of HIV seropositive (HIV+) individuals. The reduction in CD4 T lymphocyte counts is the hallmark of HIV infection; nevertheless, long before the reduction in CD4 counts reaches critical levels, a series of profound and complex defects that impair the function of CD4 T lymphocytes can be detected. Thus, HIV infection is characterized by quantitative and qualitative defects affecting CD4 T lymphocytes. It was suggested recently that programmed cell death (PCD) is an important mechanism leading to CD4 depletion in HIV infection, and that susceptibility of peripheral lymphocytes to PCD is differentially regulated by diverse cytokines. Thus, type 1 cytokines would protect CD4 lymphocytes against PCD, whereas type 2 cytokines would not protect against, and could augment, PCD. We suggest that the qualitative alterations of the immune response provoke the CD4 depletion characteristic of HIV disease via type 2 cytokinemediated augmentation of PCD, and are therefore ultimately responsible for the progression of HIV infection. Finally, we summarize recent data showing that three correlates of disease progression: emergence of HIV strains with syncitium-inducing ability (SI), type 1-to-type 2 cytokine shift, and CD4 depletion, are significantly associated, suggesting a complex interconnected virologic-immunologic pathogenesis of HIV infection.     

Evaluation of the energetic contribution of an ionic network to beta-sheet stability

We have evaluated the interaction energy of a three-residue ionic network constructed on the beta-sheet surface of protein G using double mutant cycles. Although the two individual ion pairs were each stabilizing by 0.6 kcal/mol, the excess gain in stability for the triad was small (0.06 kcal/mol).     

Cell surface and cytokine phenotypes of skin immunocompetent cells involved in ultraviolet-induced immunosuppression

Immunocellular migrations out of and into the skin and modulations of functional cell surface molecules on antigen-presenting cells (APCs), as well as their immunoregulatory cytokine production, are important factors involved in the mechanism of UV-induced immunosuppression and tolerance. Of particular interest here are the effects of low-dose UVB exposures that can suppress the ability of a contact sensitizer to induce contact hypersensitivity (CHS) through the site (local immunosuppression) without inducing suppression of CHS induced through skin distant to the UV exposure. Such UV-irradiated skin has many changes with respect to composition of immunocompetent cells and cytokine production. After UV exposure, Langerhans cells/dendritic cells migrate from the skin to draining lymph nodes (DLNs) as they do from contact sensitizer-applied normal skin. On the other hand, UV causes monocytic/macrophagic cells to infiltrate into the dermis and then into the epidermis; these can also be shown to be induced by contact sesitizers to migrate to DLNs. Alterations in cell surface and immunoregulatory cytokine phenotypes of the cutaneous APCs in both the skin and DLNs are critical for CHS suppression and tolerance induction. Here we describe the phenotypic changes of immunocompetent cells in UV-irradiated skin in regard to CHS suppression and tolerance and methodologies to approach this area.     

The myeloid cytokine network in AIDS pathogenesis

The complex pathogenesis of HIV and SIV infections involves the activation, dysfunction, and increased turnover of numerous immune cell subsets. Myeloid cells, including monocytes, macrophages, and myeloid dendritic cells (mDCs), are a particularly relevant cell type capable of providing targets for virus infection as well as a source of immunomodulatory cytokines and chemokines. Here, we review recent literature about the interplay between HIV/SIV and myeloid cells, including viral infection, type I interferon signaling, and the contribution of myeloid cells to HIV-associated immune activation. Understanding the cytokine and chemokine networks in which monocytes, macrophages, and mDCs participate during HIV infection may yield new insights into the pathogenesis of the disease.     

Effects of the polysaccharide from Pholiota nameko on human cytokine network in serum

Some physico-chemical characterizations of Pholiota nameko polysaccharides (PNPS-1) were studied, including sulfate content, UV/visible and infrared spectra, also the variation of cytokine communication network in serum to clarify the pharmacological effects of PNPS-1 by determination of 39 cytokines in serum of healthy volunteers. The result proved that PNPS-1 possessed significant anti-inflammatory activity. Further, we use Microsoft Visio 2007 software to map out the cell-cell communication network diagram. The analysis to the diagram suggested that PNPS-1 could take effect on the innate and adaptive immunity and hematopoiesis of volunteers.     

基于聚类系数的DNA序列性质的复杂网络研究

利用一种新的基于图论理论的DNA序列(片段)分析的方法,即通过复杂网络研究生物体的拓扑结构,主要通过测量聚类系数(集团系数)构建网络的拓扑结构。依据DNA序列的前缀、后缀关联性质构造了所选取DNA序列(片段)的相关网络,发现该网络分布满足幂率特征,有较大的聚类系数。结果表明构建得到的网络同时满足小世界网络和无尺度网络的特征,证明DNA序列不全是随机的序列,而是有随机扰动的确定结构的序列。     

The effects of immunosuppression on regulatory CD4(+)CD25(+) T cells: impact on immunosuppression selection in transplantation

During immune response and T-cell activation, both effector T cells and regulatory T(T(reg)) cells are activated and regulated simultaneously by both positive and negative pathways. CD4(+)CD25(+) T(reg) cells play a critical role in immune tolerance to self antigens as well as to allografts in some transplant settings. Effective immunosuppressive regimens significantly reduced the incidence of acute allograft rejection in patients following organ transplantation. However, the impact of immunosuppressive treatment on the potential induction of transplant tolerance has not been well determined. In this review we summarize the effects of immunosuppressive reagents on CD4(+)CD25(+) T(reg) cells in order to bring attention to this issue, which may affect the choice of immunosuppressive regimen in the clinical setting.