The role of cytokines in the pathogenesis and treatment of HIV infection

HIV immune activation plays an important role in the immunopathogenesis of the disease. The mechanisms driving this immune activation are partially defined and likely are the result of multiple factors. The introduction of combination antiretroviral therapy (cART) has improved the life expectancy of HIV infected individuals, however there is evidence that in the setting of "undetectable" HIV-RNA plasma levels, there is some level of persistent immune activation in these patients. A better understanding of the immune activation pathways should be of value in developing complementary therapies to restore the immune systems of patients with HIV infection. This review discusses the cytokine mediated pathways of immune activation of the CD4 and CD8 T cell pools during HIV infection.     

Leishmania and the pathogenesis of HIV infection

Acquired immunodeficiency syndrome (AIDS) and leishmaniasis overlap in several parts of the world, and microorganisms responsible for these human diseases infect and replicate within the macrophage. Therefore, the opportunity that the pathogenesis of the human immunodeficiency virus (HIV) and Leishmania infections could be modulated within dually infected individual is optimized. The most prominent clinical feature of AIDS is the development of debilitating secondary infections induced by several opportunistic microorganisms, including protozoa. Michel Tremblay, Martin Olivier and Richard Bernier here focus on the recently reported information on the putative cofactor role that the intracellular pathogen of the genus Leishmania may play in the pathogenesis of HIV infection.     

The immunogenetic aspects of erysipelas infection

The distribution of the antigens of the HLA system in 517 erysipelas patients, constant residents of Voroshilovgrad and the adjoining region (the Ukrainian SSR), has been studied. The HLA system has been found to take part in the formation of predisposition to erysipelas and its clinical forms. Predisposition to erysipelas infection has a polygenic nature and is associated with antigens HLA-A2, B5, B12, Bw35. The specific features of HLA-A10, Aw12, B7, B8 have, seemingly, a protective character. The most pronounced connection between the disease and histocompatibility antigens has been detected in patients with frequent and multiple relapses of erysipelas.     

The role of fibronectin in the pathogenesis of meningococcal infection

We have characterized an interaction of 20 strains of Neisseria meningitidis serogroups A, B, C, 29E, W-135 and Z with immobilized fibronectin of human plasma. The adhesion of meningococci to fibronectin was determined by the extent of piliated cells and did not depend on the meningococcal serogroup. Binding of non-piliated or weakly piliated strains (2-5% of piliated cells in the stock) was sufficiently greater than those piliated (8-10%), where the adhesion to fibronectin was not at all observed. The examination of two well-piliated strains showed that the loss of pili resulted in the increase of bacterial adhesion to fibronectin. Constants of association and dissociation of piliated and non-piliated strains to fibronectin were calculated. The role of meningococci-fibronectin interaction in the pathogenesis of meningococcal infection is discussed.     

The role of interleukin-21 in HIV infection

Interleukin (IL)-21 is one of a group of cytokines including IL-2, IL-4, IL-7, IL-9 and IL-15 whose receptor complexes share the common γ chain (γ(c)). Secretion of IL-21 is restricted mainly to T follicular helper (TFH) CD4 T cell subset with contributions from Th17, natural killer (NK) T cells, but the effects of IL-21 are pleiotropic, owing to the broad cellular distribution of the IL-21 receptor. The role of IL-21 in sustaining and regulating T cell, B cell and NK cell responses during chronic viral infections has recently come into focus. This chapter reviews current knowledge about the biology of IL-21 in the context of HIV infection.     

The role of glycosphingolipids in HIV signaling, entry and pathogenesis

Although HIV uses CD4 and coreceptors (CCR5 and CXCR4) for productive infection of T cells, glycosphingolipids (GSL) may play ancillary roles in lymphoid and non-lymphoid cells. Interactions of the HIV Envelope Glycoprotein (Env) with GSL may help HIV in various steps of its pathogenesis. Physical-chemical aspects of the interactions between HIV Env and GSL leading to CD4-dependent entry into lymphocytes, the role of GSL in HIV transcytosis, and CD4-independent entry into non-lymphoid cells are reviewed. An overview of signaling properties of HIV receptors is provided with some speculation on how GSL may play a role in these events by virtue of being in membrane rafts. Finally, we summarize how interactions between HIV and coreceptors leading to signaling and/or fusion can be analyzed by the use of various tyrosine kinase and cytoskeletal inhibitors. Published in 2004. This revised version was published online in August 2006 with corrections to the Cover Date.     

The role of glycosphingolipids in HIV signaling, entry and pathogenesis

Although HIV uses CD4 and coreceptors (CCR5 and CXCR4) for productive infection of T cells, glycosphingolipids (GSL) may play ancillary roles in lymphoid and non-lymphoid cells. Interactions of the HIV Envelope Glycoprotein (Env) with GSL may help HIV in various steps of its pathogenesis. Physical-chemical aspects of the interactions between HIV Env and GSL leading to CD4-dependent entry into lymphocytes, the role of GSL in HIV transcytosis, and CD4-independent entry into non-lymphoid cells are reviewed. An overview of signaling properties of HIV receptors is provided with some speculation on how GSL may play a role in these events by virtue of being in membrane rafts. Finally, we summarize how interactions between HIV and coreceptors leading to signaling and/or fusion can be analyzed by the use of various tyrosine kinase and cytoskeletal inhibitors.     

The possible role of hydrogen sulfide on the pathogenesis of spontaneous hypertension in rats

Hydrogen sulfide (H(2)S) is a newly found modulator in vascular system. This work showed that gene expression of cystathionine gamma-lyase (CSE), a H(2)S generating enzyme, and the activity of CSE in thoracic aorta were suppressed in hypertension rats. The plasma level of H(2)S also decreased in those rats. Exogenous administration of H(2)S could increase the plasma level of H(2)S and enhance the CSE activity of aorta. Exogenous administration of H(2)S also attenuated the elevation of pressure and lessened the aorta structural remodeling during the development of hypertension. In WKY rats, the gene expression and activity of CSE also decreased when the endogenous production of H(2)S was deprived by administration of DL-propargylglycine (specific inhibitor of CSE), accompanying the elevated pressure and the development of vascular remodeling. The results showed that endogenous H(2)S system was involved in both the maintenance of basal blood pressure and the development of hypertension. Exogenous H(2)S could exert beneficial effect on the pathogenesis of spontaneous hypertension.     

The role of exosomal transport of viral agents in persistent HIV pathogenesis

Human immunodeficiency virus (HIV) infection, despite great advances in antiretroviral therapy, remains a lifelong affliction. Though current treatment regimens can effectively suppress viral load to undetectable levels and preserve healthy immune function, they cannot fully alleviate all symptoms caused by the presence of the virus, such as HIV-associated neurocognitive disorders. Exosomes are small vesicles that transport cellular proteins, RNA, and small molecules between cells as a mechanism of intercellular communication. Recent research has shown that HIV proteins and RNA can be packaged into exosomes and transported between cells, to pathogenic effect. This review summarizes the current knowledge on the diverse mechanisms involved in the sorting of viral elements into exosomes and the damage those exosomal agents can inflict. In addition, potential therapeutic options to counteract exosome-mediated HIV pathogenesis are reviewed and considered.     

The cytosolic domain of APP and its possible role in the pathogenesis of Alzheimer's disease

APP is a type I membrane protein of unknown function, whose proteolytic processing, driven by beta- and gamma-secretases, generates the beta-amyloid peptides, one of the hallmarks of the pathogenesis of Alzheimer's disease. The short cytosolic domain of APP is the center of a complex network of protein-protein interactions. This network appears to play a crucial role in the regulation of the APP processing and in turn in the generation of the amyloid peptides, thus suggesting candidate targets for new therapeutic approaches. Furthermore, some possible functions of APP could just emerge from the study of this cytodomain and its partners.     

Cytotoxic factor-autoantibodies: possible role in the pathogenesis of dengue haemorrhagic fever

During dengue virus infection a unique cytokine, cytotoxic factor (hCF), is produced that is pathogenesis-related and plays a key role in the development of dengue haemorrhagic fever (DHF). However, what regulates the adverse effects of hCF is not known. We have previously shown that anti-hCF antibodies raised in mice, neutralise the pathogenic effects of hCF. In this study we have investigated the presence and levels of hCF-autoantibodies in sera of patients with various severity of dengue illness (n=136) and normal healthy controls (n=50). The highest levels of hCF-autoantibodies (mean+/-S.D.=36+/-20 U ml(-1)) were seen in patients with mild illness, the dengue fever (DF), and 48 out of 50 (96%) of the sera were positive. On the other hand the hCF-autoantibody levels declined sharply with the development of DHF and the levels were lowest in patients with DHF grade IV (mean+/-S.D.=5+/-2 U ml(-1); P=<0.001 as compared to DF). Only one of the 13 DHF grade IV patients had an antibody level above the 'cut-off' value (mean plus 3 S.D. of the control sera). The analysis of data with respect to different days of illness further showed that the highest levels of hCF-autoantibodies were present in DF patients at >9 days of illness. Moreover, the DF patients at all time points, i.e. 1-4, 5-8 and >9 days of illness had significantly higher levels of hCF-autoantibodies (P<0.001) than patients with DHF grade I, II, III and IV. In addition DHF grade I and grade II patients had significantly more positive specimens than DHF grade III and grade IV patients at all time points. These results suggest that elevated levels of hCF-autoantibodies protect the patients against the development of severe forms of DHF and, therefore, it may be useful as a prognostic indicator.     

The role of endocrine factors in the pathogenesis of spontaneous abortion after IVF-ET

There is large body of evidence to show that the risk of early pregnancy loss is higher after IVF-ET than after natural conception. Several hypotheses have been proposed to explain this phenomenon. One of the possible etiopathogetic factors is the patient's age which is significantly higher in women undergoing IVF than in the general population of naturally conceiving women. Immunologic factors have also been suggested. It seems that procedures like ICSI do not increase the risk of spontaneous abortion (SAB) after IVF-ET. Moreover, the proportion of products of conception with chromosomal aberration in cases of SAB following ICSI procedure is not elevated. Many authors point to the problem of iatrogenic luteal defect after IVF-ET. The use of luteal support after IVF-ET is widely recommended. Interestingly, firm evidence is lacking regarding the efficacy of progestagen or hCG supplementation on the risk of SAB after IVF-ET. However the issue of the effectiveness of progesterone support in decreasing the risk of SAB after ART procedures is far from being conclusively resolved--it deserves well planned, randomized studied to be performed.     

The role of public organizations in the prevention of HIV infection in Russia

The problem of the role of public organizations in the prevention of the spread of HIV infection in Russia is discussed. The correctly chosen strategy of cooperation between governmental structures and non-governmental public associations corresponds to the modern principles of state policy of enhancing the interest of the population in the problems of public health. Relationships built on the principles of mutual respect and partnership in the common work on the prevention of the spread of HIV infection in Russia must increase its effectiveness.     

New insights on the role of apoptosis and autophagy in HIV pathogenesis

Viruses manipulate host cells to ensure their own survival and, at late stages of the viral life cycle, they kill the infected target cell to ensure their propagation. In addition, some viruses induce a bystander killing, a viral strategy to escape from the host's innate and cognate defense systems. In HIV-infection, the disabling of the immune system is initially due to the preferential depletion by apoptosis of virus-specific CD4⁺ T cells in lymphoid tissues, followed by the destruction of non-infected bystander cells. Both the extrinsic and the intrinsic pathways are activated, and this is the consequence of systemic immune activation. This review presents recent developments showing that the gastrointestinal tract is the major reservoir of infected cells and the site of rapid and profound loss of CD4 T cells, and that microbial translocation from the gastrointestinal tract is the cause of immune activation. Furthermore, apoptosis mechanisms involved in HIV-induced neuropathological disorders are discussed, including the role of syncytia that involve the sequential activation of ATM, p38MAPK and p53. Finally, HIV-associated dementia (HAD) was recently found in monkey models to be linked to inhibition of autophagy in neurons, suggesting that homeostasis of autophagy is a reliable security factor for neurons, and challenging the development of new therapeutics aimed at boosting neuronal autophagy to prevent HAD.     

Proteases of the pathogenic neisseriae: possible role in infection

Proteolytic enzymes are produced by animal as well as human pathogens. Several micro-organisms including Neisseriae produce IgA1 specific proteases. This protease specifically hydrolyses IgA1 protein. IgA1-specific protease(s) synthesized by Neisseria species are briefly reviewed with particular reference to their role in infection.     

The toxic role of alpha-haemolysin in the pathogenesis of experimental Escherichia coli infection in mice

Filtrates from strains of Escherichia coli possessing plasmid-cloned haemolysin (Hly) genes and from strains possessing 'wild' Hly plasmids were lethal for mice on intravenous inoculation; similar doses of preparations from derivatives of these strains in which the Hly genes had been rendered non-functional or which did not possess the 'wild' plasmids were not. Live cultures of both kinds of Hly+ strain usually had a lower lethal dose for mice on intraperitoneal inoculation than the corresponding Hly- forms. Mice that had been inoculated with Hly+ forms had shorter survival times and lower numbers of organisms in peritoneal washings, lungs and blood at point of death than mice that had been inoculated with the corresponding Hly- forms; this was also so for mice pre-treated with FeSO4, a procedure which rendered mice equally susceptible to the lethal effects of the Hly+ and Hly- forms of a strain. In FeSO4-treated mice the numbers of organisms in the tissues of those dying from infection with Hly+ organisms were no higher than they were at the same time after inoculation in others given the corresponding Hly- forms; before mice of the latter category died the numbers of organisms in their tissues increased greatly. The clinical and pathological signs exhibited by mice inoculated with Hly+ organisms, but not with Hly- organisms, resembled those exhibited by mice inoculated with bacteria-free haemolysin preparations. These results suggest that haemolysin played a significant role in the pathogenesis of the disease produced by the Hly+ organisms by having a direct toxic action on the host.