The role of Th17 cytokines in primary mucosal immunity

The T helper type 17 (Th17) lineage of CD4+ T-cells produce several effector molecules including IL-17A, IL-17F, IL-21, and IL-22. In addition to CD4+, αβ T-cells, these cytokines can be produced by natural killer and γδ T-cells. These effector cytokines can be produced rapidly upon infection at mucosal sites and evidence to date strongly implicates that this arm of the immune system plays a critical role in mucosal immunity to many extracellular pathogens. Moreover these cytokines can also coordinate adaptive immunity to some intracellular pathogens. In this review, we will highlight recent progress in our understanding of these cytokines, and mechanisms of their effector function in the mucosa.     

The role of HIV replicative fitness in perinatal transmission of HIV

Perinatal transmission of Human immunodeficiency virus(HIV),also called mother-to-child transmission(MTCT),accounts for 90% of infections in infants worldwide and occurs in 30%-45% of children born to untreated HIV-1 infected mothers.Among HIV-1 infected mothers,some viruses are transmitted from mothers to their infants while others are not.The relationship between virologic properties and the pathogenesis caused by HIV-1 remains unclear.Previous studies have demonstrated that one obvious source of selective pressure in the perinatal transmission of HIV-1 is maternal neutralizing antibodies.Recent studies have shown that viruses which are successfully transmitted to the child have growth advantages over those not transmitted,when those two viruses are grown together.Furthermore,the higher fitness is determined by the gp120 protein of the virus envelope.This suggests that the selective transmission of viruses with higher fitness occurred exclusively,regardless of transmission routes.There are many factors contributing to the selective transmission and HIV replicative fitness is an important one that should not be neglected.This review summarizes current knowledge of the role of HIV replicative fitness in HIV MTCT transmission and the determinants of viral fitness upon MTCT.     

The role of sexually transmitted diseases in HIV transmission

More than 42 million people worldwide are now infected with HIV, in spite of sustained prevention activities. Although the spread of HIV has been primarily sexual, epidemiological studies have indicated that the efficiency of the spread of HIV is poor, perhaps as infrequently as 1 in every 1,000 episodes of sexual intercourse. However, sexually transmitted diseases (STDs) that cause ulcers or inflammation greatly increase the efficiency of HIV transmission--by increasing both the infectiousness of, and the susceptibility to HIV infection. STDs might be particularly important in the early stages of a localized HIV epidemic, when people with risky sexual behaviour are most likely to become infected. In China, eastern Europe and Russia, there has been a remarkable increase in the incidence of STDs in recent years, and this is reflected in the rapid increase in the spread of HIV in these areas. Targeted STD detection and treatment should have a central role in HIV prevention in these emerging epidemics.     

The role of Th1/Th2 polarization in mucosal immunity

Mucosal immunity relies on the delicate balance between antigen responsiveness and tolerance. The polarization of T helper cells plays a key role in maintaining or disrupting this equilibrium.     

Constitutive expression of stromal derived factor-1 by mucosal epithelia and its role in HIV transmission and propagation

HIV particles that use the chemokine receptor CXCR4 as a coreceptor for entry into cells (X4-HIV) inefficiently transmit infection across mucosal surfaces [1], despite their presence in seminal fluid and mucosal secretions from infected individuals [2] [3] [4]. In addition, although intestinal lymphocytes are susceptible to infection with either X4-HIV particles or particles that use the chemokine receptor CCR5 for viral entry (R5-HIV) during ex vivo culture [5], only systemic inoculation of R5-chimeric simian-HIV (S-HIV) results in a rapid loss of CD4(+) intestinal lymphocytes in macaques [6]. The mechanisms underlying the inefficient capacity of X4-HIV to transmit infection across mucosal surfaces and to infect intestinal lymphocytes in vivo have remained elusive. The CCR5 ligands RANTES, MIP-1alpha and MIP-1beta suppress infection by R5-HIV-1 particles via induction of CCR5 internalization, and individuals whose peripheral blood lymphocytes produce high levels of these chemokines are relatively resistant to infection [7] [8] [9]. Here, we show that the CXCR4 ligand stromal derived factor-1 (SDF-1) is constitutively expressed by mucosal epithelial cells at sites of HIV transmission and propagation. Furthermore, CXCR4 is selectively downmodulated on intestinal lymphocytes within the setting of prominent SDF-1 expression. We postulate that mucosally derived SDF-1 continuously downmodulates CXCR4 on resident HIV target cells, thereby reducing the transmission and propagation of X4-HIV at mucosal sites. Moreover, such a mechanism could contribute to the delayed emergence of X4 isolates, which predominantly occurs during the later stages of the HIV infection.     

Intestinal epithelial cells and their role in innate mucosal immunity

The mucosal surfaces of the respiratory, gastrointestinal and urogenital tracts are covered by a layer of epithelial cells that are responsible for sensing and promoting a host immune response in order to establish the limits not only for commensal microorganisms but also for foreign organisms or particles. This is a remarkable task as the human body represents a composite of about 10 trillion human-self cells plus non-self cells from autochthonous or indigenous microbes that outnumber human cells 10:1. Hence, the homeostasis of epithelial cells that line mucosal surfaces relies on a fine-tuned immune system that patrols the boundaries between human and microbial cells. In the case of the intestine, the epithelial layer is composed of at least six epithelial cell lineages that act as a physiological barrier in addition to aiding digestion and the absorption of nutrients, water and electrolytes. In this review, we highlight the immense role of the intestinal epithelium in coordinating the mucosal innate immune response.     

Cellular immunity for prevention and clearance of HIV infection

Despite the major strides that have been made in HIV therapy with the advent of potent anti-retroviral drugs, these medications are quite expensive and are still not readily available for the vast majority of infected individuals worldwide. Even when available, the long-term toxicities associated with anti-retroviral medications and the frequent emergence of drug-resistance mutations can complicate therapy, making the formulation of effective vaccines imperative. This chapter will review the current state of understanding regarding cell-mediated immune responses that are associated with control of HIV replication. This knowledge has generated sound hypotheses regarding the prospects for augmenting cell-mediated immunity through immune-based therapies. With regard to prophylactic vaccines, it is presently unclear which vaccine-induced immune responses will protect against infection. While much progress has been made in formulating vaccine constructs designed to elicit cell-mediated immune responses, sterilizing immunity is unlikely to be achieved with the current vaccines. However, the ability to control viremia and prevent disease progression in animal infection models looks promising. The ability to measure immune responses has also advanced markedly over the past few years and will allow investigators to more accurately measure the immunogenicity of vaccine constructs, and correlate the magnitude and breadth of these responses with protection.     

Using HIV transmission networks to investigate community effects in HIV prevention trials

Effective population screening of HIV and prevention of HIV transmission are only part of the global fight against AIDS. Community-level effects, for example those aimed at thwarting future transmission, are potential outcomes of treatment and may be important in stemming the epidemic. However, current clinical trial designs are incapable of detecting a reduction in future transmission due to treatment. We took advantage of the fact that HIV is an evolving pathogen whose transmission network can be reconstructed using genetic sequence information to address this shortcoming. Here, we use an HIV transmission network inferred from recently infected men who have sex with men (MSM) in San Diego, California. We developed and tested a network-based statistic for measuring treatment effects using simulated clinical trials on our inferred transmission network. We explored the statistical power of this network-based statistic against conventional efficacy measures and find that when future transmission is reduced, the potential for increased statistical power can be realized. Furthermore, our simulations demonstrate that the network statistic is able to detect community-level effects (e.g., reduction in onward transmission) of HIV treatment in a clinical trial setting. This study demonstrates the potential utility of a network-based statistical metric when investigating HIV treatment options as a method to reduce onward transmission in a clinical trial setting.     

The gut as a lymphoepithelial organ: The role of intestinal epithelial cells in mucosal immunity

Mucosal surfaces covered by a layer of epithelial cells represent the largest and most critical interface between the organism and its environment. The barrier function of mucosal surfaces is performed by the epithelial layer and immune cells present in the mucosal compartment. As recently found, epithelial cells, apart from their participation in absorptive, digestive and secretory processes perform more than a passive barrier function and are directly involved in immune processes. Besides the well known role of epithelial cells in the transfer of polymeric immunoglobulins produced by lamina propria B lymphocytes to the luminal content of mucosals (secretory Igs), these cells were found to perform various other immunological functions, to interact with other cells of the immune system and to induce an efficient inflammatory response to microbial invasion: enzymic processing of dietary antigens, expression of class I and II MHC antigens, presentation of antigens to lymphocytes, expression of adhesive molecules mediating interaction with intraepithelial lymphocytes and components of extracellular matrix, production of cytokines and probable participation in extrathymic T cell development of intraepithelial lymphocytes. All these functions were suggested to influence substantially the mucosal immune system and its response. Under immunopathological conditions,e.g. during infections and inflammatory bowel and celiac diseases, both epithelial cells and intraepithelial lymphocytes participate substantially in inflammatory reactions. Moreover, enterocytes could become a target of mucosal immune factors. Mucosal immunosurveillance function is of crucial importance in various pathological conditions but especially in the case of the most frequent malignity occurring in the intestinal compartment,i.e. colorectal carcinoma. Proper understanding of the differentiation processes and functions of epithelial cells in interaction with other components of the mucosal immune system is therefore highly desirable. Dedicated to Professor J. Šterzl on the occasion of his 70th birthday     

Innate immunity against HIV: a priority target for HIV prevention research

The xenotropic/polytropic subgroup of mouse leukemia viruses (MLVs) all rely on the XPR1 receptor for entry, but these viruses vary in tropism, distribution among wild and laboratory mice, pathogenicity, strategies used for transmission, and sensitivity to host restriction factors. Most, but not all, isolates have typical xenotropic or polytropic host range, and these two MLV tropism types have now been detected in humans as viral sequences or as infectious virus, termed XMRV, or xenotropic murine leukemia virus-related virus. The mouse xenotropic MLVs (X-MLVs) were originally defined by their inability to infect cells of their natural mouse hosts. It is now clear, however, that X-MLVs actually have the broadest host range of the MLVs. Nearly all nonrodent mammals are susceptible to X-MLVs, and all species of wild mice and several common strains of laboratory mice are X-MLV susceptible. The polytropic MLVs, named for their apparent broad host range, show a more limited host range than the X-MLVs in that they fail to infect cells of many mouse species as well as many nonrodent mammals. The co-evolution of these viruses with their receptor and other host factors that affect their replication has produced a heterogeneous group of viruses capable of inducing various diseases, as well as endogenized viral genomes, some of which have been domesticated by their hosts to serve in antiviral defense.     

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.     

Transplacental transmission of HIV: a potential role for HIV binding lectins

Although the majority of vertical transmission of HIV occurs around the time of birth, 1.5-2% of pregnancies in HIV-positive women appear to result in the vertical transmission of HIV across the placenta. HIV infection of a number of placental cell types has been demonstrated, but the exact mechanisms of intrauterine vertical transmission remain obscure. The recent discovery of the HIV binding lectins dendritic cell-specific ICAM-grabbing non-integrin (DC-SIGN) and DC-SIGN-related molecule (DC-SIGNR) provides one possible explanation. Cells expressing these lectins are able to adsorb the virus and mediate high efficiency HIV infection of other cell types. Both lectins are expressed by the placenta, with DC-SIGN expression also being present on maternal cells intimately associated with the placenta. This review focuses on possible mechanisms by which these lectins may potentiate the intrauterine vertical transmission of HIV.     

M-cells: origin, morphology and role in mucosal immunity and microbial pathogenesis

M-cells are specialized cells found in the follicle-associated epithelium of intestinal Peyer's patches of gut-associated lymphoid tissue and in isolated lymphoid follicles, appendix and in mucosal-associated lymphoid tissue sites outside the gastrointestinal tract. In the gastrointestinal tract, M-cells play an important role in transport of antigen from the lumen of the small intestine to mucosal lymphoid tissues, where processing and initiation of immune responses occur. Thus, M-cells act as gateways to the mucosal immune system and this function has been exploited by many invading pathogens. Understanding the mechanism by which M-cells sample antigen will inform the design of oral vaccines with improved efficacy in priming mucosal and systemic immune responses. In this review, the origin and morphology of M-cells, and their role in mucosal immunity and pathogenesis of infections are discussed.     

The role of HIF in immunity

Oxygen is an essential nutrient for eukaryotic life and in complex organisms a finely tuned system, based on Hypoxia Inducible Factor (HIF), has evolved to control the cellular, local and organism-wide responses to its availability. Cells of the immune system must function in a variety of local environments and it is now clear that oxygen availability is an important signal for the cells involved in immune defence. This review summarises the mechanisms by which activation of the HIF pathway influences, and is influenced by, both immune activation state and oxygen tension. It is likely that understanding how oxygen tension modulates immune function will provide insights into disease pathogenesis, and may offer new opportunities for treatment.     

Salmonella-mediated mucosal cell-mediated immunity.

Oral immunization with the recombinant Salmonella typhimurium strain (BRD 847) expressing the C fragment of tetanus toxin (TT) induces brisk Ag-specific mucosal S-IgA and serum Ab responses characterized by strong IgG2a Abs to the encoded antigen. We have constructed an attenuated Salmonella typhimurium (aroA- aroD-) strain that expresses chicken egg albumin (OVA) to further elucidate the role of Salmonella-induced Th1 cell phenotype on mucosal cell-mediated immunity (CMI). Peyer's patches and spleen lymphocytes from mice that received the oral Salmonella-OVA vaccine showed dramatic increases in the percent cell lysis of the H-2b restricted EG7.OVA tumor cell line. These results indicate that a single dose of rSalmonella vaccine antigen vector is required to illicit systemic and mucosal Th1-type responses and CTLs. These results also support the existence of a highly regulated relationship between specific cell-mediated immunity and a branch of the humoral immune system, i.e. mucosal IgA responses.     

NALT- versus Peyer's-patch-mediated mucosal immunity

Recent studies indicate that the mechanism of nasopharynx-associated lymphoid tissue (NALT) organogenesis is different from that of other lymphoid tissues. NALT has an important role in the induction of mucosal immune responses, including the generation of T helper 1 and T helper 2 cells, and IgA-committed B cells. Moreover, intranasal immunization can lead to the induction of antigen-specific protective immunity in both the mucosal and systemic immune compartments. Therefore, a greater understanding of the differences between NALT and other organized lymphoid tissues, such as Peyer's patches, should facilitate the development of nasal vaccines.