RESUMEN
Human immunodeficiency virus (HIV)-1 amino acid sequence polymorphisms associated with expression of specific human histocompatibility leukocyte antigen (HLA) class I alleles suggest sites of cytotoxic T lymphocyte (CTL)-mediated selection pressure and immune escape. The associations most frequently observed are between expression of an HLA class I molecule and variation from the consensus sequence. However, a substantial number of sites have been identified in which particular HLA class I allele expression is associated with preservation of the consensus sequence. The mechanism behind this is so far unexplained. The current studies, focusing on two examples of "negatively associated" or apparently preserved epitopes, suggest an explanation for this phenomenon: negative associations can arise as a result of positive selection of an escape mutation, which is stable on transmission and therefore accumulates in the population to the point at which it defines the consensus sequence. Such negative associations may only be in evidence transiently, because the statistical power to detect them diminishes as the mutations accumulate. If an escape variant reaches fixation in the population, the epitope will be lost as a potential target to the immune system. These data help to explain how HIV is evolving at a population level. Understanding the direction of HIV evolution has important implications for vaccine development.
Asunto(s)
Epítopos de Linfocito T/inmunología , Infecciones por VIH/transmisión , VIH-1/inmunología , Antígenos HLA/inmunología , Polimorfismo Genético/inmunología , Linfocitos T Citotóxicos/inmunología , Vacunas contra el SIDA , Adulto , Alelos , Secuencia de Aminoácidos , Niño , Preescolar , Secuencia de Consenso/genética , Secuencia de Consenso/inmunología , Epítopos de Linfocito T/genética , Evolución Molecular , Femenino , Regulación de la Expresión Génica/genética , Regulación de la Expresión Génica/inmunología , Infecciones por VIH/genética , Infecciones por VIH/inmunología , VIH-1/genética , Antígenos HLA/genética , Humanos , Masculino , Datos de Secuencia Molecular , Mutación/genética , Mutación/inmunología , Polimorfismo Genético/genéticaRESUMEN
The extreme polymorphism in the human leukocyte antigen (HLA) class I region of the human genome is suggested to provide an advantage in pathogen defence mediated by CD8+ T cells. HLA class I molecules present pathogen-derived peptides on the surface of infected cells for recognition by CD8+ T cells. However, the relative contributions of HLA-A and -B alleles have not been evaluated. We performed a comprehensive analysis of the class I restricted CD8+ T-cell responses against human immunodeficiency virus (HIV-1), immune control of which is dependent upon virus-specific CD8+ T-cell activity. In 375 HIV-1-infected study subjects from southern Africa, a significantly greater number of CD8+ T-cell responses are HLA-B-restricted, compared to HLA-A (2.5-fold; P = 0.0033). Here we show that variation in viral set-point, in absolute CD4 count and, by inference, in rate of disease progression in the cohort, is strongly associated with particular HLA-B but not HLA-A allele expression (P < 0.0001 and P = 0.91, respectively). Moreover, substantially greater selection pressure is imposed on HIV-1 by HLA-B alleles than by HLA-A (4.4-fold, P = 0.0003). These data indicate that the principal focus of HIV-specific activity is at the HLA-B locus. Furthermore, HLA-B gene frequencies in the population are those likely to be most influenced by HIV disease, consistent with the observation that B alleles evolve more rapidly than A alleles. The dominant involvement of HLA-B in influencing HIV disease outcome is of specific relevance to the direction of HIV research and to vaccine design.
Asunto(s)
Evolución Biológica , Infecciones por VIH/inmunología , Infecciones por VIH/virología , VIH-1/inmunología , VIH-1/fisiología , Antígenos HLA-B/inmunología , África Austral , Linfocitos T CD8-positivos/citología , Linfocitos T CD8-positivos/inmunología , Epítopos de Linfocito T/inmunología , Femenino , Frecuencia de los Genes , Productos del Gen nef/química , VIH-1/genética , Antígenos HLA-A/genética , Antígenos HLA-A/inmunología , Antígenos HLA-B/genética , Humanos , Lactante , Masculino , Polimorfismo Genético/genética , Carga Viral , Productos del Gen nef del Virus de la Inmunodeficiencia HumanaRESUMEN
Cytokines, as immune activators, have been investigated in mammalian systems as natural adjuvants and therapeutics. In particular, interleukin-2 (IL-2) has been studied widely as a vaccine adjuvant and immuno-enhancer because of its role in activating T cell proliferation. We show here that the first nonmammalian IL-2 gene cloned, chicken IL-2 (ChIL-2), exhibits similar biologic activities to those of mammalian IL-2. To assess the activities of ChIL-2 in vivo, we injected birds with recombinant ChIL-2 (rChIL-2) protein. rChIL-2 treatment induced peripheral blood lymphocytes to express cell surface IL-2 receptors (IL-2R) within 48 h and resulted in an increase in the proportion of peripheral blood CD4+ and CD8+ T cells. Using bromodeoxyuridine (BrdU) incorporation as a measurement of cell proliferation, we showed the increase in T cell populations to be due to cell proliferation. The ability of ChIL-2 to cause both activation and proliferation of T cells in vivo indicates that it has the potential to be used as an immune activator.
Asunto(s)
Pollos/inmunología , Interleucina-2/fisiología , Activación de Linfocitos/efectos de los fármacos , Subgrupos de Linfocitos T/efectos de los fármacos , Animales , Linfocitos T CD4-Positivos/efectos de los fármacos , Linfocitos T CD4-Positivos/inmunología , Linfocitos T CD8-positivos/efectos de los fármacos , Linfocitos T CD8-positivos/inmunología , Células COS , División Celular/efectos de los fármacos , Pollos/genética , Chlorocebus aethiops , Clonación Molecular , Replicación del ADN/efectos de los fármacos , Interleucina-2/genética , Interleucina-2/farmacología , Recuento de Linfocitos , Receptores de Interleucina-1/biosíntesis , Receptores de Interleucina-1/genética , Proteínas Recombinantes/farmacología , Especificidad de la Especie , Organismos Libres de Patógenos Específicos , Subgrupos de Linfocitos T/inmunología , Regulación hacia Arriba/efectos de los fármacosRESUMEN
The use of antibiotic feed additives and chemical antimicrobials in food production animals is a double-edged sword. On one hand, it helps to prevent the outbreak of disease and promotes the growth of animals, but on the other hand, concerns are mounting over the emergence of antibiotic-resistant bacteria. As a consequence, some countries have already banned the use of in-feed antibiotics which has resulted in meat producers urgently seeking environmentally friendly alternative methods to control disease. Cytokines are proteins that control the type and extent of an immune response following infection or vaccination. They therefore represent excellent naturally occurring therapeutics. The use of cytokines in poultry has become more feasible with the discovery of a number of avian cytokine genes. Since the immune system of chickens is similar to that of mammals, they offer an attractive model system to study the effectiveness of cytokine therapy in the control of disease in livestock. This review will focus on the recent advances made in avian cytokines, with a particular focus on their assessment as therapeutic agents and vaccine adjuvants.
Asunto(s)
Pollos/inmunología , Citocinas/inmunología , Inmunización/veterinaria , Enfermedades de las Aves de Corral/inmunología , Adyuvantes Inmunológicos , Animales , Citocinas/genética , Citocinas/farmacología , Enfermedades de las Aves de Corral/prevención & controlRESUMEN
The induction of IFN-beta by the paramyxovirus PIV5 (formerly known as SV5) is limited by the action of the viral V protein that targets the cellular RNA helicase mda-5. Here we show that 12 other paramyxoviruses also target mda-5 by a direct interaction between the conserved cysteine-rich C-terminus of their V proteins and the helicase domain of mda-5. The inhibition of IFN-beta induction is not species-restricted, being observed in a range of mammalian cells as well as in avian cells, and we show that the inhibition of mda-5 function is also not restricted to mammalian cells. In contrast, the V proteins do not bind to the related RNA helicase RIG-I and do not inhibit its activity. The relative contributions of mda-5 and RIG-I to IFN-beta induction are discussed.
Asunto(s)
ARN Helicasas DEAD-box/antagonistas & inhibidores , ARN Helicasas DEAD-box/metabolismo , Virus de la Parainfluenza 5/fisiología , Proteínas Estructurales Virales/metabolismo , Secuencia de Aminoácidos , Animales , Aves , Bovinos , Línea Celular , Chlorocebus aethiops , ARN Helicasas DEAD-box/química , Humanos , Inmunoprecipitación , Interferón beta/biosíntesis , Datos de Secuencia Molecular , Unión Proteica , Mapeo de Interacción de Proteínas , Estructura Terciaria de Proteína , Homología de Secuencia de Aminoácido , Técnicas del Sistema de Dos Híbridos , Proteínas Estructurales Virales/químicaRESUMEN
Classical swine fever virus (CSFV) is a member of the genus Pestivirus in the family Flaviviridae. The N(pro) product of CSFV targets the host's innate immune response and can prevent the production of type I interferon (IFN). The mechanism by which CSFV orchestrates this inhibition was investigated and it is shown that, like the related pestivirus bovine viral diarrhea virus (BVDV), this involves the N(pro) protein targeting interferon regulatory factor-3 (IRF-3) for degradation by proteasomes and thus preventing IRF-3 from activating transcription from the IFN-beta promoter. Like BVDV, the steady-state levels of IRF-3 mRNA are not reduced markedly by CSFV infection or N(pro) overexpression. Moreover, IFN-alpha stimulation of CSFV-infected cells induces the antiviral protein MxA, indicating that, as in BVDV-infected cells, the JAK/STAT pathway is not targeted for inhibition.
Asunto(s)
Virus de la Fiebre Porcina Clásica/inmunología , Endopeptidasas/inmunología , Factor 3 Regulador del Interferón/antagonistas & inhibidores , Factor 3 Regulador del Interferón/inmunología , Proteínas Virales/inmunología , Animales , Western Blotting , Línea Celular , Complejo de la Endopetidasa Proteasomal/metabolismo , PorcinosRESUMEN
Bovine viral diarrhea virus (BVDV) is a pestivirus that can establish a persistent infection in the developing fetus and has the ability to disable the production of type I interferon. In this report, we extend our previous observations that BVDV encodes a protein able to specifically block the activity of interferon regulatory factor 3 (IRF-3), a transcription factor essential for interferon promoter activation, by demonstrating that this is a property of the N-terminal protease fragment (NPro) of the BVDV polyprotein. Although BVDV infections cause relocalization of cellular IRF-3 from the cytoplasm to the nucleus early in infection, NPro blocks IRF-3 from binding to DNA. NPro has the additional property of targeting IRF-3 for polyubiquitination and subsequent destruction by cellular multicatalytic proteasomes. The autoprotease activity of NPro is not required for the inhibition of type I interferon induction or the targeting of IRF-3 for degradation.
Asunto(s)
Proteínas de Unión al ADN/metabolismo , Virus de la Diarrea Viral Bovina/fisiología , Factor 3 Regulador del Interferón/metabolismo , Complejo de la Endopetidasa Proteasomal/metabolismo , Proteínas Virales/metabolismo , Animales , Línea Celular , Virus de la Diarrea Viral Bovina/patogenicidad , Factor 3 Regulador del Interferón/antagonistas & inhibidores , Interferón-alfa/antagonistas & inhibidores , Interferón-alfa/metabolismo , Interferón beta/antagonistas & inhibidores , Interferón beta/metabolismo , Complejo de la Endopetidasa Proteasomal/efectos de los fármacos , Complejo de la Endopetidasa Proteasomal/genética , Proteínas Virales/farmacologíaRESUMEN
The worldwide trend towards a reduced reliance on in-feed antibiotics has increased the pressure to develop alternative strategies to manage infectious diseases in poultry. With this in mind, there is a great emphasis on vaccine use and the enhancement of existing vaccines to provide long-term protection. Currently existing adjuvants for poultry can have deleterious side-effects, such as inflammation, resulting in the down-grading of meat quality and a subsequent reduction in profits. Therefore, to enhance the use of vaccination, alternative adjuvants must be developed. The use of recombinant cytokines as adjuvants in poultry is attracting considerable attention, and their potential role as such has been addressed by several studies. The recent identification of a number of chicken cytokine genes has provided the possibility to study their effectiveness in enhancing the immune response during infection and vaccination. This review focuses on the recent studies involving the assessment of cytokines as vaccine adjuvants.