RESUMEN
The study of free-living animal populations is necessary to understand life history trade-offs associated with immune investment. To investigate the role of life history strategies in shaping proinflammatory cell-mediated immune function, we analyzed age, sex, and reproductive status as predictors of urinary neopterin in 70 sexually mature chimpanzees (Pan troglodytes) at Ngogo, Kibale National Park, Uganda. In the absence of clinical signs of acute infectious disease, neopterin levels significantly increased with age in both male and female chimpanzees, as observed in humans and several other vertebrate species. Furthermore, males exhibited higher neopterin levels than females across adulthood. Finally, females with full sexual swellings, pregnant females, and post-reproductive females, the oldest individuals in our sample, exhibited higher neopterin levels than lactating females and cycling females without full swellings. Variation in females' neopterin levels by reproductive status is consistent with post-ovulatory and pregnancy-related immune patterns documented in humans. Together, our results provide evidence of ample variation in chimpanzee immune activity corresponding to biodemographic and physiological variation. Future studies comparing immune activity across ecological conditions and social systems are essential for understanding the life histories of primates and other mammals.
Asunto(s)
Inmunidad Celular , Neopterin/orina , Pan troglodytes/inmunología , Pan troglodytes/orina , Fenómenos Fisiológicos Reproductivos , Envejecimiento , Animales , Animales Salvajes , Femenino , Lactancia , Masculino , Ciclo Menstrual , Posmenopausia , Embarazo , Caracteres SexualesRESUMEN
Despite their close genetic relatedness, apes and African and Asian monkeys (AAMs) differ in their susceptibility to severe bacterial and viral infections that are important causes of human disease. Such differences between humans and other primates are thought to be a result, at least in part, of interspecies differences in immune response to infection. However, because of the lack of comparative functional data across species, it remains unclear in what ways the immune systems of humans and other primates differ. Here, we report the whole-genome transcriptomic responses of ape species (human and chimpanzee) and AAMs (rhesus macaque and baboon) to bacterial and viral stimulation. We find stark differences in the responsiveness of these groups, with apes mounting a markedly stronger early transcriptional response to both viral and bacterial stimulation, altering the transcription of â¼40% more genes than AAMs. Additionally, we find that genes involved in the regulation of inflammatory and interferon responses show the most divergent early transcriptional responses across primates and that this divergence is attenuated over time. Finally, we find that relative to AAMs, apes engage a much less specific immune response to different classes of pathogens during the early hours of infection, up-regulating genes typical of anti-viral and anti-bacterial responses regardless of the nature of the stimulus. Overall, these findings suggest apes exhibit increased sensitivity to bacterial and viral immune stimulation, activating a broader array of defense molecules that may be beneficial for early pathogen killing at the potential cost of increased energy expenditure and tissue damage.
Asunto(s)
Bacterias/inmunología , Metabolismo Energético/inmunología , Interacciones Huésped-Patógeno/inmunología , Inmunidad Innata/genética , Virus/inmunología , Adulto , Animales , Evolución Biológica , Metabolismo Energético/genética , Femenino , Regulación de la Expresión Génica/inmunología , Interacciones Huésped-Patógeno/genética , Humanos , Macaca mulatta/genética , Macaca mulatta/inmunología , Masculino , Persona de Mediana Edad , Pan troglodytes/genética , Pan troglodytes/inmunología , Papio/genética , Papio/inmunología , RNA-Seq , Especificidad de la Especie , Secuenciación del Exoma , Adulto JovenRESUMEN
Based on a large study conducted on wild great ape fecal samples collected in regions of Gabon where previous human outbreaks of Ebola virus disease have occurred between 1994 and 2002, we provide evidence for prevalence of Zaire ebolavirus (EBOV)-specific antibodies of 3.9% (immunoglobulin G (IgG)) and 3.5% (immunoglobulin M (IgM)) in chimpanzees and 8.8% (IgG) and 2.4% (IgM) in gorillas. Importantly, we observed a high local prevalence (31.2%) of anti-EBOV IgG antibodies in gorilla samples. This high local rate of positivity among wild great apes raises the question of a spatially and temporally localized increase in EBOV exposure risk and the role that can be played by these animals as sentinels of the virus's spread or reemergence in a given area.
Asunto(s)
Enfermedades del Simio Antropoideo/inmunología , Enfermedades del Simio Antropoideo/virología , Ebolavirus , Gorilla gorilla/inmunología , Gorilla gorilla/virología , Fiebre Hemorrágica Ebola/veterinaria , Animales , Anticuerpos Antivirales , Enfermedades del Simio Antropoideo/diagnóstico , Enfermedades del Simio Antropoideo/epidemiología , Heces/virología , Gabón/epidemiología , Geografía , Inmunoglobulina G/inmunología , Inmunoglobulina M/inmunología , Pan troglodytes/inmunología , ARN Viral , Análisis de Secuencia de ADNRESUMEN
The major histocompatibility complex (MHC) class I region of humans, chimpanzees (Pan troglodytes), and bonobos (Pan paniscus) is highly similar, and orthologues of HLA-A, -B, and -C are present in both Pan species. Based on functional characteristics, the different HLA-A allotypes are classified into different supertypes. One of them, the HLA A03 supertype, is widely distributed among different human populations. All contemporary known chimpanzee and bonobo MHC class I A allotypes cluster genetically into one of the six HLA-A families, the HLA-A1/A3/A11/A30 family. We report here that the peptide-binding motif of the Patr-A*05:01 allotype, which is commonly present in a cohort of western African chimpanzees, has a strong preference for binding peptides with basic amino acids at the carboxyl terminus. This phenomenon is shared with the family members of the HLA A03 supertype. Based on the chemical similarities in the peptide-binding pocket, we inferred that the preference for binding peptides with basic amino acids at the carboxyl terminus is widely present among the human, chimpanzee, and bonobo MHC-A allotypes. Subsequent in silico peptide-binding predictions illustrated that these allotypes have the capacity to target conserved parts of the proteome of human immunodeficiency virus type 1 (HIV-1) and the simian immunodeficiency virus SIVcpz.IMPORTANCE Most experimentally infected chimpanzees seem to control an HIV-1 infection and are therefore considered to be relatively resistant to developing AIDS. Contemporary free-ranging chimpanzees may carry SIVcpz, and there is evidence for AIDS-like symptoms in these free-ranging animals, whereas SIV infections in bonobos appear to be absent. In humans, the natural control of an HIV-1 infection is strongly associated with the presence of particular HLA class I allotypes. The ancestor of the contemporary living chimpanzees and bonobos survived a selective sweep targeting the MHC class I repertoire. We have put forward a hypothesis that this may have been caused by an ancestral retroviral infection similar to SIVcpz. Characterization of the relevant MHC allotypes may contribute to understanding the shaping of their immune repertoire. The abundant presence of MHC-A allotypes that prefer peptides with basic amino acids at the C termini suggests that these molecules may contribute to the control of retroviral infections in humans, chimpanzees, and bonobos.
Asunto(s)
Genes MHC Clase I/inmunología , Antígeno HLA-A3/inmunología , Primates/inmunología , Alelos , Secuencia de Aminoácidos , Animales , VIH-1/inmunología , Antígeno HLA-A3/metabolismo , Antígenos de Histocompatibilidad , Antígenos de Histocompatibilidad Clase I/inmunología , Humanos , Pan paniscus/inmunología , Pan troglodytes/inmunología , Péptidos/metabolismo , Filogenia , Unión Proteica/inmunología , Infecciones por Retroviridae/inmunología , Virus de la Inmunodeficiencia de los Simios/inmunologíaRESUMEN
Chimpanzees, humans' closest relatives, are in danger of extinction. Aside from direct human impacts such as hunting and habitat destruction, a key threat is transmissible disease. As humans continue to encroach upon their habitats, which shrink in size and grow in density, the risk of inter-population and cross-species viral transmission increases, a point dramatically made in the reverse with the global HIV/AIDS pandemic. Inhabiting central Africa, the four subspecies of chimpanzees differ in demographic history and geographical range, and are likely differentially adapted to their particular local environments. To quantitatively explore genetic adaptation, we investigated the genic enrichment for SNPs highly differentiated between chimpanzee subspecies. Previous analyses of such patterns in human populations exhibited limited evidence of adaptation. In contrast, chimpanzees show evidence of recent positive selection, with differences among subspecies. Specifically, we observe strong evidence of recent selection in eastern chimpanzees, with highly differentiated SNPs being uniquely enriched in genic sites in a way that is expected under recent adaptation but not under neutral evolution or background selection. These sites are enriched for genes involved in immune responses to pathogens, and for genes inferred to differentiate the immune response to infection by simian immunodeficiency virus (SIV) in natural vs. non-natural host species. Conversely, central chimpanzees exhibit an enrichment of signatures of positive selection only at cytokine receptors, due to selective sweeps in CCR3, CCR9 and CXCR6 -paralogs of CCR5 and CXCR4, the two major receptors utilized by HIV to enter human cells. Thus, our results suggest that positive selection has contributed to the genetic and phenotypic differentiation of chimpanzee subspecies, and that viruses likely play a predominate role in this differentiation, with SIV being a likely selective agent. Interestingly, our results suggest that SIV has elicited distinctive adaptive responses in these two chimpanzee subspecies.
Asunto(s)
Adaptación Fisiológica/genética , Inmunidad Innata/genética , Pan troglodytes/genética , Selección Genética/genética , Adaptación Fisiológica/inmunología , Animales , Demografía , Flujo Genético , Especiación Genética , VIH/genética , VIH/inmunología , VIH/patogenicidad , Humanos , Pan troglodytes/inmunología , Pan troglodytes/virología , Polimorfismo de Nucleótido Simple/genética , Receptores CCR/genética , Receptores CCR3/genética , Receptores CCR5/genética , Receptores CXCR4/genética , Receptores CXCR6/inmunología , Virus de la Inmunodeficiencia de los Simios/genética , Virus de la Inmunodeficiencia de los Simios/inmunología , Virus de la Inmunodeficiencia de los Simios/patogenicidadRESUMEN
Pandemic HIV-1 (group M) emerged following the cross-species transmission of a simian immunodeficiency virus from chimpanzees (SIVcpz) to humans. Primate lentiviruses (HIV/SIV) require the T cell receptor CD4 to enter into target cells. By surveying the sequence and function of CD4 in 50 chimpanzee individuals, we find that all chimpanzee CD4 alleles encode a fixed, chimpanzee-specific substitution (34T) that creates a glycosylation site on the virus binding surface of the CD4 receptor. Additionally, a single nucleotide polymorphism (SNP) has arisen in chimpanzee CD4 (68T) that creates a second glycosylation site on the same virus-binding interface. This substitution is not yet fixed, but instead alleles containing this SNP are still circulating within chimpanzee populations. Thus, all allelic versions of chimpanzee CD4 are singly glycosylated at the virus binding surface, and some allelic versions are doubly glycosylated. Doubly glycosylated forms of chimpanzee CD4 reduce HIV-1 and SIVcpz infection by as much as two orders of magnitude. Full restoration of virus infection in cells bearing chimpanzee CD4 requires reversion of both threonines at sites 34 and 68, destroying both of the glycosylation sites, suggesting that the effects of the glycans are additive. Differentially glycosylated CD4 receptors were biochemically purified and used in neutralization assays and microscale thermophoresis to show that the glycans on chimpanzee CD4 reduce binding affinity with the lentiviral surface glycoprotein, Env. These glycans create a shield that protects CD4 from being engaged by viruses, demonstrating a powerful form of host resistance against deadly primate lentiviruses.
Asunto(s)
Antígenos CD4/inmunología , Infecciones por VIH/inmunología , VIH-1/inmunología , Pan troglodytes/inmunología , Pan troglodytes/virología , Polisacáridos/inmunología , Síndrome de Inmunodeficiencia Adquirida del Simio/inmunología , Virus de la Inmunodeficiencia de los Simios/inmunología , Animales , Línea Celular , Glicosilación , Células HEK293 , Infecciones por VIH/virología , Humanos , Polimorfismo de Nucleótido Simple/inmunología , Síndrome de Inmunodeficiencia Adquirida del Simio/virologíaRESUMEN
Human and simian immunodeficiency viruses (HIV/SIVs) use CD4 as the primary receptor to enter target cells. Here, we show that the chimpanzee CD4 is highly polymorphic, with nine coding variants present in wild populations, and that this diversity interferes with SIV envelope (Env)-CD4 interactions. Testing the replication fitness of SIVcpz strains in CD4+ T cells from captive chimpanzees, we found that certain viruses were unable to infect cells from certain hosts. These differences were recapitulated in CD4 transfection assays, which revealed a strong association between CD4 genotypes and SIVcpz infection phenotypes. The most striking differences were observed for three substitutions (Q25R, Q40R, and P68T), with P68T generating a second N-linked glycosylation site (N66) in addition to an invariant N32 encoded by all chimpanzee CD4 alleles. In silico modeling and site-directed mutagenesis identified charged residues at the CD4-Env interface and clashes between CD4- and Env-encoded glycans as mechanisms of inhibition. CD4 polymorphisms also reduced Env-mediated cell entry of monkey SIVs, which was dependent on at least one D1 domain glycan. CD4 allele frequencies varied among wild chimpanzees, with high diversity in all but the western subspecies, which appeared to have undergone a selective sweep. One allele was associated with lower SIVcpz prevalence rates in the wild. These results indicate that substitutions in the D1 domain of the chimpanzee CD4 can prevent SIV cell entry. Although some SIVcpz strains have adapted to utilize these variants, CD4 diversity is maintained, protecting chimpanzees against infection with SIVcpz and other SIVs to which they are exposed.
Asunto(s)
Antígenos CD4/genética , Síndrome de Inmunodeficiencia Adquirida del Simio/genética , Virus de la Inmunodeficiencia de los Simios/genética , Proteínas del Envoltorio Viral/genética , Animales , Antígenos CD4/inmunología , Linfocitos T CD4-Positivos/inmunología , Evolución Molecular , Variación Genética/inmunología , VIH/genética , VIH/patogenicidad , Humanos , Pan troglodytes/genética , Pan troglodytes/inmunología , Polisacáridos/genética , Polisacáridos/inmunología , Síndrome de Inmunodeficiencia Adquirida del Simio/inmunología , Síndrome de Inmunodeficiencia Adquirida del Simio/virología , Virus de la Inmunodeficiencia de los Simios/patogenicidad , Proteínas del Envoltorio Viral/inmunologíaRESUMEN
The selective pressure by infectious agents is a major driving force in the evolution of humans and other mammals. Members of the carcinoembryonic antigen-related cell adhesion molecule (CEACAM) family serve as receptors for bacterial pathogens of the genera Haemophilus, Helicobacter, Neisseria, and Moraxella, which engage CEACAMs via distinct surface adhesins. While microbial attachment to epithelial CEACAMs facilitates host colonization, recognition by CEACAM3, a phagocytic receptor expressed by granulocytes, eliminates CEACAM-binding bacteria. Sequence analysis of primate CEACAM3 orthologs reveals that this innate immune receptor is one of the most rapidly evolving human proteins. In particular, the pathogen-binding extracellular domain of CEACAM3 shows a high degree of non-synonymous versus synonymous nucleotide exchanges, indicating an exceptionally strong positive selection. Using CEACAM3 domains derived from different primates, we find that the amino acid alterations found in CEACAM3 translate into characteristic binding patterns for bacterial adhesins. One such amino acid residue is F62 in human and chimp CEACAM3, which is not present in other primates and which is critical for binding the OMP P1 adhesin of Haemophilus aegyptius. Incorporation of the F62-containing motif into gorilla CEACAM3 results in a gain-of-function phenotype with regard to phagocytosis of H. aegyptius. Moreover, CEACAM3 polymorphisms found in human subpopulations widen the spectrum of recognized bacterial adhesins, suggesting an ongoing multivariate selection acting on this innate immune receptor. The species-specific detection of diverse bacterial adhesins helps to explain the exceptionally fast evolution of CEACAM3 within the primate lineage and provides an example of Red Queen dynamics in the human genome.
Asunto(s)
Adhesinas Bacterianas/fisiología , Antígeno Carcinoembrionario/genética , Evolución Molecular , Gorilla gorilla/genética , Inmunidad Innata/genética , Pan troglodytes/genética , Receptores Inmunológicos/genética , Animales , Fenómenos Fisiológicos Bacterianos , Antígeno Carcinoembrionario/inmunología , Gorilla gorilla/inmunología , Humanos , Pan troglodytes/inmunología , Receptores Inmunológicos/inmunologíaRESUMEN
Natural killer (NK) cells are primary immune effector cells with both innate and potentially adaptive functions against viral infections, but commonly become exhausted or dysfunctional during chronic diseases such as human immunodeficiency virus (HIV). Chimpanzees are the closest genetic relatives of humans and have been previously used in immunology, behavior and disease models. Due to their similarities to humans, a better understanding of chimpanzee immunology, particularly innate immune cells, can lend insight into the evolution of human immunology, as well as response to disease. However, the phenotype of NK cells has been poorly defined. In order to define NK cell phenotypes, we unbiasedly quantified NK cell markers among mononuclear cells in both naive and HIV-infected chimpanzees by flow cytometry. We identified NKG2D and NKp46 as the most dominant stable NK cells markers using multidimensional data reduction analyses. Other traditional NK cell markers such as CD8α, CD16 and perforin fluctuated during infection, while some such as CD56, NKG2A and NKp30 were generally unaltered by HIV infection, but did not delineate the full NK cell repertoire. Taken together, these data indicate that phenotypic dysregulation may not be pronounced during HIV infection of chimpanzees, but traditional NK cell phenotyping used for both humans and other non-human primate species may need to be revised to accurately identify chimpanzee NK cells.
Asunto(s)
Citometría de Flujo , Infecciones por VIH/inmunología , Infecciones por VIH/patología , Células Asesinas Naturales/citología , Células Asesinas Naturales/inmunología , Pan troglodytes/inmunología , Pan troglodytes/virología , Animales , Infecciones por VIH/sangre , Humanos , Células Asesinas Naturales/patología , Pan troglodytes/sangre , FenotipoRESUMEN
Chimpanzees have been used for some time as an animal model in research on immune-related diseases in humans. The major histocompatibility complex (MHC) region of the chimpanzee has also been the subject of studies in which the attention was mainly on the class I genes. Although full-length sequence information is available on the DRB region genes, such detailed information is lacking for the other class II genes and, if present, is based mainly on exon 2 sequences. In the present study, full-length sequencing was performed on DQ, DP, and DRA genes in a cohort of 67 pedigreed animals, thereby allowing a thorough analysis of the MHC class II repertoire. The results demonstrate that the number of MHC class II lineages and alleles is relatively low, whereas haplotype diversity (combination of genes/alleles on a chromosome) seems to have been maximised by crossing-over processes.
Asunto(s)
Genes MHC Clase II , Haplotipos , Pan troglodytes/genética , Alelos , Animales , Variación Genética , Antígenos HLA-DP/genética , Antígenos HLA-DQ/genética , Antígenos HLA-DR/genética , Pan troglodytes/inmunologíaRESUMEN
Major histocompatibility complex (MHC) class I genes are critically involved in the defense against intracellular pathogens. MHC diversity comparisons among samples of closely related taxa may reveal traces of past or ongoing selective processes. The bonobo and chimpanzee are the closest living evolutionary relatives of humans and last shared a common ancestor some 1 mya. However, little is known concerning MHC class I diversity in bonobos or in central chimpanzees, the most numerous and genetically diverse chimpanzee subspecies. Here, we used a long-read sequencing technology (PacBio) to sequence the classical MHC class I genes A, B, C, and A-like in 20 and 30 wild-born bonobos and chimpanzees, respectively, with a main focus on central chimpanzees to assess and compare diversity in those two species. We describe in total 21 and 42 novel coding region sequences for the two species, respectively. In addition, we found evidence for a reduced MHC class I diversity in bonobos as compared to central chimpanzees as well as to western chimpanzees and humans. The reduced bonobo MHC class I diversity may be the result of a selective process in their evolutionary past since their split from chimpanzees.
Asunto(s)
Variación Genética/inmunología , Antígenos de Histocompatibilidad Clase I/genética , Pan paniscus/genética , Pan troglodytes/genética , Filogenia , Alelos , Animales , Evolución Biológica , Femenino , Frecuencia de los Genes , Genotipo , Técnicas de Genotipaje , Secuenciación de Nucleótidos de Alto Rendimiento , Antígenos de Histocompatibilidad Clase I/clasificación , Antígenos de Histocompatibilidad Clase I/inmunología , Humanos , Masculino , Sistemas de Lectura Abierta , Pan paniscus/clasificación , Pan paniscus/inmunología , Pan troglodytes/clasificación , Pan troglodytes/inmunologíaRESUMEN
Common chimpanzees (Pan troglodytes) experienced a selective sweep, probably caused by a SIV-like virus, which targeted their MHC class I repertoire. Based on MHC class I intron 2 data analyses, this selective sweep took place about 2-3 million years ago. As a consequence, common chimpanzees have a skewed MHC class I repertoire that is enriched for allotypes that are able to recognise conserved regions of the SIV proteome. The bonobo (Pan paniscus) shared an ancestor with common chimpanzees approximately 1.5 to 2 million years ago. To investigate whether the signature of this selective sweep is also detectable in bonobos, the MHC class I gene repertoire of two bonobo panels comprising in total 29 animals was investigated by Sanger sequencing. We identified 14 Papa-A, 20 Papa-B and 11 Papa-C alleles, of which eight, five and eight alleles, respectively, have not been reported previously. Within this pool of MHC class I variation, we recovered only 2 Papa-A, 3 Papa-B and 6 Papa-C intron 2 sequences. As compared to humans, bonobos appear to have an even more diminished MHC class I intron 2 lineage repertoire than common chimpanzees. This supports the notion that the selective sweep may have predated the speciation of common chimpanzees and bonobos. The further reduction of the MHC class I intron 2 lineage repertoire observed in bonobos as compared to the common chimpanzee may be explained by a founding effect or other subsequent selective processes.
Asunto(s)
Especiación Genética , Antígenos de Histocompatibilidad Clase I/genética , Intrones , Pan paniscus/genética , Pan troglodytes/genética , Filogenia , Alelos , Secuencia de Aminoácidos , Animales , Femenino , Frecuencia de los Genes , Variación Genética , Secuenciación de Nucleótidos de Alto Rendimiento , Antígenos de Histocompatibilidad Clase I/clasificación , Antígenos de Histocompatibilidad Clase I/inmunología , Humanos , Masculino , Pan paniscus/clasificación , Pan paniscus/inmunología , Pan troglodytes/clasificación , Pan troglodytes/inmunología , Selección Genética , Alineación de SecuenciaAsunto(s)
Conservación de los Recursos Naturales/métodos , Vacunas contra el Virus del Ébola/administración & dosificación , Ebolavirus/inmunología , Gorilla gorilla/virología , Fiebre Hemorrágica Ebola/prevención & control , Fiebre Hemorrágica Ebola/veterinaria , Vacunación Masiva/veterinaria , Administración Oral , África/epidemiología , Animales , Animales Salvajes/inmunología , Animales Salvajes/virología , Anticuerpos Antivirales/análisis , Anticuerpos Antivirales/inmunología , Ensayos Clínicos como Asunto/veterinaria , Modelos Animales de Enfermedad , Vacunas contra el Virus del Ébola/efectos adversos , Vacunas contra el Virus del Ébola/inmunología , Ebolavirus/aislamiento & purificación , Especies en Peligro de Extinción/estadística & datos numéricos , Especies en Peligro de Extinción/tendencias , Gorilla gorilla/inmunología , Fiebre Hemorrágica Ebola/inmunología , Fiebre Hemorrágica Ebola/mortalidad , Historia del Siglo XX , Historia del Siglo XXI , Humanos , Inyecciones , Macaca mulatta/inmunología , Macaca mulatta/virología , Vacunación Masiva/métodos , Ratones , Pan troglodytes/inmunología , Parques Recreativos , Análisis de SupervivenciaRESUMEN
Following the eradication of wild poliovirus (PV), achieving and maintaining a polio-free status will require eliminating potentially pathogenic PV strains derived from the oral attenuated vaccine. For this purpose, a combination of non-cross-resistant drugs, such as small molecules and neutralizing monoclonal antibodies (mAbs), may be ideal. We previously isolated chimpanzee and human mAbs capable of neutralizing multiple PV types (cross-neutralization). Here, we describe three additional human mAbs that neutralize types 1 and 2 PV and one mAb that neutralizes all three types. Most bind conformational epitopes and have unusually long heavy chain complementarity determining 3 domains (HC CDR3). We assessed the ability of the mAbs to neutralize A12 escape mutant PV strains, and found that the neutralizing activities of the mAbs were disrupted by different amino acid substitutions. Competitive binding studies further suggested that the specific mAb:PV interactions that enable cross-neutralization differ among mAbs and serotypes. All of the cloned mAbs bind PV in the vicinity of the "canyon", a circular depression around the 5-fold axis of symmetry through which PV recognizes its cellular receptor. We were unable to generate escape mutants to two of the mAbs, suggesting that their epitopes are important for the PV life cycle. These data indicate that PV cross-neutralization involves binding to highly conserved structures within the canyon that binds to the cellular receptor. These may be facilitated by the long HC CDR3 domains, which may adopt alternative binding configurations. We propose that the human and chimpanzee mAbs described here could have potential as anti-PV therapeutics.
Asunto(s)
Anticuerpos Monoclonales/inmunología , Anticuerpos Neutralizantes/inmunología , Anticuerpos Antivirales/inmunología , Poliomielitis/inmunología , Poliovirus/inmunología , Adulto , Anciano , Animales , Antígenos Virales/inmunología , Epítopos/inmunología , Humanos , Persona de Mediana Edad , Pruebas de Neutralización/métodos , Pan troglodytes/inmunología , Pan troglodytes/virología , Poliomielitis/prevención & control , Poliomielitis/virología , SerogrupoAsunto(s)
Antropología/organización & administración , Distinciones y Premios , Pan troglodytes/inmunología , Enfermedades Respiratorias/genética , Ribonucleasa Pancreática/genética , Alergia e Inmunología/educación , Alouatta/genética , Animales , Ecología/educación , Educación de Postgrado/estadística & datos numéricos , Femenino , Historia del Siglo XXI , Humanos , Pan troglodytes/genética , Enfermedades Respiratorias/veterinaria , Uganda/epidemiologíaRESUMEN
Rift Valley Fever virus (RVFV) causes recurrent outbreaks of acute life-threatening human and livestock illness in Africa and the Arabian Peninsula. No licensed vaccines are currently available for humans and those widely used in livestock have major safety concerns. A 'One Health' vaccine development approach, in which the same vaccine is co-developed for multiple susceptible species, is an attractive strategy for RVFV. Here, we utilized a replication-deficient chimpanzee adenovirus vaccine platform with an established human and livestock safety profile, ChAdOx1, to develop a vaccine for use against RVFV in both livestock and humans. We show that single-dose immunization with ChAdOx1-GnGc vaccine, encoding RVFV envelope glycoproteins, elicits high-titre RVFV-neutralizing antibody and provides solid protection against RVFV challenge in the most susceptible natural target species of the virus-sheep, goats and cattle. In addition we demonstrate induction of RVFV-neutralizing antibody by ChAdOx1-GnGc vaccination in dromedary camels, further illustrating the potency of replication-deficient chimpanzee adenovirus vaccine platforms. Thus, ChAdOx1-GnGc warrants evaluation in human clinical trials and could potentially address the unmet human and livestock vaccine needs.
Asunto(s)
Vacunas contra el Adenovirus/administración & dosificación , Anticuerpos Neutralizantes/metabolismo , Fiebre del Valle del Rift/prevención & control , Virus de la Fiebre del Valle del Rift/metabolismo , Proteínas del Envoltorio Viral/genética , Vacunas Virales/administración & dosificación , Vacunas contra el Adenovirus/farmacología , Animales , Camelus , Bovinos , Cabras , Humanos , Pan troglodytes/inmunología , Pan troglodytes/virología , Fiebre del Valle del Rift/inmunología , Virus de la Fiebre del Valle del Rift/genética , Virus de la Fiebre del Valle del Rift/inmunología , Arabia Saudita/epidemiología , Ovinos , Reino Unido/epidemiología , Vacunación , Vacunas Sintéticas/administración & dosificación , Proteínas del Envoltorio Viral/inmunologíaRESUMEN
Cross-species transmissions of viruses from animals to humans are at the origin of major human pathogenic viruses. While the role of ecological and epidemiological factors in the emergence of new pathogens is well documented, the importance of host factors is often unknown. Chimpanzees are the closest relatives of humans and the animal reservoir at the origin of the human AIDS pandemic. However, despite being regularly exposed to monkey lentiviruses through hunting, chimpanzees are naturally infected by only a single simian immunodeficiency virus, SIVcpz. Here, we asked why chimpanzees appear to be protected against the successful emergence of other SIVs. In particular, we investigated the role of the chimpanzee APOBEC3 genes in providing a barrier to infection by most monkey lentiviruses. We found that most SIV Vifs, including Vif from SIVwrc infecting western-red colobus, the chimpanzee's main monkey prey in West Africa, could not antagonize chimpanzee APOBEC3G. Moreover, chimpanzee APOBEC3D, as well as APOBEC3F and APOBEC3H, provided additional protection against SIV Vif antagonism. Consequently, lentiviral replication in primary chimpanzee CD4(+) T cells was dependent on the presence of a lentiviral vif gene that could antagonize chimpanzee APOBEC3s. Finally, by identifying and functionally characterizing several APOBEC3 gene polymorphisms in both common chimpanzees and bonobos, we found that these ape populations encode APOBEC3 proteins that are uniformly resistant to antagonism by monkey lentiviruses.
Asunto(s)
Citidina Desaminasa/genética , Infecciones por Lentivirus/genética , Pan troglodytes/inmunología , Pan troglodytes/virología , Virus de la Inmunodeficiencia de los Simios/genética , Animales , Western Blotting , Linfocitos T CD4-Positivos/inmunología , Citidina Desaminasa/inmunología , Genes vif/genética , Haplorrinos , Lentivirus/genética , Infecciones por Lentivirus/inmunología , Datos de Secuencia Molecular , Filogenia , Reacción en Cadena de la PolimerasaRESUMEN
Major histocompatibility complex (MHC) class I molecules determine immune responses to viral infections. These polymorphic cell-surface glycoproteins bind peptide antigens, forming ligands for cytotoxic T and natural killer cell receptors. Under pressure from rapidly evolving viruses, hominoid MHC class I molecules also evolve rapidly, becoming diverse and species-specific. Little is known of the impact of infectious disease epidemics on MHC class I variant distributions in human populations, a context in which the chimpanzee is the superior animal model. Population dynamics of the chimpanzees inhabiting Gombe National Park, Tanzania have been studied for over 50 years. This population is infected with SIVcpz, the precursor of human HIV-1. Because HLA-B is the most polymorphic human MHC class I molecule and correlates strongly with HIV-1 progression, we determined sequences for its ortholog, Patr-B, in 125 Gombe chimpanzees. Eleven Patr-B variants were defined, as were their frequencies in Gombe's three communities, changes in frequency with time, and effect of SIVcpz infection. The growing populations of the northern and central communities, where SIVcpz is less prevalent, have stable distributions comprising a majority of low-frequency Patr-B variants and a few high-frequency variants. Driving the latter to high frequency has been the fecundity of immigrants to the northern community, whereas in the central community, it has been the fecundity of socially dominant individuals. In the declining population of the southern community, where greater SIVcpz prevalence is associated with mortality and emigration, Patr-B variant distributions have been changing. Enriched in this community are Patr-B variants that engage with natural killer cell receptors. Elevated among SIVcpz-infected chimpanzees, the Patr-B*06:03 variant has striking structural and functional similarities to HLA-B*57, the human allotype most strongly associated with delayed HIV-1 progression. Like HLA-B*57, Patr-B*06:03 correlates with reduced viral load, as assessed by detection of SIVcpz RNA in feces.
Asunto(s)
Genes MHC Clase I , Pan troglodytes/inmunología , Virus de la Inmunodeficiencia de los Simios/inmunología , Alelos , Animales , ADN/análisis , Heces/química , Femenino , Aptitud Genética , Variación Genética , Masculino , Pan troglodytes/genética , ReproducciónRESUMEN
Infectious disease has only recently been recognized as a major threat to the survival of Endangered chimpanzees and Critically Endangered gorillas in the wild. One potentially powerful tool, vaccination, has not been deployed in fighting this disease threat, in good part because of fears about vaccine safety. Here we report on what is, to our knowledge, the first trial in which captive chimpanzees were used to test a vaccine intended for use on wild apes rather than humans. We tested a virus-like particle vaccine against Ebola virus, a leading source of death in wild gorillas and chimpanzees. The vaccine was safe and immunogenic. Captive trials of other vaccines and of methods for vaccine delivery hold great potential as weapons in the fight against wild ape extinction.