RESUMEN
Neutralizing antibodies elicited by HIV-1 coevolve with viral envelope proteins (Env) in distinctive patterns, in some cases acquiring substantial breadth. We report that primary HIV-1 envelope proteins-when expressed by simian-human immunodeficiency viruses in rhesus macaques-elicited patterns of Env-antibody coevolution very similar to those in humans, including conserved immunogenetic, structural, and chemical solutions to epitope recognition and precise Env-amino acid substitutions, insertions, and deletions leading to virus persistence. The structure of one rhesus antibody, capable of neutralizing 49% of a 208-strain panel, revealed a V2 apex mode of recognition like that of human broadly neutralizing antibodies (bNAbs) PGT145 and PCT64-35S. Another rhesus antibody bound the CD4 binding site by CD4 mimicry, mirroring human bNAbs 8ANC131, CH235, and VRC01. Virus-antibody coevolution in macaques can thus recapitulate developmental features of human bNAbs, thereby guiding HIV-1 immunogen design.
Asunto(s)
Coevolución Biológica/inmunología , Anticuerpos ampliamente neutralizantes , Anticuerpos Anti-VIH , Proteína gp120 de Envoltorio del VIH/inmunología , Infecciones por VIH/inmunología , VIH-1/inmunología , Virus de la Inmunodeficiencia de los Simios/inmunología , Animales , Sitios de Unión , Anticuerpos ampliamente neutralizantes/química , Anticuerpos ampliamente neutralizantes/genética , Anticuerpos ampliamente neutralizantes/inmunología , Antígenos CD4/inmunología , Microscopía por Crioelectrón , Epítopos/inmunología , Anticuerpos Anti-VIH/química , Anticuerpos Anti-VIH/genética , Anticuerpos Anti-VIH/inmunología , Proteína gp120 de Envoltorio del VIH/genética , VIH-1/genética , Humanos , Macaca mulatta , Imitación Molecular/inmunología , Virus de la Inmunodeficiencia de los Simios/genética , Replicación ViralRESUMEN
TLR7 subfamily members are important pattern recognition receptors participating in the recognition of pathogen-associated molecular patterns. In this study, we successfully identified 3 members of TLR7 subfamily from the spiny eel Mastacembelus armatus (MaTLR7, MaTLR8 and MaTLR9). The amino acid sequence identities of MaTLR7 and MaTLR8 with Monopterus albus TLR7 were 87.2% and 76.5%, respectively and the identity of MaTLR9 with Seriola lalandi TLR9 was 74.7%. The phylogenetic analysis revealed MaTLRs showed close relationship to other species in Synbranchiformes or Perciformes. Quantitative real-time PCR analysis revealed that they were expressed in all tested tissues and higher expression was found in spleen or gill. After infection with Aeromonas veronii, expression of MaTLR7, MaTLR8 and MaTLR9 were all significantly downregulated in spleen and kidney. Evolutionary analysis suggested that the ancestral lineages of teleost TLR8 and TLR9 had been subject to positive selection pressures and multiple Maximum likelihood methods recovered 3 positively selected sites in teleost TLR7, 4 in TLR8 and 8 in TLR9. Domain distribution revealed most positively selected sites were located in leucine-rich repeat domain. Our results will contribute to better understanding the antibacterial mechanism of TLRs and their co-evolution with pathogens.
Asunto(s)
Evolución Molecular , Proteínas de Peces/genética , Smegmamorpha/genética , Receptor Toll-Like 7/genética , Aeromonas veronii/inmunología , Aeromonas veronii/patogenicidad , Secuencia de Aminoácidos/genética , Animales , Coevolución Biológica/genética , Coevolución Biológica/inmunología , Enfermedades de los Peces/inmunología , Enfermedades de los Peces/microbiología , Infecciones por Bacterias Gramnegativas/inmunología , Infecciones por Bacterias Gramnegativas/microbiología , Interacciones Huésped-Patógeno/genética , Interacciones Huésped-Patógeno/inmunología , Inmunidad Innata/genética , Filogenia , Dominios Proteicos/genética , Dominios Proteicos/inmunología , Selección Genética , Smegmamorpha/inmunología , Smegmamorpha/microbiología , Receptor Toll-Like 7/inmunologíaRESUMEN
APOBEC3G (A3G) is a host enzyme that mutates the genomes of retroviruses like HIV. Since A3G is expressed pre-infection, it has classically been considered an agent of innate immunity. We and others previously showed that the impact of A3G-induced mutations on the HIV genome extends to adaptive immunity also, by generating cytotoxic T cell (CTL) escape mutations. Accordingly, HIV genomic sequences encoding CTL epitopes often contain A3G-mutable "hotspot" sequence motifs, presumably to channel A3G action toward CTL escape. Here, we studied the depths and consequences of this apparent viral genome co-evolution with A3G. We identified all potential CTL epitopes in Gag, Pol, Env, and Nef restricted to several HLA class I alleles. We simulated A3G-induced mutations within CTL epitope-encoding sequences, and flanking regions. From the immune recognition perspective, we analyzed how A3G-driven mutations are predicted to impact CTL-epitope generation through modulating proteasomal processing and HLA class I binding. We found that A3G mutations were most often predicted to result in diminishing/abolishing HLA-binding affinity of peptide epitopes. From the viral genome evolution perspective, we evaluated enrichment of A3G hotspots at sequences encoding CTL epitopes and included control sequences in which the HIV genome was randomly shuffled. We found that sequences encoding immunogenic epitopes exhibited a selective enrichment of A3G hotspots, which were strongly biased to translate to non-synonymous amino acid substitutions. When superimposed on the known mutational gradient across the entire length of the HIV genome, we observed a gradient of A3G hotspot enrichment, and an HLA-specific pattern of the potential of A3G hotspots to lead to CTL escape mutations. These data illuminate the depths and extent of the co-evolution of the viral genome to subvert the host mutator A3G.
