RESUMEN
Peptides generated by proteasome-catalyzed splicing of noncontiguous amino acid sequences have been shown to constitute a source of nontemplated human leukocyte antigen class I (HLA-I) epitopes, but their role in pathogen-specific immunity remains unknown. CD8+ T cells are key mediators of HIV type 1 (HIV-1) control, and identification of novel epitopes to enhance targeting of infected cells is a priority for prophylactic and therapeutic strategies. To explore the contribution of proteasome-catalyzed peptide splicing (PCPS) to HIV-1 epitope generation, we developed a broadly applicable mass spectrometry-based discovery workflow that we employed to identify spliced HLA-I-bound peptides on HIV-infected cells. We demonstrate that HIV-1-derived spliced peptides comprise a relatively minor component of the HLA-I-bound viral immunopeptidome. Although spliced HIV-1 peptides may elicit CD8+ T cell responses relatively infrequently during infection, CD8+ T cells primed by partially overlapping contiguous epitopes in HIV-infected individuals were able to cross-recognize spliced viral peptides, suggesting a potential role for PCPS in restricting HIV-1 escape pathways. Vaccine-mediated priming of responses to spliced HIV-1 epitopes could thus provide a novel means of exploiting epitope targets typically underutilized during natural infection.
Asunto(s)
Linfocitos T CD8-positivos/inmunología , Reactividad Cruzada/genética , Infecciones por VIH/inmunología , VIH-1/inmunología , Complejo de la Endopetidasa Proteasomal/metabolismo , Vacunas contra el SIDA/inmunología , Vacunas contra el SIDA/uso terapéutico , Antígenos Virales/genética , Antígenos Virales/inmunología , Antígenos Virales/metabolismo , Linfocitos T CD8-positivos/metabolismo , Línea Celular , Estudios de Cohortes , Reacciones Cruzadas/inmunología , Conjuntos de Datos como Asunto , Epítopos de Linfocito T/genética , Epítopos de Linfocito T/inmunología , Epítopos de Linfocito T/metabolismo , Infecciones por VIH/sangre , Infecciones por VIH/terapia , Infecciones por VIH/virología , VIH-1/genética , Antígenos de Histocompatibilidad Clase I/inmunología , Antígenos de Histocompatibilidad Clase I/metabolismo , Humanos , Evasión Inmune , Péptidos/genética , Péptidos/inmunología , Péptidos/metabolismo , Complejo de la Endopetidasa Proteasomal/inmunología , Empalme del ARN/inmunología , ARN Viral/sangre , ARN Viral/genética , ARN Viral/aislamiento & purificación , RNA-Seq , Proteínas Virales/genética , Proteínas Virales/inmunología , Proteínas Virales/metabolismoRESUMEN
The Laverania clade comprises the human malaria parasite Plasmodium falciparum as well as at least seven additional parasite species that infect wild African apes. A recent analysis of Laverania genome sequences (Otto TD, et al. 2018. Genomes of all known members of a Plasmodium subgenus reveal paths to virulent human malaria. Nat Microbiol. 3: 687-697) reported three instances of interspecies gene transfer, one of which had previously been described. Generating gene sequences from additional ape parasites and re-examining sequencing reads generated in the Otto et al. study, we identified one of the newly described gene transfers as an assembly artifact of sequences derived from a sample coinfected by two parasite species. The second gene transfer between ancestors of two divergent chimpanzee parasite lineages was confirmed, but involved a much larger number of genes than originally described, many of which encode exported proteins that remodel, or bind to, erythrocytes. Because successful hybridization between Laverania species is very rare, it will be important to determine to what extent these gene transfers have shaped their host interactions.
Asunto(s)
Introgresión Genética , Pan troglodytes/parasitología , Plasmodium/genética , Virulencia/genética , Animales , Evolución Molecular , Humanos , Malaria/parasitología , Filogenia , Plasmodium/patogenicidadRESUMEN
Highly effective direct-acting antivirals against Hepatitis C virus (HCV) have created an opportunity to transplant organs from HCV-positive individuals into HCV-negative recipients, since de novo infection can be routinely cured. As this procedure is performed more widely, it becomes increasingly important to understand the biological underpinnings of virus transmission, especially the multiplicity of infection. Here, we used single genome sequencing of plasma virus in four genotype 1a HCV-positive organ donors and their seven organ recipients to assess the genetic bottleneck associated with HCV transmission following renal and cardiac transplantation. In all recipients, de novo infection was established by multiple genetically distinct viruses that reflect the full phylogenetic spectrum of replication-competent virus circulating in donor plasma. This was true in renal and cardiac transplantation and in recipients with peak viral loads ranging between 2.9 and 6.6 log10 IU/mL. The permissive transmission process characterized here contrasts sharply with sexual or injection-related transmission, which occurs less frequently per exposure and is generally associated with a stringent genetic bottleneck. These findings highlight the effectiveness of current anti-HCV regimens, while raising caution regarding the substantially higher multiplicity of infection seen in organ transplantation-associated HCV acquisition.
Asunto(s)
Trasplante de Corazón , Hepacivirus , Hepatitis C , Trasplante de Riñón , Filogenia , Femenino , Hepacivirus/genética , Hepacivirus/metabolismo , Hepatitis C/sangre , Hepatitis C/tratamiento farmacológico , Hepatitis C/genética , Hepatitis C/transmisión , Humanos , Masculino , Especificidad de ÓrganosRESUMEN
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
Eliciting HIV-1-specific broadly neutralizing antibodies (bNAbs) remains a challenge for vaccine development, and the potential of passively delivered bNAbs for prophylaxis and therapeutics is being explored. We used neutralization data from four large virus panels to comprehensively map viral signatures associated with bNAb sensitivity, including amino acids, hypervariable region characteristics, and clade effects across four different classes of bNAbs. The bNAb signatures defined for the variable loop 2 (V2) epitope region of HIV-1 Env were then employed to inform immunogen design in a proof-of-concept exploration of signature-based epitope targeted (SET) vaccines. V2 bNAb signature-guided mutations were introduced into Env 459C to create a trivalent vaccine, and immunization of guinea pigs with V2-SET vaccines resulted in increased breadth of NAb responses compared with Env 459C alone. These data demonstrate that bNAb signatures can be utilized to engineer HIV-1 Env vaccine immunogens capable of eliciting antibody responses with greater neutralization breadth.
Asunto(s)
Anticuerpos Neutralizantes/inmunología , Epítopos/inmunología , Anticuerpos Anti-VIH/inmunología , Infecciones por VIH/inmunología , Infecciones por VIH/prevención & control , Vacunas , Secuencia de Aminoácidos , Animales , Anticuerpos Neutralizantes/uso terapéutico , Formación de Anticuerpos , Modelos Animales de Enfermedad , Epítopos/genética , Femenino , Cobayas , Células HEK293 , Proteína gp120 de Envoltorio del VIH/inmunología , Infecciones por VIH/virología , VIH-1/genética , Humanos , Inmunización , Concentración 50 Inhibidora , Modelos Moleculares , Mutación , Fragmentos de Péptidos/inmunología , Unión Proteica , Vacunación , Productos del Gen env del Virus de la Inmunodeficiencia Humana/genética , Productos del Gen env del Virus de la Inmunodeficiencia Humana/inmunologíaRESUMEN
The role that broadly neutralizing antibodies (bNAbs) play in natural clearance of human hepatitis C virus (HCV) infection and the underlying mechanisms remain unknown. Here, we investigate the mechanism by which bNAbs, isolated from two humans who spontaneously cleared HCV infection, contribute to HCV control. Using viral gene sequences amplified from longitudinal plasma of the two subjects, we found that these bNAbs, which target the front layer of the HCV envelope protein E2, neutralized most autologous HCV strains. Acquisition of resistance to bNAbs by some autologous strains was accompanied by progressive loss of E2 protein function, and temporally associated with HCV clearance. These data demonstrate that bNAbs can mediate clearance of human HCV infection by neutralizing infecting strains and driving escaped viruses to an unfit state. These immunopathologic events distinguish HCV from HIV-1 and suggest that development of an HCV vaccine may be achievable.
Asunto(s)
Anticuerpos Neutralizantes/inmunología , Hepacivirus/inmunología , Anticuerpos contra la Hepatitis C/inmunología , Hepatitis C/inmunología , Animales , Anticuerpos Monoclonales/inmunología , Anticuerpos Neutralizantes/química , Especificidad de Anticuerpos , Secuencia de Bases , Sitios de Unión , Línea Celular , Cricetulus , Epítopos/inmunología , Femenino , Células HEK293 , VIH-1/inmunología , Hepacivirus/genética , Anticuerpos contra la Hepatitis C/sangre , Anticuerpos contra la Hepatitis C/química , Humanos , Memoria Inmunológica , Masculino , Modelos Moleculares , Mutagénesis Sitio-Dirigida , Proteínas del Envoltorio Viral/genética , Proteínas del Envoltorio Viral/inmunología , Carga ViralRESUMEN
Densely arranged N-linked glycans shield the HIV-1 envelope (Env) trimer from antibody recognition. Strain-specific breaches in this shield (glycan holes) can be targets of vaccine-induced neutralizing antibodies that lack breadth. To understand the interplay between glycan holes and neutralization breadth in HIV-1 infection, we developed a sequence- and structure-based approach to identify glycan holes for individual Env sequences that are shielded in most M-group viruses. Applying this approach to 12 longitudinally followed individuals, we found that transmitted viruses with more intact glycan shields correlated with development of greater neutralization breadth. Within 2 years, glycan acquisition filled most glycan holes present at transmission, indicating escape from hole-targeting neutralizing antibodies. Glycan hole filling generally preceded the time to first detectable breadth, although time intervals varied across hosts. Thus, completely glycan-shielded viruses were associated with accelerated neutralization breadth development, suggesting that Env immunogens with intact glycan shields may be preferred components of AIDS vaccines.
Asunto(s)
Anticuerpos Neutralizantes/metabolismo , VIH-1/metabolismo , Polisacáridos/metabolismo , Productos del Gen env del Virus de la Inmunodeficiencia Humana/metabolismo , Biología Computacional , Secuencia Conservada , Células HEK293 , Humanos , Cinética , Modelos Moleculares , Pruebas de Neutralización , Polisacáridos/química , Productos del Gen env del Virus de la Inmunodeficiencia Humana/químicaRESUMEN
Wild-living African apes are endemically infected with parasites that are closely related to human Plasmodium vivax, a leading cause of malaria outside Africa. This finding suggests that the origin of P. vivax was in Africa, even though the parasite is now rare in humans there. To elucidate the emergence of human P. vivax and its relationship to the ape parasites, we analyzed genome sequence data of P. vivax strains infecting six chimpanzees and one gorilla from Cameroon, Gabon, and Côte d'Ivoire. We found that ape and human parasites share nearly identical core genomes, differing by only 2% of coding sequences. However, compared with the ape parasites, human strains of P. vivax exhibit about 10-fold less diversity and have a relative excess of nonsynonymous nucleotide polymorphisms, with site-frequency spectra suggesting they are subject to greatly relaxed purifying selection. These data suggest that human P. vivax has undergone an extreme bottleneck, followed by rapid population expansion. Investigating potential host-specificity determinants, we found that ape P. vivax parasites encode intact orthologs of three reticulocyte-binding protein genes (rbp2d, rbp2e, and rbp3), which are pseudogenes in all human P. vivax strains. However, binding studies of recombinant RBP2e and RBP3 proteins to human, chimpanzee, and gorilla erythrocytes revealed no evidence of host-specific barriers to red blood cell invasion. These data suggest that, from an ancient stock of P. vivax parasites capable of infecting both humans and apes, a severely bottlenecked lineage emerged out of Africa and underwent rapid population growth as it spread globally.
Asunto(s)
Evolución Molecular , Estudio de Asociación del Genoma Completo , Plasmodium vivax/genética , Polimorfismo Genético , Proteínas Protozoarias/genética , Selección Genética , Animales , Camerún , Côte d'Ivoire , Femenino , Gabón , Gorilla gorilla , Humanos , Masculino , Pan troglodytes , Proteínas Protozoarias/metabolismo , SeudogenesRESUMEN
BACKGROUND: The effect of a brief analytical treatment interruption (ATI) on the HIV-1 latent reservoir of individuals who initiate antiretroviral therapy (ART) during chronic infection is unknown. METHODS: We evaluated the impact of transient viremia on the latent reservoir in participants who underwent an ATI and at least 6 months of subsequent viral suppression in a clinical trial testing the effect of passive infusion of the broadly neutralizing Ab VRC01 during ATI. RESULTS: Measures of total HIV-1 DNA, cell-associated RNA, and infectious units per million cells (IUPM) (measured by quantitative viral outgrowth assay [QVOA]) were not statistically different before or after ATI. Phylogenetic analyses of HIV-1 env sequences from QVOA and proviral DNA demonstrated little change in the composition of the virus populations comprising the pre- and post-ATI reservoir. Expanded clones were common in both QVOA and proviral DNA sequences. The frequency of clonal populations differed significantly between QVOA viruses, proviral DNA sequences, and the viruses that reactivated in vivo. CONCLUSIONS: The results indicate that transient viremia from ATI does not substantially alter measures of the latent reservoir, that clonal expansion is prevalent within the latent reservoir, and that characterization of latent viruses that can reactivate in vivo remains challenging. TRIAL REGISTRATION: ClinicalTrials.gov NCT02463227FUNDING. Funding was provided by the NIH.
Asunto(s)
Antirretrovirales/administración & dosificación , Infecciones por VIH/tratamiento farmacológico , Infecciones por VIH/virología , VIH-1 , Adulto , Anticuerpos Monoclonales/administración & dosificación , Anticuerpos ampliamente neutralizantes , Linfocitos T CD4-Positivos/efectos de los fármacos , Linfocitos T CD4-Positivos/virología , ADN Viral/sangre , ADN Viral/genética , Esquema de Medicación , Genes env , Variación Genética/efectos de los fármacos , Anticuerpos Anti-VIH , Proteínas gp160 de Envoltorio del VIH/genética , VIH-1/clasificación , VIH-1/efectos de los fármacos , VIH-1/genética , Humanos , Masculino , Persona de Mediana Edad , Filogenia , Provirus/clasificación , Provirus/efectos de los fármacos , Provirus/genética , Carga Viral/efectos de los fármacos , Viremia/tratamiento farmacológico , Viremia/virología , Latencia del Virus/efectos de los fármacos , Latencia del Virus/genéticaRESUMEN
HIV-1 causes chronic inflammation and AIDS in humans, whereas related simian immunodeficiency viruses (SIVs) replicate efficiently in their natural hosts without causing disease. It is currently unknown to what extent virus-specific properties are responsible for these different clinical outcomes. Here, we incorporate two putative HIV-1 virulence determinants, i.e., a Vpu protein that antagonizes tetherin and blocks NF-κB activation and a Nef protein that fails to suppress T cell activation via downmodulation of CD3, into a non-pathogenic SIVagm strain and test their impact on viral replication and pathogenicity in African green monkeys. Despite sustained high-level viremia over more than 4 years, moderately increased immune activation and transcriptional signatures of inflammation, the HIV-1-like SIVagm does not cause immunodeficiency or any other disease. These data indicate that species-specific host factors rather than intrinsic viral virulence factors determine the pathogenicity of primate lentiviruses.
Asunto(s)
VIH-1/patogenicidad , Especificidad del Huésped , Proteínas del Virus de la Inmunodeficiencia Humana/inmunología , Lentivirus de los Primates/crecimiento & desarrollo , Virus de la Inmunodeficiencia de los Simios/patogenicidad , Proteínas Reguladoras y Accesorias Virales/inmunología , Productos del Gen nef del Virus de la Inmunodeficiencia Humana/inmunología , Secuencia de Aminoácidos , Animales , Antígeno 2 del Estroma de la Médula Ósea/genética , Antígeno 2 del Estroma de la Médula Ósea/inmunología , Complejo CD3/genética , Complejo CD3/inmunología , Chlorocebus aethiops , Femenino , Regulación de la Expresión Génica , VIH-1/crecimiento & desarrollo , Proteínas del Virus de la Inmunodeficiencia Humana/genética , Humanos , Lentivirus de los Primates/patogenicidad , Activación de Linfocitos , FN-kappa B/genética , FN-kappa B/inmunología , Alineación de Secuencia , Transducción de Señal , Virus de la Inmunodeficiencia de los Simios/crecimiento & desarrollo , Transcripción Genética , Carga Viral , Proteínas Reguladoras y Accesorias Virales/genética , Virulencia , Replicación Viral , Productos del Gen nef del Virus de la Inmunodeficiencia Humana/genéticaRESUMEN
African apes are endemically infected with numerous Plasmodium spp. including close relatives of human Plasmodium falciparum, Plasmodium vivax, Plasmodium ovale, and Plasmodium malariae. Although these ape parasites are not believed to pose a zoonotic threat, their ability to colonise humans has not been fully explored. In particular, it remains unknown whether ape parasites are able to initiate exo-erythrocytic replication in human hepatocytes following the bite of an infective mosquito. Since animal studies have shown that liver stage infection can result in the excretion of parasite nucleic acids into the bile, we screened faecal samples from 504 rural Cameroonians for Plasmodium DNA. Using pan-Laverania as well as P. malariae- and P. vivax-specific primer sets, we amplified human P. falciparum (nâ¯=â¯14), P. malariae (nâ¯=â¯1), and P. ovale wallikeri (nâ¯=â¯1) mitochondrial sequences from faecal DNA of 15 individuals. However, despite using an intensified PCR screening approach we failed to detect ape Laverania, ape P. vivax or ape P. malariae parasites in these same subjects. One faecal sample from a hunter-gatherer contained a sequence closely related to the porcupine parasite Plasmodium atheruri. Since this same faecal sample also contained porcupine mitochondrial DNA, but a matching blood sample was Plasmodium-negative, it is likely that this hunter-gatherer consumed Plasmodium-infected bushmeat. Faecal Plasmodium detection was not secondary to intestinal bleeding and/or infection with gastrointestinal parasites, but indicative of blood parasitaemia. Quantitative PCR identified 26-fold more parasite DNA in the blood of faecal Plasmodium-positive than faecal Plasmodium-negative individuals (Pâ¯=â¯0.01). However, among blood-positive individuals only 10% - 20% had detectable Plasmodium sequences in their stool. Thus, faecal screening of rural Cameroonians failed to uncover abortive ape Plasmodium infections, but detected infection with human parasites, albeit with reduced sensitivity compared with blood analysis.
Asunto(s)
ADN Protozoario/aislamiento & purificación , Heces/parasitología , Hominidae/parasitología , Malaria/veterinaria , Plasmodium/clasificación , Zoonosis , Animales , Camerún/epidemiología , Humanos , Malaria/epidemiología , Malaria/parasitología , Filogenia , Plasmodium/genéticaRESUMEN
Plasmodium falciparum, the major cause of malaria morbidity and mortality in humans, has been shown to have emerged after cross-species transmission of one of six host-specific parasites (subgenus Laverania) infecting wild chimpanzees (Pan troglodytes) and western gorillas (Gorilla gorilla). Binding of the parasite-encoded ligand RH5 to the host protein basigin is essential for erythrocyte invasion and has been implicated in host specificity. A recent study claimed to have found two amino acid changes in RH5 that "drove the host shift leading to the emergence of P. falciparum as a human pathogen." However, the ape Laverania data available at that time, which included only a single distantly related chimpanzee parasite sequence, were inadequate to justify any such conclusion. Here, we have investigated Laverania Rh5 gene evolution using sequences from all six ape parasite species. Searching for gene-wide episodic selection across the entire Laverania phylogeny, we found eight codons to be under positive selection, including three that correspond to contact residues known to form hydrogen bonds between P. falciparum RH5 and human basigin. One of these sites (residue 197) has changed subsequent to the transmission from apes to humans that gave rise to P. falciparum, suggesting a possible role in the adaptation of the gorilla parasite to the human host. We also found evidence that the patterns of nucleotide polymorphisms in P. falciparum are not typical of Laverania species and likely reflect the recent demographic history of the human parasite.IMPORTANCE A number of closely related, host-specific malaria parasites infecting wild chimpanzees and gorillas have recently been described. The most important cause of human malaria, Plasmodium falciparum, is now known to have resulted from a cross-species transmission of one of the gorilla parasites. Overcoming species-specific interactions between a parasite ligand, RH5, and its receptor on host cells, basigin, was likely an important step in the origin of the human parasite. We have investigated the evolution of the Rh5 gene and found evidence of adaptive changes during the diversification of the ape parasite species at sites that are known to form bonds with human basigin. One of these changes occurred at the origin of P. falciparum, implicating it as an important adaptation to the human host.
Asunto(s)
Enfermedades del Simio Antropoideo/parasitología , Evolución Molecular , Malaria/parasitología , Malaria/veterinaria , Plasmodium/genética , Proteínas Protozoarias/genética , Animales , Basigina/metabolismo , Sitios de Unión , Hominidae , Humanos , Unión Proteica , Proteínas Protozoarias/metabolismo , Selección GenéticaRESUMEN
Malaria parasites, though widespread among wild chimpanzees and gorillas, have not been detected in bonobos. Here, we show that wild-living bonobos are endemically Plasmodium infected in the eastern-most part of their range. Testing 1556 faecal samples from 11 field sites, we identify high prevalence Laverania infections in the Tshuapa-Lomami-Lualaba (TL2) area, but not at other locations across the Congo. TL2 bonobos harbour P. gaboni, formerly only found in chimpanzees, as well as a potential new species, Plasmodium lomamiensis sp. nov. Rare co-infections with non-Laverania parasites were also observed. Phylogenetic relationships among Laverania species are consistent with co-divergence with their gorilla, chimpanzee and bonobo hosts, suggesting a timescale for their evolution. The absence of Plasmodium from most field sites could not be explained by parasite seasonality, nor by bonobo population structure, diet or gut microbiota. Thus, the geographic restriction of bonobo Plasmodium reflects still unidentified factors that likely influence parasite transmission.
Asunto(s)
Malaria/veterinaria , Pan paniscus/parasitología , Plasmodium/aislamiento & purificación , Enfermedades de los Primates/parasitología , Animales , Animales Salvajes/parasitología , Congo , Heces/parasitología , Malaria/parasitología , Filogenia , Plasmodium/clasificación , Plasmodium/genéticaRESUMEN
[This corrects the article DOI: 10.1371/journal.pone.0058965.].
RESUMEN
BACKGROUND: Simian immunodeficiency virus of chimpanzees (SIVcpz), the progenitor of human immunodeficiency virus type 1 (HIV-1), is associated with increased mortality and AIDS-like immunopathology in wild-living chimpanzees (Pan troglodytes). Surprisingly, however, similar findings have not been reported for chimpanzees experimentally infected with SIVcpz in captivity, raising questions about the intrinsic pathogenicity of this lentivirus. FINDINGS: Here, we report progressive immunodeficiency and clinical disease in a captive western chimpanzee (P. t. verus) infected twenty years ago by intrarectal inoculation with an SIVcpz strain (ANT) from a wild-caught eastern chimpanzee (P. t. schweinfurthii). With sustained plasma viral loads of 105 to 106 RNA copies/ml for the past 15 years, this chimpanzee developed CD4+ T cell depletion (220 cells/µl), thrombocytopenia (90,000 platelets/µl), and persistent soft tissue infections refractory to antibacterial therapy. Combination antiretroviral therapy consisting of emtricitabine (FTC), tenofovir disoproxil fumarate (TDF), and dolutegravir (DTG) decreased plasma viremia to undetectable levels (<200 copies/ml), improved CD4+ T cell counts (509 cell/µl), and resulted in the rapid resolution of all soft tissue infections. However, initial lack of adherence and/or differences in pharmacokinetics led to low plasma drug concentrations, which resulted in transient rebound viremia and the emergence of FTC resistance mutations (M184V/I) identical to those observed in HIV-1 infected humans. CONCLUSIONS: These data demonstrate that SIVcpz can cause immunodeficiency and other hallmarks of AIDS in captive chimpanzees, including P. t. verus apes that are not naturally infected with this virus. Moreover, SIVcpz-associated immunodeficiency can be effectively treated with antiretroviral therapy, although sufficiently high plasma concentrations must be maintained to prevent the emergence of drug resistance. These findings extend a growing body of evidence documenting the immunopathogenicity of SIVcpz and suggest that experimentally infected chimpanzees may benefit from clinical monitoring and therapeutic intervention.
Asunto(s)
Antirretrovirales/uso terapéutico , Enfermedades del Simio Antropoideo/tratamiento farmacológico , Enfermedades del Simio Antropoideo/virología , Pan troglodytes/virología , Síndrome de Inmunodeficiencia Adquirida del Simio/tratamiento farmacológico , Virus de la Inmunodeficiencia de los Simios/efectos de los fármacos , Animales , Antirretrovirales/administración & dosificación , Antirretrovirales/sangre , Terapia Antirretroviral Altamente Activa/efectos adversos , Recuento de Linfocito CD4 , Farmacorresistencia Viral , Masculino , Mutación , ARN Viral/sangre , Síndrome de Inmunodeficiencia Adquirida del Simio/virología , Virus de la Inmunodeficiencia de los Simios/genética , Virus de la Inmunodeficiencia de los Simios/fisiología , Carga Viral/efectos de los fármacosRESUMEN
Here, we report the isolation of broadly neutralizing mAbs (bNAbs) from persons with broadly neutralizing serum who spontaneously cleared hepatitis C virus (HCV) infection. We found that bNAbs from two donors bound the same epitope and were encoded by the same germline heavy chain variable gene segment. Remarkably, these bNAbs were encoded by antibody variable genes with sparse somatic mutations. For one of the most potent bNAbs, these somatic mutations were critical for antibody neutralizing breadth and for binding to autologous envelope variants circulating late in infection. However, somatic mutations were not necessary for binding of the bNAb unmutated ancestor to envelope proteins of early autologous transmitted/founder viruses. This study identifies a public B cell clonotype favoring early recognition of a conserved HCV epitope, proving that anti-HCV bNAbs can achieve substantial neutralizing breadth with relatively few somatic mutations, and identifies HCV envelope variants that favored selection and maturation of an anti-HCV bNAb in vivo. These data provide insight into the molecular mechanisms of immune-mediated clearance of HCV infection and present a roadmap to guide development of a vaccine capable of stimulating anti-HCV bNAbs with a physiologic number of somatic mutations characteristic of vaccine responses.
RESUMEN
Simian immunodeficiency viruses (SIVs) use their Nef proteins to counteract the restriction factor tetherin. However, a deletion in human tetherin prevents antagonism by the Nef proteins of SIVcpz and SIVgor, which represent the ape precursors of human immunodeficiency virus type 1 (HIV-1). To promote virus release from infected cells, pandemic HIV-1 group M strains evolved Vpu as a tetherin antagonist, while the Nef protein of less widespread HIV-1 group O strains acquired the ability to target a region adjacent to this deletion. In this study, we identified an unusual HIV-1 group O strain (RBF206) that evolved Vpu as an effective antagonist of human tetherin. While both RBF206 Vpu and Nef exert anti-tetherin activity in transient-transfection assays, mainly Vpu promotes RBF206 release in infected CD4+ T cells. Although mutations distinct from the adaptive changes observed in group M Vpus (M-Vpus) were critical for the acquisition of its anti-tetherin activity, RBF206 O-Vpu potently suppresses NF-κB activation and reduces CD4 cell surface expression. Interestingly, RBF206 Vpu counteracts tetherin in a largely species-independent manner, degrading both the long and short isoforms of human tetherin. Downmodulation of CD4, but not counteraction of tetherin, by RBF206 Vpu was dependent on the cellular ubiquitin ligase machinery. Our data present the first example of an HIV-1 group O Vpu that efficiently antagonizes human tetherin and suggest that counteraction by O-Nefs may be suboptimal.IMPORTANCE Previous studies showed that HIV-1 groups M and O evolved two alternative strategies to counteract the human ortholog of the restriction factor tetherin. While HIV-1 group M switched from Nef to Vpu due to a deletion in the cytoplasmic domain of human tetherin, HIV-1 group O, which lacks Vpu-mediated anti-tetherin activity, acquired a Nef protein that is able to target a region adjacent to the deletion. Here we report an unusual exception, identifying a strain of HIV-1 group O (RBF206) whose Vpu protein evolved an effective antagonism of human tetherin. Interestingly, the adaptive changes in RBF206 Vpu are distinct from those found in M-Vpus and mediate efficient counteraction of both the long and short isoforms of this restriction factor. Our results further illustrate the enormous flexibility of HIV-1 in counteracting human defense mechanisms.