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1.
Cell ; 161(2): 191-2, 2015 Apr 09.
Artículo en Inglés | MEDLINE | ID: mdl-25860599

RESUMEN

An epidemic of leukemia among bivalve molluscs is spreading along the Atlantic coast of North America, with a serious population decline of soft-shelled clams. In this issue of Cell, Metzger et al. use forensic DNA markers to demonstrate that the leukemia cells have a clonal origin and appear to be transmitted through sea water.


Asunto(s)
Mya/citología , Animales
2.
Cell ; 161(6): 1280-92, 2015 Jun 04.
Artículo en Inglés | MEDLINE | ID: mdl-26004070

RESUMEN

The site on the HIV-1 gp120 glycoprotein that binds the CD4 receptor is recognized by broadly reactive antibodies, several of which neutralize over 90% of HIV-1 strains. To understand how antibodies achieve such neutralization, we isolated CD4-binding-site (CD4bs) antibodies and analyzed 16 co-crystal structures -8 determined here- of CD4bs antibodies from 14 donors. The 16 antibodies segregated by recognition mode and developmental ontogeny into two types: CDR H3-dominated and VH-gene-restricted. Both could achieve greater than 80% neutralization breadth, and both could develop in the same donor. Although paratope chemistries differed, all 16 gp120-CD4bs antibody complexes showed geometric similarity, with antibody-neutralization breadth correlating with antibody-angle of approach relative to the most effective antibody of each type. The repertoire for effective recognition of the CD4 supersite thus comprises antibodies with distinct paratopes arrayed about two optimal geometric orientations, one achieved by CDR H3 ontogenies and the other achieved by VH-gene-restricted ontogenies.


Asunto(s)
Anticuerpos Neutralizantes/química , Anticuerpos Antivirales/química , Proteína gp120 de Envoltorio del VIH/química , Proteína gp120 de Envoltorio del VIH/metabolismo , VIH-1/fisiología , Secuencia de Aminoácidos , Anticuerpos Neutralizantes/metabolismo , Anticuerpos Antivirales/metabolismo , Linfocitos B/inmunología , Antígenos CD4/metabolismo , Regiones Determinantes de Complementariedad , Epítopos de Linfocito B , Proteína gp120 de Envoltorio del VIH/inmunología , Humanos , Modelos Moleculares , Datos de Secuencia Molecular , Alineación de Secuencia
4.
Cell ; 135(6): 983-6, 2008 Dec 12.
Artículo en Inglés | MEDLINE | ID: mdl-19070561

RESUMEN

This year's Nobel Prize in Physiology or Medicine rewards the discoverers of two viruses that cause major afflictions of humankind. Identifying human papilloma virus (HPV) and human immunodeficiency virus (HIV) might now appear to have been simple, but the way forward was far from obvious at the time.


Asunto(s)
VIH , Papillomavirus Humano 16 , Papillomavirus Humano 18 , Premio Nobel , Síndrome de Inmunodeficiencia Adquirida/virología , Femenino , Historia del Siglo XX , Historia del Siglo XXI , Humanos , Neoplasias del Cuello Uterino/virología , Virología/historia
5.
Cancer Metastasis Rev ; 39(4): 1023-1028, 2020 12.
Artículo en Inglés | MEDLINE | ID: mdl-32728828

RESUMEN

The name of the oncogene, ras, has its origin in studies of murine leukemia viruses in the 1960s by Jenny Harvey (H-ras) and by Werner Kirsten (K-ras) which, at high doses, produced sarcomas in rats. Transforming retroviruses were isolated, and its oncogene was named ras after rat sarcoma. From 1979, cellular ras sequences with transforming properties were identified by transfection of tumor DNA initially by Robert Weinberg from rodent tumors, and the isolation of homologous oncogenes from human tumors soon followed, including HRAS and KRAS, and a new member of the family named NRAS. I review these discoveries, placing emphasis on the pioneering research of Christopher Marshall and Alan Hall, who subsequently made immense contributions to our understanding of the functions of RAS and related small GTPases to signal transduction pathways, cell structure, and the behavior of normal and malignant cells.


Asunto(s)
Genes ras , Genética/historia , Neoplasias/genética , Animales , Genes Supresores de Tumor , Historia del Siglo XX , Historia del Siglo XXI , Humanos
6.
BMC Biol ; 16(1): 115, 2018 10 15.
Artículo en Inglés | MEDLINE | ID: mdl-30322384

RESUMEN

The ability of certain tumor cells of mammals and molluscs to spread from the original host to others reopens the question of distinguishing self from non-self. It is part of a wider phenomenon of cellular parasitism and cell chimerism including germ cells.


Asunto(s)
Mamíferos/inmunología , Moluscos/inmunología , Células Neoplásicas Circulantes/inmunología , Animales , Neoplasias
7.
Curr Top Microbiol Immunol ; 407: 1-29, 2017.
Artículo en Inglés | MEDLINE | ID: mdl-28550453

RESUMEN

Although genetic transfer between viruses and vertebrate hosts occurs less frequently than gene flow between bacteriophages and prokaryotes, it is extensive and has affected the evolution of both parties. With retroviruses, the integration of proviral DNA into chromosomal DNA can result in the activation of adjacent host gene expression and in the transduction of host transcripts into retroviral genomes as oncogenes. Yet in contrast to lysogenic phage, there is little evidence that viral oncogenes persist in a chain of natural transmission or that retroviral transduction is a significant driver of the horizontal spread of host genes. Conversely, integration of proviruses into the host germ line has generated endogenous retroviral genomes (ERV) in all vertebrate genomes sequenced to date. Some of these genomes retain potential infectivity and upon reactivation may transmit to other host species. During mammalian evolution, sequences of retroviral origin have been repurposed to serve host functions, such as the viral envelope glycoproteins crucial to the development of the placenta. Beyond retroviruses, DNA viruses with complex genomes have acquired numerous genes of host origin which influence replication, pathogenesis and immune evasion, while host species have accumulated germline sequences of both DNA and RNA viruses. A codicil is added on lateral transmission of cancer cells between hosts and on migration of host mitochondria into cancer cells.


Asunto(s)
Evolución Molecular , Transferencia de Gen Horizontal/genética , Genes Virales/genética , Especificidad del Huésped/genética , Provirus/genética , Virus/genética , Animales , Retrovirus Endógenos/genética
8.
PLoS Pathog ; 10(12): e1004552, 2014 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-25522326

RESUMEN

To date, no immunization of humans or animals has elicited broadly neutralizing sera able to prevent HIV-1 transmission; however, elicitation of broad and potent heavy chain only antibodies (HCAb) has previously been reported in llamas. In this study, the anti-HIV immune responses in immunized llamas were studied via deep sequencing analysis using broadly neutralizing monoclonal HCAbs as a guides. Distinct neutralizing antibody lineages were identified in each animal, including two defined by novel antibodies (as variable regions called VHH) identified by robotic screening of over 6000 clones. The combined application of five VHH against viruses from clades A, B, C and CRF_AG resulted in neutralization as potent as any of the VHH individually and a predicted 100% coverage with a median IC50 of 0.17 µg/ml for the panel of 60 viruses tested. Molecular analysis of the VHH repertoires of two sets of immunized animals showed that each neutralizing lineage was only observed following immunization, demonstrating that they were elicited de novo. Our results show that immunization can induce potent and broadly neutralizing antibodies in llamas with features similar to human antibodies and provide a framework to analyze the effectiveness of immunization protocols.


Asunto(s)
Anticuerpos Neutralizantes/inmunología , Antígenos Virales/inmunología , Sitios de Unión de Anticuerpos/inmunología , Antígenos CD4/inmunología , Camélidos del Nuevo Mundo/inmunología , Evolución Molecular , VIH-1/inmunología , Vacunas contra el SIDA/inmunología , Vacunas contra el SIDA/uso terapéutico , Animales , Anticuerpos Neutralizantes/genética , Camélidos del Nuevo Mundo/genética , Modelos Animales de Enfermedad , Infecciones por VIH/inmunología , Infecciones por VIH/prevención & control , Región Variable de Inmunoglobulina/genética , Región Variable de Inmunoglobulina/inmunología , Mutación/genética
9.
J Gen Virol ; 96(9): 2501-2510, 2015 Sep.
Artículo en Inglés | MEDLINE | ID: mdl-26296666

RESUMEN

The interchange between retroviruses and their hosts is an intimate one because retroviruses integrate proviral DNA into host chromosomal DNA as an obligate step in the replication cycle. This has resulted in the occasional transduction of host genes into retroviral genomes as oncogenes, and also led to the integration of viral genomes into the host germ line that gives rise to endogenous retroviruses. I shall reflect on the evolutionary consequences of these events for virus and host. Then, I shall discuss the emergence of non-viral infections of host origin, namely, how malignant cells can give rise to eukaryotic single cell 'parasites' that colonize new hosts and how these in turn have been colonized by host mitochondria.


Asunto(s)
Provirus/fisiología , Infecciones por Retroviridae/virología , Retroviridae/fisiología , Virología/historia , Animales , Distinciones y Premios , Genoma Viral , Historia del Siglo XIX , Historia del Siglo XX , Historia del Siglo XXI , Especificidad del Huésped , Humanos , Provirus/genética , Retroviridae/genética , Reino Unido
10.
PLoS Pathog ; 9(3): e1003202, 2013 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-23505368

RESUMEN

The membrane proximal external region (MPER) of the HIV-1 glycoprotein gp41 is targeted by the broadly neutralizing antibodies 2F5 and 4E10. To date, no immunization regimen in animals or humans has produced HIV-1 neutralizing MPER-specific antibodies. We immunized llamas with gp41-MPER proteoliposomes and selected a MPER-specific single chain antibody (VHH), 2H10, whose epitope overlaps with that of mAb 2F5. Bi-2H10, a bivalent form of 2H10, which displayed an approximately 20-fold increased affinity compared to the monovalent 2H10, neutralized various sensitive and resistant HIV-1 strains, as well as SHIV strains in TZM-bl cells. X-ray and NMR analyses combined with mutagenesis and modeling revealed that 2H10 recognizes its gp41 epitope in a helical conformation. Notably, tryptophan 100 at the tip of the long CDR3 is not required for gp41 interaction but essential for neutralization. Thus bi-2H10 is an anti-MPER antibody generated by immunization that requires hydrophobic CDR3 determinants in addition to epitope recognition for neutralization similar to the mode of neutralization employed by mAbs 2F5 and 4E10.


Asunto(s)
Anticuerpos Neutralizantes/inmunología , Camélidos del Nuevo Mundo/inmunología , Regiones Determinantes de Complementariedad/inmunología , Anticuerpos Anti-VIH/inmunología , Proteína gp41 de Envoltorio del VIH/inmunología , Secuencia de Aminoácidos , Animales , Secuencia de Bases , Línea Celular , Epítopos/inmunología , Humanos , Interacciones Hidrofóbicas e Hidrofílicas , Inmunización , Datos de Secuencia Molecular , Mutagénesis Sitio-Dirigida , Pruebas de Neutralización , Proteolípidos/administración & dosificación , Proteolípidos/inmunología , Anticuerpos de Dominio Único , Resonancia por Plasmón de Superficie
11.
Retrovirology ; 11: 83, 2014 Oct 02.
Artículo en Inglés | MEDLINE | ID: mdl-25700025

RESUMEN

BACKGROUND: Direct cell-cell spread of HIV-1 is a very efficient mode of viral dissemination, with increasing evidence suggesting that it may pose a considerable challenge to controlling viral replication in vivo. Much current vaccine research involves the study of broadly neutralising antibodies (bNabs) that arise during natural infection with the aims of eliciting such antibodies by vaccination or incorporating them into novel therapeutics. However, whether cell-cell spread of HIV-1 can be effectively targeted by bNabs remains unclear, and there is much interest in identifying antibodies capable of efficiently neutralising virus transmitted by cell-cell contact. RESULTS: In this study we have tested a panel of bNAbs for inhibition of cell-cell spread, including some not previously evaluated for inhibition of this mode of HIV-1 transmission. We found that three CD4 binding site antibodies, one from an immunised llama (J3) and two isolated from HIV-1-positive patients (VRC01 and HJ16) neutralised cell-cell spread between T cells, while antibodies specific for glycan moieties (2G12, PG9, PG16) and the MPER (2F5) displayed variable efficacy. Notably, while J3 displayed a high level of potency during cell-cell spread we found that the small size of the llama heavy chain-only variable region (VHH) J3 is not required for efficient neutralisation since recombinant J3 containing a full-length human heavy chain Fc domain was significantly more potent. J3 and J3-Fc also neutralised cell-cell spread of HIV-1 from primary macrophages to CD4+ T cells. CONCLUSIONS: In conclusion, while bNabs display variable efficacy at preventing cell-cell spread of HIV-1, we find that some CD4 binding site antibodies can inhibit this mode of HIV-1 dissemination and identify the recently described llama antibody J3 as a particularly potent inhibitor. Effective neutralisation of cell-cell spread between physiologically relevant cell types by J3 and J3-Fc supports the development of VHH J3 nanobodies for therapeutic or prophylactic applications.


Asunto(s)
Anticuerpos Neutralizantes/inmunología , Anticuerpos Anti-VIH/inmunología , Infecciones por VIH/prevención & control , VIH-1/inmunología , Linfocitos T/virología , Animales , Antígenos CD4/metabolismo , Camélidos del Nuevo Mundo , Infecciones por VIH/transmisión , Humanos , Macrófagos/virología , Reacción en Cadena en Tiempo Real de la Polimerasa
12.
BMC Biol ; 11: 57, 2013 May 21.
Artículo en Inglés | MEDLINE | ID: mdl-23692808

RESUMEN

During 30 years of research on human immunodeficiency virus (HIV), our knowledge of its cellular receptors--CD4, CCR5 and CXCR4--has illuminated aspects of the pathogenesis of the acquired immune deficiency syndrome (AIDS). Studying how the HIV envelope glycoproteins interact with the receptors led to anti-retroviral drugs based on blocking the docking or fusion of virus to the host cell. Genetic polymorphisms of CCR5 determine resistance to HIV infection and the rate of progression to AIDS. Eliciting neutralizing antibodies to the sites of receptor interaction on HIV glycoproteins is a promising approach to HIV vaccine development.


Asunto(s)
Infecciones por VIH/prevención & control , Receptores del VIH/metabolismo , Farmacorresistencia Viral , Glicoproteínas/metabolismo , VIH/fisiología , Infecciones por VIH/terapia , Infecciones por VIH/virología , Humanos , Productos del Gen env del Virus de la Inmunodeficiencia Humana/metabolismo
16.
J Infect Dis ; 203(8): 1063-72, 2011 Apr 15.
Artículo en Inglés | MEDLINE | ID: mdl-21450996

RESUMEN

Influenza A virus infections impose a recurrent and global disease burden. Current antivirals against influenza are not always effective. We assessed the protective potential of monovalent and bivalent Nanobodies (Ablynx) against challenge with this virus. These Nanobodies were derived from llamas and target H5N1 hemagglutinin. Intranasal administration of Nanobodies effectively controlled homologous influenza A virus replication. Administration of Nanobodies before challenge strongly reduced H5N1 virus replication in the lungs and protected mice from morbidity and mortality after a lethal challenge with H5N1 virus. The bivalent Nanobody was at least 60-fold more effective than the monovalent Nanobody in controlling virus replication. In addition, Nanobody therapy after challenge strongly reduced viral replication and significantly delayed time to death. Epitope mapping revealed that the VHH Nanobody binds to antigenic site B in H5 hemagglutinin. Because Nanobodies are small, stable, and simple to produce, they are a promising, novel therapeutic agent against influenza.


Asunto(s)
Anticuerpos Monoclonales/inmunología , Anticuerpos Neutralizantes/inmunología , Subtipo H5N1 del Virus de la Influenza A/inmunología , Infecciones por Orthomyxoviridae/prevención & control , Animales , Especificidad de Anticuerpos , Femenino , Ratones , Ratones Endogámicos BALB C , Modelos Moleculares , Nanocápsulas , Conformación Proteica , Organismos Libres de Patógenos Específicos , Factores de Tiempo
17.
Fac Rev ; 11: 2, 2022.
Artículo en Inglés | MEDLINE | ID: mdl-35156099

RESUMEN

Infectious diseases emerge via many routes and may need to overcome stepwise bottlenecks to burgeon into epidemics and pandemics. About 60% of human infections have animal origins, whereas 40% either co-evolved with humans or emerged from non-zoonotic environmental sources. Although the dynamic interaction between wildlife, domestic animals, and humans is important for the surveillance of zoonotic potential, exotic origins tend to be overemphasized since many zoonoses come from anthropophilic wild species (for example, rats and bats). We examine the equivocal evidence of whether the appearance of novel infections is accelerating and relate technological developments to the risk of novel disease outbreaks. Then we briefly compare selected epidemics, ancient and modern, from the Plague of Athens to COVID-19.

18.
Science ; 375(6586): 1235, 2022 Mar 18.
Artículo en Inglés | MEDLINE | ID: mdl-35298253

RESUMEN

Discoverer of the human immunodeficiency virus.

19.
Structure ; 30(6): 862-875.e4, 2022 06 02.
Artículo en Inglés | MEDLINE | ID: mdl-35413243

RESUMEN

Nanobodies can achieve remarkable neutralization of genetically diverse pathogens, including HIV-1. To gain insight into their recognition, we determined crystal structures of four llama nanobodies (J3, A12, C8, and D7), all of which targeted the CD4-binding site, in complex with the HIV-1 envelope (Env) gp120 core, and determined a cryoelectron microscopy (cryo-EM) structure of J3 with the Env trimer. Crystal and cryo-EM structures of J3 complexes revealed this nanobody to mimic binding to the prefusion-closed trimer for the primary site of CD4 recognition as well as a secondary quaternary site. In contrast, crystal structures of A12, C8, and D7 with gp120 revealed epitopes that included portions of the gp120 inner domain, inaccessible on the prefusion-closed trimer. Overall, these structures explain the broad and potent neutralization of J3 and limited neutralization of A12, C8, and D7, which utilized binding modes incompatible with the neutralization-targeted prefusion-closed conformation of Env.


Asunto(s)
Camélidos del Nuevo Mundo , VIH-1 , Anticuerpos de Dominio Único , Animales , Anticuerpos Neutralizantes/química , Sitios de Unión , Antígenos CD4 , Camélidos del Nuevo Mundo/metabolismo , Microscopía por Crioelectrón , Anticuerpos Anti-VIH , Proteína gp120 de Envoltorio del VIH , VIH-1/química
20.
J Biol Chem ; 285(25): 19116-24, 2010 Jun 18.
Artículo en Inglés | MEDLINE | ID: mdl-20400507

RESUMEN

Recently, we described llama antibody fragments (VHH) that can neutralize human immunodeficiency virus, type 1 (HIV-1). These VHH were obtained after selective elution of phages carrying an immune library raised against gp120 of HIV-1 subtype B/C CN54 with soluble CD4. We describe here a new, family-specific approach to obtain the largest possible diversity of related VHH that compete with soluble CD4 for binding to the HIV-1 envelope glycoprotein. The creation of this family-specific library of homologous VHH has enabled us to isolate phages carrying similar nucleotide sequences as the parental VHH. These VHH displayed varying binding affinities and neutralization phenotypes to a panel of different strains and subtypes of HIV-1. Sequence analysis of the homologs showed that the C-terminal three amino acids of the CDR3 loop were crucial in determining the specificity of these VHH for different subtype C HIV-1 strains. There was a positive correlation between affinity of VHH binding to gp120 of HIV-1 IIIB and the breadth of neutralization of diverse HIV-1 envelopes. The family-specific approach has therefore allowed us to better understand the interaction of the CD4-binding site antibodies with virus strain specificity and has potential use for the bioengineering of antibodies and HIV-1 vaccine development.


Asunto(s)
VIH-1/metabolismo , Anticuerpos de Cadena Única/química , Vacunas contra el SIDA/química , Anticuerpos/química , Secuencia de Bases , Sitios de Unión , Antígenos CD4/metabolismo , Proteína gp120 de Envoltorio del VIH/química , Humanos , Cinética , Datos de Secuencia Molecular , Mutación , Biblioteca de Péptidos , Homología de Secuencia de Ácido Nucleico
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