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1.
PLoS Pathog ; 18(6): e1010574, 2022 06.
Artículo en Inglés | MEDLINE | ID: mdl-35709309

RESUMEN

Both SIV and SHIV are powerful tools for evaluating antibody-mediated prevention and treatment of HIV-1. However, owing to a lack of rhesus-derived SIV broadly neutralizing antibodies (bnAbs), testing of bnAbs for HIV-1 prevention or treatment has thus far been performed exclusively in the SHIV NHP model using bnAbs from HIV-1-infected individuals. Here we describe the isolation and characterization of multiple rhesus-derived SIV bnAbs capable of neutralizing most isolates of SIV. Eight antibodies belonging to two clonal families, ITS102 and ITS103, which target unique epitopes in the CD4 binding site (CD4bs) region, were found to be broadly neutralizing and together neutralized all SIV strains tested. A rare feature of these bnAbs and two additional antibody families, ITS92 and ITS101, which mediate strain-specific neutralizing activity against SIV from sooty mangabeys (SIVsm), was their ability to achieve near complete (i.e. 100%) neutralization of moderately and highly neutralization-resistant SIV. Overall, these newly identified SIV bnAbs highlight the potential for evaluating HIV-1 prophylactic and therapeutic interventions using fully simian, rhesus-derived bnAbs in the SIV NHP model, thereby circumventing issues related to rapid antibody clearance of human-derived antibodies, Fc mismatch and limited genetic diversity of SHIV compared to SIV.


Asunto(s)
Infecciones por VIH , VIH-1 , Virus de la Inmunodeficiencia de los Simios , Animales , Anticuerpos Neutralizantes , Anticuerpos ampliamente neutralizantes , Anticuerpos Anti-VIH , Macaca mulatta
2.
Bioconjug Chem ; 35(8): 1218-1232, 2024 Aug 21.
Artículo en Inglés | MEDLINE | ID: mdl-39081220

RESUMEN

Minimal immunogen vaccines are being developed to focus antibody responses against otherwise challenging targets, including human immunodeficiency virus (HIV), but multimerization of the minimal peptide immunogen on a carrier platform is required for activity. Star copolymers comprising multiple hydrophilic polymer chains ("arms") radiating from a central dendrimer unit ("core") were recently reported to be an effective platform for arraying minimal immunogens for inducing antibody responses in mice and primates. However, the impact of different parameters of the star copolymer (e.g., minimal immunogen density and hydrodynamic size) on antibody responses and the optimal synthetic route for controlling those parameters remains to be fully explored. We synthesized a library of star copolymers composed of poly[N-(2-hydroxypropyl)methacrylamide] hydrophilic arms extending from poly(amidoamine) dendrimer cores with the aim of identifying the optimal composition for use as minimal immunogen vaccines. Our results show that the length of the polymer arms has a crucial impact on the star copolymer hydrodynamic size and is precisely tunable over a range of 20-50 nm diameter, while the dendrimer generation affects the maximum number of arms (and therefore minimal immunogens) that can be attached to the surface of the dendrimer. In addition, high-resolution images of selected star copolymer taken by a custom-modified environmental scanning electron microscope enabled the acquisition of high-resolution images, providing new insights into the star copolymer structure. Finally, in vivo studies assessing a star copolymer vaccine comprising an HIV minimal immunogen showed the criticality of polymer arm length in promoting antibody responses and highlighting the importance of composition tunability to yield the desired biological effect.


Asunto(s)
Dendrímeros , Animales , Dendrímeros/química , Ratones , Polímeros/química , Portadores de Fármacos/química , Vacunas/inmunología , Vacunas/química , Vacunas/administración & dosificación , Humanos , Vacunas contra el SIDA/inmunología , Vacunas contra el SIDA/química , Vacunas contra el SIDA/administración & dosificación , Poliaminas
3.
PLoS Pathog ; 14(12): e1007395, 2018 12.
Artículo en Inglés | MEDLINE | ID: mdl-30517201

RESUMEN

Gene based delivery of immunoglobulins promises to safely and durably provide protective immunity to individuals at risk of acquiring infectious diseases such as HIV. We used a rhesus macaque animal model to optimize delivery of naturally-arising, autologous anti-SIV neutralizing antibodies expressed by Adeno-Associated Virus 8 (AAV8) vectors. Vectored transgene expression was confirmed by quantitation of target antibody abundance in serum and mucosal surfaces. We tested the expression achieved at varying doses and numbers of injections. Expression of the transgene reached a saturation at about 2 x 10(12) AAV8 genome copies (gc) per needle-injection, a physical limitation that may not scale clinically into human trials. In contrast, expression increased proportionately with the number of injections. In terms of anti-drug immunity, anti-vector antibody responses were universally strong, while those directed against the natural transgene mAb were detected in only 20% of animals. An anti-transgene antibody response was invariably associated with loss of detectable plasma expression of the antibody. Despite having atypical glycosylation profiles, transgenes derived from AAV-directed muscle cell expression retained full functional activity, including mucosal accumulation, in vitro neutralization, and protection against repeated limiting dose SIVsmE660 swarm challenge. Our findings demonstrate feasibility of a gene therapy-based passive immunization strategy against infectious disease, and illustrate the potential for the nonhuman primate model to inform clinical AAV-based approaches to passive immunization.


Asunto(s)
Anticuerpos Antivirales/administración & dosificación , Terapia Genética/métodos , Inmunización Pasiva/métodos , Vacunas contra el SIDAS , Proteínas del Envoltorio Viral/inmunología , Animales , Anticuerpos Monoclonales/administración & dosificación , Anticuerpos Monoclonales/inmunología , Anticuerpos Neutralizantes/administración & dosificación , Anticuerpos Neutralizantes/inmunología , Dependovirus , Vectores Genéticos , Macaca mulatta , Síndrome de Inmunodeficiencia Adquirida del Simio/prevención & control , Virus de la Inmunodeficiencia de los Simios , Transgenes
4.
Nature ; 505(7484): 502-8, 2014 Jan 23.
Artículo en Inglés | MEDLINE | ID: mdl-24352234

RESUMEN

A major challenge for the development of a highly effective AIDS vaccine is the identification of mechanisms of protective immunity. To address this question, we used a nonhuman primate challenge model with simian immunodeficiency virus (SIV). We show that antibodies to the SIV envelope are necessary and sufficient to prevent infection. Moreover, sequencing of viruses from breakthrough infections revealed selective pressure against neutralization-sensitive viruses; we identified a two-amino-acid signature that alters antigenicity and confers neutralization resistance. A similar signature confers resistance of human immunodeficiency virus (HIV)-1 to neutralization by monoclonal antibodies against variable regions 1 and 2 (V1V2), suggesting that SIV and HIV share a fundamental mechanism of immune escape from vaccine-elicited or naturally elicited antibodies. These analyses provide insight into the limited efficacy seen in HIV vaccine trials.


Asunto(s)
Vacunas contra el SIDA/inmunología , Infecciones por VIH/prevención & control , Infecciones por VIH/virología , VIH-1/inmunología , Vacunas contra el SIDAS/inmunología , Virus de la Inmunodeficiencia de los Simios/inmunología , Secuencia de Aminoácidos , Animales , Anticuerpos Neutralizantes/inmunología , Susceptibilidad a Enfermedades/inmunología , Femenino , Efecto Fundador , Anticuerpos Anti-VIH/inmunología , Infecciones por VIH/inmunología , VIH-1/química , Humanos , Evasión Inmune/inmunología , Macaca mulatta , Masculino , Datos de Secuencia Molecular , Filogenia , Riesgo , Síndrome de Inmunodeficiencia Adquirida del Simio/inmunología , Síndrome de Inmunodeficiencia Adquirida del Simio/prevención & control , Síndrome de Inmunodeficiencia Adquirida del Simio/virología , Virus de la Inmunodeficiencia de los Simios/química , Virus de la Inmunodeficiencia de los Simios/genética , Virus de la Inmunodeficiencia de los Simios/fisiología , Productos del Gen env del Virus de la Inmunodeficiencia Humana/inmunología
5.
PLoS Pathog ; 12(4): e1005537, 2016 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-27064278

RESUMEN

The simian immunodeficiency virus (SIV) challenge model of lentiviral infection is often used as a model to human immunodeficiency virus type 1 (HIV-1) for studying vaccine mediated and immune correlates of protection. However, knowledge of the structure of the SIV envelope (Env) glycoprotein is limited, as is knowledge of binding specificity, function and potential efficacy of SIV antibody responses. In this study we describe the use of a competitive probe binding sort strategy as well as scaffolded probes for targeted isolation of SIV Env-specific monoclonal antibodies (mAbs). We isolated nearly 70 SIV-specific mAbs directed against major sites of SIV Env vulnerability analogous to broadly neutralizing antibody (bnAb) targets of HIV-1, namely, the CD4 binding site (CD4bs), CD4-induced (CD4i)-site, peptide epitopes in variable loops 1, 2 and 3 (V1, V2, V3) and potentially glycan targets of SIV Env. The range of SIV mAbs isolated includes those exhibiting varying degrees of neutralization breadth and potency as well as others that demonstrated binding but not neutralization. Several SIV mAbs displayed broad and potent neutralization of a diverse panel of 20 SIV viral isolates with some also neutralizing HIV-2(7312A). This extensive panel of SIV mAbs will facilitate more effective use of the SIV non-human primate (NHP) model for understanding the variables in development of a HIV vaccine or immunotherapy.


Asunto(s)
Productos del Gen env/inmunología , Anticuerpos Anti-VIH/inmunología , Virus de la Inmunodeficiencia de los Simios/inmunología , Secuencia de Aminoácidos , Animales , Anticuerpos Monoclonales/inmunología , Anticuerpos Neutralizantes/inmunología , Sitios de Unión , Epítopos/inmunología , Anticuerpos Anti-VIH/aislamiento & purificación , Humanos , Pruebas de Neutralización/métodos
7.
Eur J Immunol ; 43(4): 939-48, 2013 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-23436562

RESUMEN

Protective immunity to Mycobacterium tuberculosis (Mtb) is commonly ascribed to a Th1 profile; however, the involvement of Th17 cells remains to be clarified. Here, we characterized Mtb-specific CD4(+) T cells in blood and bronchoalveolar lavages (BALs) from untreated subjects with either active tuberculosis disease (TB) or latent Mtb infection (LTBI), considered as prototypic models of uncontrolled or controlled infection, respectively. The production of IL-17A, IFN-γ, TNF-α, and IL-2 by Mtb-specific CD4(+) T cells was assessed both directly ex vivo and following in vitro antigen-specific T-cell expansion. Unlike for extracellular bacteria, Mtb-specific CD4(+) T-cell responses lacked immediate ex vivo IL-17A effector function in both LTBI and TB individuals. Furthermore, Mtb-specific Th17 cells were absent in BALs, while extracellular bacteria-specific Th17 cells were identified in gut biopsies of healthy individuals. Interestingly, only Mtb-specific CD4(+) T cells from 50% of LTBI but not from TB subjects acquired the ability to produce IL-17A following Mtb-specific T-cell expansion. Finally, IL-17A acquisition by Mtb-specific CD4(+) T cells correlated with the coexpression of CXCR3 and CCR6, currently associated to Th1 or Th17 profiles, respectively. Our data demonstrate that Mtb-specific Th17 cells are selectively undetectable in peripheral blood and BALs from TB patients.


Asunto(s)
Linfocitos T CD4-Positivos/inmunología , Linfocitos T CD4-Positivos/metabolismo , Epítopos de Linfocito T/inmunología , Interleucina-17/biosíntesis , Mycobacterium tuberculosis/inmunología , Tuberculosis/inmunología , Líquido del Lavado Bronquioalveolar/citología , Líquido del Lavado Bronquioalveolar/inmunología , Humanos , Receptores CCR6/metabolismo , Receptores CXCR3/metabolismo , Células Th17/inmunología , Células Th17/metabolismo , Tuberculosis/metabolismo
8.
Mucosal Immunol ; 17(5): 1089-1101, 2024 Oct.
Artículo en Inglés | MEDLINE | ID: mdl-39089468

RESUMEN

Microbial translocation is a significant contributor to chronic inflammation in people living with HIV (PLWH) and is associated with increased mortality and morbidity in individuals treated for long periods with antiretrovirals. The use of therapeutics to treat microbial translocation has yielded mixed effects, in part, because the species and mechanisms contributing to translocation in HIV remain incompletely characterized. To characterize translocating bacteria, we cultured translocators from chronically SIV-infected rhesus macaques. Proteomic profiling of these bacteria identified cytosine-specific methyltransferases as a common feature and therefore, a potential driver of translocation. Treatment of translocating bacteria with the cytosine methyltransferase inhibitor decitabine significantly impaired growth for several species in vitro. In rhesus macaques, oral treatment with decitabine led to some transient decreases in translocator taxa in the gut microbiome. These data provide mechanistic insight into bacterial translocation in lentiviral infection and explore a novel therapeutic intervention that may improve the prognosis of PLWH.


Asunto(s)
Traslocación Bacteriana , Microbioma Gastrointestinal , Macaca mulatta , Síndrome de Inmunodeficiencia Adquirida del Simio , Virus de la Inmunodeficiencia de los Simios , Animales , Síndrome de Inmunodeficiencia Adquirida del Simio/inmunología , Virus de la Inmunodeficiencia de los Simios/fisiología , Humanos , Bacterias , Decitabina/farmacología , Proteómica
9.
J Virol ; 86(11): 6279-85, 2012 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-22491454

RESUMEN

Adenovirus serotype 5 (Ad5) vectors and specific neutralizing antibodies (NAbs) generate immune complexes (ICs) which are potent inducers of dendritic cell (DC) maturation. Here we show that ICs generated with rare Ad vector serotypes, such as Ad26 and Ad35, which are lead candidates in HIV vaccine development, are poor inducers of DC maturation and that their potency in inducing DC maturation strongly correlated with the number of Toll-like receptor 9 (TLR9)-agonist motifs present in the Ad vector's genome. In addition, we showed that antihexon but not antifiber antibodies are responsible for the induction of Ad IC-mediated DC maturation.


Asunto(s)
Adenovirus Humanos/genética , Adenovirus Humanos/inmunología , Complejo Antígeno-Anticuerpo , Células Dendríticas/inmunología , Células Dendríticas/virología , Receptor Toll-Like 9/agonistas , Receptor Toll-Like 9/inmunología , Secuencias de Aminoácidos , Anticuerpos Neutralizantes/inmunología , Anticuerpos Antivirales/inmunología , Humanos , Proteínas Virales/genética
10.
J Virol ; 85(19): 9854-62, 2011 Oct.
Artículo en Inglés | MEDLINE | ID: mdl-21775454

RESUMEN

In the present study, we have investigated the anatomic distribution in blood and gut mucosal tissues of memory poxvirus-specific CD4 and CD8 T cells in subjects vaccinated with smallpox and compared it with vector (NYVAC)-specific and HIV insert-specific T-cell responses induced by an experimental DNA-C/ NYVAC-C vaccine regimen. Smallpox-specific CD4 T-cell responses were present in the blood of 52% of the subjects studied, while smallpox-specific CD8 T cells were rarely detected (12%). With one exception, smallpox-specific T cells were not measurable in gut tissues. Interestingly, NYVAC vector-specific and HIV-specific CD4 and CD8 T-cell responses were detected in almost 100% of the subjects immunized with DNA-C/NYVAC-C in blood and gut tissues. The large majority (83%) of NYVAC-specific CD4 T cells expressed α4ß7 integrins and the HIV coreceptor CCR5. These results demonstrate that the experimental DNA-C/NYVAC-C HIV vaccine regimen induces the homing of potentially protective HIV-specific CD4 and CD8 T cells in the gut, the port of entry of HIV and one of the major sites for HIV spreading and the depletion of CD4 T cells.


Asunto(s)
Vacunas contra el SIDA/inmunología , Linfocitos T CD4-Positivos/inmunología , Linfocitos T CD8-positivos/inmunología , Mucosa Intestinal/inmunología , Vacuna contra Viruela/inmunología , Vacunas de ADN/inmunología , Vacunas Virales/inmunología , Vacunas contra el SIDA/administración & dosificación , Adulto , Sangre/inmunología , Humanos , Persona de Mediana Edad , Vacuna contra Viruela/administración & dosificación , Vacunación/métodos , Vacunas de ADN/administración & dosificación , Vacunas Virales/administración & dosificación
11.
Sci Transl Med ; 14(658): eabl3927, 2022 08 17.
Artículo en Inglés | MEDLINE | ID: mdl-35976997

RESUMEN

Unique gut microbiota compositions have been associated with inflammatory diseases, but identifying gut bacterial functions linked to immune activation in humans remains challenging. Translocation of pathogens from mucosal surfaces into peripheral tissues can elicit immune activation, although whether and which gut commensal bacteria translocate in inflammatory diseases is difficult to assess. We report that a subset of commensal gut microbiota constituents that translocate across the gut barrier in mice and humans are associated with heightened systemic immunoglobulin G (IgG) responses. We present a modified high-throughput, culture-independent approach to quantify systemic IgG against gut commensal bacteria in human serum samples without the need for paired stool samples. Using this approach, we highlight several commensal bacterial species that elicit elevated IgG responses in patients with inflammatory bowel disease (IBD) including taxa within the clades Collinsella, Bifidobacterium, Lachnospiraceae, and Ruminococcaceae. These and other taxa identified as translocating bacteria or targets of systemic immunity in IBD concomitantly exhibited heightened transcriptional activity and growth rates in IBD patient gut microbiomes. Our approach represents a complementary tool to illuminate interactions between the host and its gut microbiota and may provide an additional method to identify microbes linked to inflammatory disease.


Asunto(s)
Microbioma Gastrointestinal , Enfermedades Inflamatorias del Intestino , Microbiota , Animales , Bacterias , Microbioma Gastrointestinal/fisiología , Humanos , Inmunoglobulina G , Enfermedades Inflamatorias del Intestino/microbiología , Ratones
12.
Nat Struct Mol Biol ; 29(11): 1080-1091, 2022 11.
Artículo en Inglés | MEDLINE | ID: mdl-36344847

RESUMEN

Simian immunodeficiency viruses (SIVs) are lentiviruses that naturally infect non-human primates of African origin and seeded cross-species transmissions of HIV-1 and HIV-2. Here we report prefusion stabilization and cryo-EM structures of soluble envelope (Env) trimers from rhesus macaque SIV (SIVmac) in complex with neutralizing antibodies. These structures provide residue-level definition for SIV-specific disulfide-bonded variable loops (V1 and V2), which we used to delineate variable-loop coverage of the Env trimer. The defined variable loops enabled us to investigate assembled Env-glycan shields throughout SIV, which we found to comprise both N- and O-linked glycans, the latter emanating from V1 inserts, which bound the O-link-specific lectin jacalin. We also investigated in situ SIVmac-Env trimers on virions, determining cryo-electron tomography structures at subnanometer resolutions for an antibody-bound complex and a ligand-free state. Collectively, these structures define the prefusion-closed structure of the SIV-Env trimer and delineate variable-loop and glycan-shielding mechanisms of immune evasion conserved throughout SIV evolution.


Asunto(s)
Anticuerpos Neutralizantes , VIH-1 , Animales , Microscopía por Crioelectrón , Macaca mulatta/metabolismo , VIH-1/metabolismo , Tomografía con Microscopio Electrónico , Productos del Gen env del Virus de la Inmunodeficiencia Humana/química , Productos del Gen env del Virus de la Inmunodeficiencia Humana/metabolismo , Anticuerpos Anti-VIH
13.
Science ; 365(6457): 1033-1036, 2019 09 06.
Artículo en Inglés | MEDLINE | ID: mdl-31488690

RESUMEN

A study in nonhuman primates reported that infusions of an antibody against α4ß7 integrin, in combination with antiretroviral therapy, showed consistent, durable control of simian immunodeficiency virus (SIV) in rhesus macaques. The antibody used has pleiotropic effects, so we set out to gain insight into the underlying mechanism by comparing this treatment to treatment with non-neutralizing monoclonal antibodies against the SIV envelope glycoprotein that only block α4ß7 binding to SIV Env but have no other host-directed effects. Similar to the initial study, we used an attenuated strain of SIV containing a stop codon in nef. The study used 30 macaques that all began antiretroviral therapy and then were divided into five groups to receive different antibody treatments. Unlike the published report, we found no sustained virologic control by these treatments in vivo.


Asunto(s)
Anticuerpos Monoclonales/uso terapéutico , Anticuerpos Antivirales/uso terapéutico , Integrina alfa4/inmunología , Cadenas beta de Integrinas/inmunología , Síndrome de Inmunodeficiencia Adquirida del Simio/terapia , Síndrome de Inmunodeficiencia Adquirida del Simio/virología , Virus de la Inmunodeficiencia de los Simios/genética , Virus de la Inmunodeficiencia de los Simios/inmunología , Animales , Anticuerpos Monoclonales/administración & dosificación , Anticuerpos Antivirales/administración & dosificación , ADN Viral/sangre , Productos del Gen env/inmunología , Infecciones por VIH/terapia , Macaca mulatta , ARN Viral/sangre , Síndrome de Inmunodeficiencia Adquirida del Simio/sangre , Síndrome de Inmunodeficiencia Adquirida del Simio/tratamiento farmacológico , Virus de la Inmunodeficiencia de los Simios/fisiología , Linfocitos T/inmunología , Carga Viral , Proteínas Reguladoras y Accesorias Virales/genética , Proteínas Reguladoras y Accesorias Virales/inmunología , Replicación Viral
15.
J Clin Oncol ; 33(1): 74-82, 2015 Jan 01.
Artículo en Inglés | MEDLINE | ID: mdl-25403209

RESUMEN

PURPOSE: Interleukin-15 (IL-15) has significant potential in cancer immunotherapy as an activator of antitumor CD8 T and natural killer (NK) cells. The primary objectives of this trial were to determine safety, adverse event profile, dose-limiting toxicity, and maximum-tolerated dose of recombinant human IL-15 (rhIL-15) administered as a daily intravenous bolus infusion for 12 consecutive days in patients with metastatic malignancy. PATIENTS AND METHODS: We performed a first in-human trial of Escherichia coli-produced rhIL-15. Bolus infusions of 3.0, 1.0, and 0.3 µg/kg per day of IL-15 were administered for 12 consecutive days to patients with metastatic malignant melanoma or metastatic renal cell cancer. RESULTS: Flow cytometry of peripheral blood lymphocytes revealed dramatic efflux of NK and memory CD8 T cells from the circulating blood within minutes of IL-15 administration, followed by influx and hyperproliferation yielding 10-fold expansions of NK cells that ultimately returned to baseline. Up to 50-fold increases of serum levels of multiple inflammatory cytokines were observed. Dose-limiting toxicities observed in patients receiving 3.0 and 1.0 µg/kg per day were grade 3 hypotension, thrombocytopenia, and elevations of ALT and AST, resulting in 0.3 µg/kg per day being determined the maximum-tolerated dose. Indications of activity included clearance of lung lesions in two patients. CONCLUSION: IL-15 could be safely administered to patients with metastatic malignancy. IL-15 administration markedly altered homeostasis of lymphocyte subsets in blood, with NK cells and γδ cells most dramatically affected, followed by CD8 memory T cells. To reduce toxicity and increase efficacy, alternative dosing strategies have been initiated, including continuous intravenous infusions and subcutaneous IL-15 administration.


Asunto(s)
Linfocitos T CD4-Positivos/efectos de los fármacos , Proliferación Celular/efectos de los fármacos , Interleucina-15/uso terapéutico , Células Asesinas Naturales/efectos de los fármacos , Neoplasias/tratamiento farmacológico , Adulto , Anciano , Anciano de 80 o más Años , Área Bajo la Curva , Linfocitos T CD4-Positivos/metabolismo , Relación Dosis-Respuesta a Droga , Esquema de Medicación , Femenino , Fiebre/inducido químicamente , Humanos , Infusiones Intravenosas , Interleucina-15/efectos adversos , Interleucina-15/genética , Células Asesinas Naturales/metabolismo , Activación de Linfocitos/efectos de los fármacos , Masculino , Tasa de Depuración Metabólica , Persona de Mediana Edad , Náusea/inducido químicamente , Metástasis de la Neoplasia , Neoplasias/inmunología , Neoplasias/metabolismo , Neutropenia/inducido químicamente , Proteínas Recombinantes/administración & dosificación , Proteínas Recombinantes/farmacocinética , Proteínas Recombinantes/uso terapéutico , Resultado del Tratamiento , Adulto Joven
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