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1.
Nat Med ; 26(2): 222-227, 2020 02.
Artículo en Inglés | MEDLINE | ID: mdl-32015556

RESUMEN

Combination antiretroviral therapy (ART) is highly effective in controlling human immunodeficiency virus (HIV)-1 but requires lifelong medication due to the existence of a latent viral reservoir1,2. Potent broadly neutralizing antibodies (bNAbs) represent a potential alternative or adjuvant to ART. In addition to suppressing viremia, bNAbs may have T cell immunomodulatory effects as seen for other forms of immunotherapy3. However, this has not been established in individuals who are infected with HIV-1. Here, we document increased HIV-1 Gag-specific CD8+ T cell responses in the peripheral blood of all nine study participants who were infected with HIV-1 with suppressed blood viremia, while receiving bNAb therapy during ART interruption4. Increased CD4+ T cell responses were detected in eight individuals. The increased T cell responses were due both to newly detectable reactivity to HIV-1 Gag epitopes and the expansion of pre-existing measurable responses. These data demonstrate that bNAb therapy during ART interruption is associated with enhanced HIV-1-specific T cell responses. Whether these augmented T cell responses can contribute to bNAb-mediated viral control remains to be determined.


Asunto(s)
Anticuerpos Anti-VIH/inmunología , Infecciones por VIH/inmunología , Infecciones por VIH/terapia , Inmunoterapia/métodos , Linfocitos T/inmunología , Adulto , Anticuerpos Neutralizantes/inmunología , Linfocitos T CD4-Positivos/inmunología , Linfocitos T CD4-Positivos/virología , Linfocitos T CD8-positivos/inmunología , Linfocitos T CD8-positivos/virología , Epítopos/inmunología , Femenino , Productos del Gen gag/metabolismo , Infecciones por VIH/virología , VIH-1 , Humanos , Sistema Inmunológico , Interferón gamma/inmunología , Masculino , Persona de Mediana Edad , Linfocitos T/virología , Viremia
2.
PLoS One ; 14(8): e0219142, 2019.
Artículo en Inglés | MEDLINE | ID: mdl-31393868

RESUMEN

BACKGROUND: Additional forms of pre-exposure prophylaxis are needed to prevent HIV-1 infection. 3BNC117 and 10-1074 are broadly neutralizing anti-HIV-1 antibodies that target non-overlapping epitopes on the HIV-1 envelope. We investigated the safety, tolerability, pharmacokinetics, and immunogenicity of the intravenous administration of the combination of 3BNC117 and 10-1074 in healthy adults. METHODS: This randomized, double-blind, placebo-controlled, single center, phase 1 study enrolled healthy adults aged 18-65 years to receive one infusion of 3BNC117 immediately followed by 10-1074 at 10 mg/kg, three infusions of 3BNC117 followed by 10-1074 at 3 mg/kg or 10 mg/kg every 8 weeks, or placebo infusions. The primary outcomes were safety and pharmacokinetics. This trial is registered with ClinicalTrials.gov, number NCT02824536. FINDINGS: Twenty-four participants were enrolled in a 3:1 ratio to receive the study products or placebo. The combination of 3BNC117 and 10-1074 was safe and generally well tolerated. There were no serious adverse events considered related to the infusions. The mean elimination half-lives of 3BNC117 and 10-1074 were 16.4 ± 4.6 days and 23.0 ± 5.4 days, respectively, similar to what was observed in previous studies in which each antibody was administered alone. Anti-drug antibody responses were rare and without evidence of related adverse events or impact on elimination kinetics. INTERPRETATION: Single and repeated doses of the combination of 3BNC117 and 10-1074 were well tolerated in healthy adults. These data support the further development of the combination of 3BNC117 and 10-1074 as a long-acting injectable form of pre-exposure prophylaxis for the prevention of HIV-1 infection.


Asunto(s)
Anticuerpos Monoclonales Humanizados/farmacología , Anticuerpos ampliamente neutralizantes/farmacología , Anticuerpos Anti-VIH/farmacología , Infecciones por VIH/inmunología , Administración Intravenosa/métodos , Adulto , Anticuerpos Monoclonales/inmunología , Anticuerpos Monoclonales/farmacología , Anticuerpos Monoclonales Humanizados/inmunología , Anticuerpos Monoclonales Humanizados/farmacocinética , Anticuerpos ampliamente neutralizantes/inmunología , Método Doble Ciego , Quimioterapia Combinada/métodos , Femenino , Anticuerpos Anti-VIH/inmunología , Infecciones por VIH/prevención & control , Seropositividad para VIH/tratamiento farmacológico , VIH-1/inmunología , VIH-1/patogenicidad , Voluntarios Sanos , Humanos , Masculino , Efecto Placebo , Profilaxis Pre-Exposición/métodos
3.
Nature ; 561(7724): 479-484, 2018 09.
Artículo en Inglés | MEDLINE | ID: mdl-30258136

RESUMEN

Individuals infected with HIV-1 require lifelong antiretroviral therapy, because interruption of treatment leads to rapid rebound viraemia. Here we report on a phase 1b clinical trial in which a combination of 3BNC117 and 10-1074, two potent monoclonal anti-HIV-1 broadly neutralizing antibodies that target independent sites on the HIV-1 envelope spike, was administered during analytical treatment interruption. Participants received three infusions of 30 mg kg-1 of each antibody at 0, 3 and 6 weeks. Infusions of the two antibodies were generally well-tolerated. The nine enrolled individuals with antibody-sensitive latent viral reservoirs maintained suppression for between 15 and more than 30 weeks (median of 21 weeks), and none developed viruses that were resistant to both antibodies. We conclude that the combination of the anti-HIV-1 monoclonal antibodies 3BNC117 and 10-1074 can maintain long-term suppression in the absence of antiretroviral therapy in individuals with antibody-sensitive viral reservoirs.


Asunto(s)
Anticuerpos Monoclonales/uso terapéutico , Anticuerpos Neutralizantes/uso terapéutico , Anticuerpos Anti-VIH/uso terapéutico , Infecciones por VIH/tratamiento farmacológico , Infecciones por VIH/inmunología , VIH-1/inmunología , Latencia del Virus/inmunología , Adolescente , Adulto , Anciano , Fármacos Anti-VIH/administración & dosificación , Fármacos Anti-VIH/inmunología , Fármacos Anti-VIH/uso terapéutico , Anticuerpos Monoclonales/administración & dosificación , Anticuerpos Monoclonales/efectos adversos , Anticuerpos Monoclonales/inmunología , Anticuerpos Monoclonales Humanizados , Anticuerpos Neutralizantes/administración & dosificación , Anticuerpos Neutralizantes/efectos adversos , Anticuerpos Neutralizantes/inmunología , Sitios de Unión de Anticuerpos , Anticuerpos ampliamente neutralizantes , Portador Sano/tratamiento farmacológico , Portador Sano/inmunología , Portador Sano/virología , Combinación de Medicamentos , Farmacorresistencia Viral , Femenino , Anticuerpos Anti-VIH/administración & dosificación , Anticuerpos Anti-VIH/efectos adversos , Anticuerpos Anti-VIH/inmunología , Proteínas gp160 de Envoltorio del VIH/inmunología , Infecciones por VIH/virología , VIH-1/aislamiento & purificación , Estudio Históricamente Controlado , Humanos , Infusiones Intravenosas , Masculino , Persona de Mediana Edad , Filogenia , Viremia/tratamiento farmacológico , Viremia/inmunología , Viremia/prevención & control , Viremia/virología , Activación Viral/inmunología , Adulto Joven
4.
Nat Med ; 24(11): 1701-1707, 2018 11.
Artículo en Inglés | MEDLINE | ID: mdl-30258217

RESUMEN

Monotherapy of HIV-1 infection with single antiretroviral agents is ineffective because error-prone HIV-1 replication leads to the production of drug-resistant viral variants1,2. Combinations of drugs can establish long-term control, however, antiretroviral therapy (ART) requires daily dosing, can cause side effects and does not eradicate the infection3,4. Although anti-HIV-1 antibodies constitute a potential alternative to ART5,6, treatment of viremic individuals with a single antibody also results in emergence of resistant viral variants7-9. Moreover, combinations of first-generation anti-HIV-1 broadly neutralizing antibodies (bNAbs) had little measurable effect on the infection10-12. Here we report on a phase 1b clinical trial ( NCT02825797 ) in which two potent bNAbs, 3BNC11713 and 10-107414, were administered in combination to seven HIV-1 viremic individuals. Infusions of 30 mg kg-1 of each of the antibodies were well-tolerated. In the four individuals with dual antibody-sensitive viruses, immunotherapy resulted in an average reduction in HIV-1 viral load of 2.05 log10 copies per ml that remained significantly reduced for three months following the first of up to three infusions. In addition, none of these individuals developed resistance to both antibodies. Larger studies will be necessary to confirm the efficacy of antibody combinations in reducing HIV-1 viremia and limiting the emergence of resistant viral variants.


Asunto(s)
Anticuerpos Neutralizantes/administración & dosificación , Infecciones por VIH/tratamiento farmacológico , Inmunoterapia , Viremia/tratamiento farmacológico , Adolescente , Adulto , Anciano , Anticuerpos Neutralizantes/efectos adversos , Terapia Antirretroviral Altamente Activa , Femenino , Infecciones por VIH/virología , Seropositividad para VIH , VIH-1/patogenicidad , Humanos , Masculino , Persona de Mediana Edad , Carga Viral/efectos de los fármacos , Viremia/virología , Adulto Joven
5.
J Exp Med ; 215(9): 2311-2324, 2018 09 03.
Artículo en Inglés | MEDLINE | ID: mdl-30072495

RESUMEN

A clinical trial was performed to evaluate 3BNC117, a potent anti-HIV-1 antibody, in infected individuals during suppressive antiretroviral therapy and subsequent analytical treatment interruption (ATI). The circulating reservoir was evaluated by quantitative and qualitative viral outgrowth assay (Q2VOA) at entry and after 6 mo. There were no significant quantitative changes in the size of the reservoir before ATI, and the composition of circulating reservoir clones varied in a manner that did not correlate with 3BNC117 sensitivity. 3BNC117 binding site amino acid variants found in rebound viruses preexisted in the latent reservoir. However, only 3 of 217 rebound viruses were identical to 868 latent viruses isolated by Q2VOA and near full-length sequencing. Instead, 63% of the rebound viruses appeared to be recombinants, even in individuals with 3BNC117-resistant reservoir viruses. In conclusion, viruses emerging during ATI in individuals treated with 3BNC117 are not the dominant species found in the circulating latent reservoir, but frequently appear to represent recombinants of latent viruses.


Asunto(s)
Antirretrovirales/administración & dosificación , Anticuerpos Anti-VIH/administración & dosificación , Infecciones por VIH , VIH-1 , Recombinación Genética , Carga Viral , Adolescente , Adulto , Anciano , Antirretrovirales/inmunología , Femenino , Estudios de Seguimiento , Anticuerpos Anti-VIH/inmunología , Infecciones por VIH/sangre , Infecciones por VIH/tratamiento farmacológico , Infecciones por VIH/genética , Infecciones por VIH/inmunología , VIH-1/genética , VIH-1/inmunología , Humanos , Masculino , Persona de Mediana Edad , Recombinación Genética/efectos de los fármacos , Recombinación Genética/inmunología , Carga Viral/genética , Carga Viral/inmunología
6.
Nat Med ; 24(5): 604-609, 2018 05.
Artículo en Inglés | MEDLINE | ID: mdl-29686423

RESUMEN

Despite suppressive combination antiretroviral therapy (ART), latent HIV-1 proviruses persist in patients. This latent reservoir is established within 48-72 h after infection, has a long half-life1,2, enables viral rebound when ART is interrupted, and is the major barrier to a cure for HIV-1 3 . Latent cells are exceedingly rare in blood (∼1 per 1 × 106 CD4+ T cells) and are typically enumerated by indirect means, such as viral outgrowth assays4,5. We report a new strategy to purify and characterize single reactivated latent cells from HIV-1-infected individuals on suppressive ART. Surface expression of viral envelope protein was used to enrich reactivated latent T cells producing HIV RNA, and single-cell analysis was performed to identify intact virus. Reactivated latent cells produce full-length viruses that are identical to those found in viral outgrowth cultures and represent clones of in vivo expanded T cells, as determined by their T cell receptor sequence. Gene-expression analysis revealed that these cells share a transcriptional profile that includes expression of genes implicated in silencing the virus. We conclude that reactivated latent T cells isolated from blood can share a gene-expression program that allows for cell division without activation of the cell death pathways that are normally triggered by HIV-1 replication.


Asunto(s)
Linfocitos T CD4-Positivos/metabolismo , Linfocitos T CD4-Positivos/virología , Perfilación de la Expresión Génica , VIH-1/fisiología , Latencia del Virus/fisiología , Células Clonales , Humanos , Análisis de Componente Principal , ARN Viral/metabolismo , Análisis de Secuencia de ARN , Análisis de la Célula Individual
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