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Métodos Terapéuticos y Terapias MTCI
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1.
JCI Insight ; 6(3)2021 02 08.
Artículo en Inglés | MEDLINE | ID: mdl-33400687

RESUMEN

Antiretroviral therapies (ARTs) abrogate HIV replication; however, infection persists as long-lived reservoirs of infected cells with integrated proviruses, which reseed replication if ART is interrupted. A central tenet of our current understanding of this persistence is that infected cells are shielded from immune recognition and elimination through a lack of antigen expression from proviruses. Efforts to cure HIV infection have therefore focused on reactivating latent proviruses to enable immune-mediated clearance, but these have yet to succeed in reducing viral reservoirs. Here, we revisited the question of whether HIV reservoirs are predominately immunologically silent from a new angle: by querying the dynamics of HIV-specific T cell responses over long-term ART for evidence of ongoing recognition of HIV-infected cells. In longitudinal assessments, we show that the rates of change in persisting HIV Nef-specific responses, but not responses to other HIV gene products, were associated with residual frequencies of infected cells. These Nef-specific responses were highly stable over time and disproportionately exhibited a cytotoxic, effector functional profile, indicative of recent in vivo recognition of HIV antigens. These results indicate substantial visibility of the HIV-infected cells to T cells on stable ART, presenting both opportunities and challenges for the development of therapeutic approaches to curing infection.


Asunto(s)
Fármacos Anti-VIH/uso terapéutico , Antígenos VIH/inmunología , Infecciones por VIH/tratamiento farmacológico , Infecciones por VIH/inmunología , VIH-1/inmunología , Linfocitos T/inmunología , Linfocitos T/virología , Adulto , Anciano , Linfocitos T CD4-Positivos/efectos de los fármacos , Linfocitos T CD4-Positivos/inmunología , Linfocitos T CD4-Positivos/virología , Linfocitos T CD8-positivos/efectos de los fármacos , Linfocitos T CD8-positivos/inmunología , Linfocitos T CD8-positivos/virología , Estudios de Cohortes , Femenino , Granzimas/metabolismo , Infecciones por VIH/virología , Interacciones Microbiota-Huesped/efectos de los fármacos , Interacciones Microbiota-Huesped/inmunología , Humanos , Evasión Inmune , Interferón gamma/metabolismo , Estudios Longitudinales , Masculino , Persona de Mediana Edad , Linfocitos T/efectos de los fármacos , Carga Viral , Adulto Joven
2.
JCI Insight ; 3(19)2018 10 04.
Artículo en Inglés | MEDLINE | ID: mdl-30282829

RESUMEN

The presence of a reservoir of latently infected cells in HIV-infected patients is a major barrier towards finding a cure. One active cure strategy is to find latency-reversing agents that induce viral reactivation, thus leading to immune cell recognition and elimination of latently infected cells, known as the shock-and-kill strategy. Therefore, the identification of molecules that reactivate latent HIV and increase immune activation has the potential to further these strategies into the clinic. Here, we characterized synthetic molecules composed of a TLR2 and a TLR7 agonist (dual TLR2/7 agonists) as latency-reversing agents and compared their activity with that of the TLR2 agonist Pam2CSK4 and the TLR7 agonist GS-9620. We found that these dual TLR2/7 agonists reactivate latency by 2 complementary mechanisms. The TLR2 component reactivates HIV by inducing NF-κB activation in memory CD4+ T cells, while the TLR7 component induces the secretion of TNF-α by monocytes and plasmacytoid dendritic cells, promoting viral reactivation in CD4+ T cells. Furthermore, the TLR2 component induces the secretion of IL-22, which promotes an antiviral state and blocks HIV infection in CD4+ T cells. Our study provides insight into the use of these agonists as a multipronged approach targeting eradication of latent HIV.


Asunto(s)
Fármacos Anti-VIH/farmacología , Infecciones por VIH/tratamiento farmacológico , VIH-1/fisiología , Receptor Toll-Like 2/agonistas , Receptor Toll-Like 7/agonistas , Activación Viral/efectos de los fármacos , Adolescente , Adulto , Anciano , Fármacos Anti-VIH/uso terapéutico , Linfocitos T CD4-Positivos/efectos de los fármacos , Linfocitos T CD4-Positivos/inmunología , Linfocitos T CD4-Positivos/virología , Células Dendríticas/efectos de los fármacos , Células Dendríticas/inmunología , Células Dendríticas/metabolismo , Evaluación Preclínica de Medicamentos , Femenino , Infecciones por VIH/inmunología , Infecciones por VIH/virología , VIH-1/efectos de los fármacos , Humanos , Interleucinas/inmunología , Interleucinas/metabolismo , Células Jurkat , Lipopéptidos/farmacología , Lipopéptidos/uso terapéutico , Masculino , Persona de Mediana Edad , Cultivo Primario de Células , Pteridinas/farmacología , Pteridinas/uso terapéutico , Receptor Toll-Like 2/inmunología , Receptor Toll-Like 2/metabolismo , Receptor Toll-Like 7/inmunología , Receptor Toll-Like 7/metabolismo , Activación Viral/inmunología , Latencia del Virus/efectos de los fármacos , Latencia del Virus/inmunología , Adulto Joven , Interleucina-22
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