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1.
bioRxiv ; 2023 Dec 02.
Artículo en Inglés | MEDLINE | ID: mdl-37693451

RESUMEN

Viruses exploit host cytoskeletal elements and motor proteins for trafficking through the dense cytoplasm. Yet the molecular mechanism that describes how viruses connect to the motor machinery is unknown. Here, we demonstrate the first example of viral microtubule trafficking from purified components: HIV-1 hijacking microtubule transport machinery. We discover that HIV-1 directly binds to the retrograde microtubule-associated motor, dynein, and not via a cargo adaptor, as previously suggested. Moreover, we show that HIV-1 motility is supported by multiple, diverse dynein cargo adaptors as HIV-1 binds to dynein light and intermediate chains on dynein's tail. Further, we demonstrate that multiple dynein motors tethered to rigid cargoes, like HIV-1 capsids, display reduced motility, distinct from the behavior of multiple motors on membranous cargoes. Our results introduce a new model of viral trafficking wherein a pathogen opportunistically 'hijacks' the microtubule transport machinery for motility, enabling multiple transport pathways through the host cytoplasm.

2.
Cell Rep ; 31(12): 107810, 2020 06 23.
Artículo en Inglés | MEDLINE | ID: mdl-32579936

RESUMEN

Cellular metabolism governs the susceptibility of CD4 T cells to HIV-1 infection. Multiple early post-fusion steps of HIV-1 replication are restricted in resting peripheral blood CD4 T cells; however, molecular mechanisms that underlie metabolic control of these steps remain undefined. Here, we show that mTOR activity following T cell stimulatory signals overcomes metabolic restrictions in these cells by enabling the expansion of dNTPs to fuel HIV-1 reverse transcription (RT), as well as increasing acetyl-CoA to stabilize microtubules that transport RT products. We find that catalytic mTOR inhibition diminishes the expansion of pools of both of these metabolites by limiting glucose and glutamine utilization in several pathways, thereby suppressing HIV-1 infection. We demonstrate how mTOR-coordinated biosyntheses enable the early steps of HIV-1 replication, add metabolic mechanisms by which mTOR inhibitors block HIV-1, and identify some metabolic modules downstream of mTOR as druggable targets for HIV-1 inhibition.


Asunto(s)
VIH-1/genética , VIH-1/metabolismo , Espacio Intracelular/metabolismo , Transcripción Reversa/genética , Serina-Treonina Quinasas TOR/metabolismo , Acetilcoenzima A/metabolismo , Acetilación , Transporte Biológico , Linfocitos T CD4-Positivos/virología , Citocinas/metabolismo , Retroalimentación Fisiológica , Glucólisis , VIH-1/inmunología , VIH-1/fisiología , Humanos , Lisina/metabolismo , Diana Mecanicista del Complejo 1 de la Rapamicina/metabolismo , Diana Mecanicista del Complejo 2 de la Rapamicina/metabolismo , Microtúbulos/metabolismo , Modelos Biológicos , Receptores de Antígenos de Linfocitos T/metabolismo , Tubulina (Proteína)/metabolismo , Replicación Viral/genética
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