Rol de las cadenas livianas del complejo dineina citoplasmático en la infección por el virus de la inmunodeficiencia humana de tipo 1 (HIV-1) y el virus de la leucemia murina (MLV)
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Fecha
2015
Autores
Profesor/a Guía
Facultad/escuela
Idioma
es
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Universidad Andrés Bello
Nombre de Curso
Licencia CC
Licencia CC
Resumen
Los retrovirus son parásitos intracelulares obligados, que necesitan
incorporar su genoma en el ADN del hospedero para poder llevar a cabo su ciclo
replicativo. En la actualidad, los estudios que describen el ciclo replicativo de los
retrovirus son muchos, pero la información que entregan es escasa.
El complejo de dineina citoplasmático juega un rol fundamental en el
transporte intracelular, incluso es usado por algunos virus para transportarse a
través del citoplasma. Distintas investigaciones muestran que las cadenas livianas
del complejo dineina citoplasmático son usadas por virus de diversas familias para
su transporte en el citoplasma. Resultados preliminares del laboratorio, asocian al
complejo de preintegración de MLV con proteínas del complejo de dineina
citoplasmático. Por este motivo planteamos como hipótesis que "las cadenas
livianas del complejo de dineina citoplasmático participan en el proceso infectivo
de MLVy HIV-1".
Mediante el silenciamiento de las distintas cadenas livianas del complejo de
dineina citoplasmático y posterior infección con virus HIV-1 y MLV reporteros
demostramos que la proteína DYNLT3 es necesaria en las etapas tempranas de
infección de HIV-1. En el caso de MLV, las proteínas DYNLRB2 y DYNLT1 tienen
un rol en las etapas tempranas de la infección, en un punto posterior a la
transcripción reversa y anterior a la entrada al núcleo. Estos resultados confirman
nuestra hipótesis, lo cual sugiere que estas proteínas participan en el transporte
de estos virus a través del citoplasma para alcanzar el núcleo celular y poder llevar
a cabo su ciclo replicativo.
El aporte de esta investigación será de vital importancia para el desarrollo
de nuevas terapias para el tratamiento de las enfermedades asociadas a estos
virus.
Retroviruses are strict intracellular parasites; they need to integrate their genome into host DNA for their replication. The studies that describes retroviral replicative cycle have allow us to learn much about them, but there still information that is unknown. Cytoplasmic dynein complex plays a crucial role in intracellular transport, and it has been reported that is used by sorne viruses for their transport across the cytoplasm. Many reports shown that cytoplasmic dynein light chains are being used by different viruses for their transport across the cytoplasm. Our laboratory preliminary data associates Murine Leukemia Virus preintegration complex with cytoplasmic dynein complex proteins. For this reason we hypothesize that "cytoplasmic dynein light chains participates in the infection process of MLV and HIV-1". Using as method genetic knockdown, in this thesis we silenced every cytoplasmic dynein light chain and then we evaluated the infection of this cells, using reporter versions for HIV-1 and MLV viruses. We observe that DYNL T3 is necessary for early steps on HIV-1 infection. For MLV infection, DYNLRB2 and DYNL T1 have a role in the early steps of infective cycle, in the knockdown cells; we also show that the infection in knockdown cells is being blocked in a step after reverse transcription and before nuclear entry. These results, sustain our hypothesis, suggesting the participation of these proteins in retroviral transport across cytoplasm to achieve cell nucleus and complete the early phase of replication cycle. This investigation will contribute in the generation and development of new therapies for treatment in diseases caused by retroviruses.
Retroviruses are strict intracellular parasites; they need to integrate their genome into host DNA for their replication. The studies that describes retroviral replicative cycle have allow us to learn much about them, but there still information that is unknown. Cytoplasmic dynein complex plays a crucial role in intracellular transport, and it has been reported that is used by sorne viruses for their transport across the cytoplasm. Many reports shown that cytoplasmic dynein light chains are being used by different viruses for their transport across the cytoplasm. Our laboratory preliminary data associates Murine Leukemia Virus preintegration complex with cytoplasmic dynein complex proteins. For this reason we hypothesize that "cytoplasmic dynein light chains participates in the infection process of MLV and HIV-1". Using as method genetic knockdown, in this thesis we silenced every cytoplasmic dynein light chain and then we evaluated the infection of this cells, using reporter versions for HIV-1 and MLV viruses. We observe that DYNL T3 is necessary for early steps on HIV-1 infection. For MLV infection, DYNLRB2 and DYNL T1 have a role in the early steps of infective cycle, in the knockdown cells; we also show that the infection in knockdown cells is being blocked in a step after reverse transcription and before nuclear entry. These results, sustain our hypothesis, suggesting the participation of these proteins in retroviral transport across cytoplasm to achieve cell nucleus and complete the early phase of replication cycle. This investigation will contribute in the generation and development of new therapies for treatment in diseases caused by retroviruses.
Notas
Tesis (Magíster en Biotecnología)
Palabras clave
Retrovirus, Ciclo replicativo de enfermedades transmisibles, Tratamiento y Rehabilitación, Chile