Protein kinase activation and modulation of extracellular vesicle secretion by the HIV-1 pathogenicity factor nef

Zhe Zhao

Tutkimustuotos: OpinnäyteVäitöskirjaArtikkelikokoelma

Abstrakti

By July 17, 2021, the human immunodeficiency virus (HIV) has claimed more than 36.3 million lives worldwide. Currently, an estimated 38 million people are living with HIV. Although 67% of these infected individuals (approximately 25 million people) have been receiving antiretroviral therapy (ART), and 59% (around 22 million) have successfully suppressed the HIV replication with no risk of spreading to others, still, 10-40% of such aviremic HIV patients are suffering from persistent inflammation. Such chronic immune activation contributes to HIV-associated neurocognitive impairment, resulting in loss of life quality during ageing. This thesis addresses the mechanisms of the proinflammatory effector TACE secretion into extracellular vesicles (EVs) triggered by HIV accessory protein Nef. Such TACE-containing circulating EV levels are associated with low CD4+ T cell counts in aviremic HIV patients. In addition, the results reveal that HIV-1 Nef activates Src family kinase member Hck to promote the EV packaging of TACE, and such TACE secretion utilizes an unconventional Golgi bypass route. Moreover, this thesis unveils the roles of the Raf-MEK-ERK kinase cascade in HIV-induced TACE secretion. Clinically approved MEK inhibitors could suppress HIV-driven EV packaging of TACE significantly. Lastly, this study identifies a molecular structure in Nef, termed “R-clamp,” playing a pivotal role in the SH3 domain-mediated interaction between Nef and Hck. This thesis supplies evidences supporting a hypothesis that the Nef protein of HIV-1 is involved in HIV-induced chronic immune activation. Besides, this study offers a potential novel strategy for treating such HIV-associated immune activation.
Alkuperäiskielienglanti
Myöntävä instituutio
  • Helsingin yliopisto
Valvoja/neuvonantaja
  • Saksela, Kalle, Valvoja
JulkaisupaikkaHelsinki
Kustantaja
Painoksen ISBN978-951-51-7686-8
Sähköinen ISBN978-951-51-7687-5
TilaJulkaistu - 2021
OKM-julkaisutyyppiG5 Tohtorinväitöskirja (artikkeli)

Lisätietoja

M1 - 85 s. + liitteet

Tieteenalat

  • 3111 Biolääketieteet

Siteeraa tätä