자료유형  

 학위논문

Control Number  

0017160474

International Standard Book Number  

9798382214863

Dewey Decimal Classification Number  

576.6

Main Entry-Personal Name  

Kulsuptrakul, Jessie.

Publication, Distribution, etc. (Imprint  

[S.l.] : University of Washington., 2024

Publication, Distribution, etc. (Imprint  

Ann Arbor : ProQuest Dissertations & Theses, 2024

Physical Description  

128 p.

General Note  

Source: Dissertations Abstracts International, Volume: 85-10, Section: B.

General Note  

Advisor: Emerman, Michael;Mitchell, Patrick.

Dissertation Note  

Thesis (Ph.D.)--University of Washington, 2024.

Summary, Etc.  

요약Inflammasomes are host cytosolic innate immune complexes that assemble upon detection of diverse pathogen-associated cues and play a crucial role in host defense but can also contribute to inflammatory pathogenesis. In prior work, the inflammasome-forming sensor CARD8 was reported to recognize the enzymatic activity of the protease of human immunodeficiency virus type 1 (HIV-1). I demonstrated that human CARD8 has a unique motif among hominoids and Old World monkeys that renders it susceptible to cleavage by HIV-1 protease (HIV-1PR). Furthermore, the protease from the precursor to HIV-1, SIVcpz, can cleave human CARD8, but not chimpanzee CARD8. This indicates that the precursor viruses to HIV-1 were poised to cleave human CARD8 prior to cross-species transmission into human. In addition, I show that CARD8 sensing can happen during acute HIV-1 infection, using multiple modes of infection in cancer and primary cell lines, in a manner dependent on HIV-1PR cleavage of the human-specific motif in CARD8, resulting in a lytic form of cell death called pyroptosis and the release of proinflammatory cytokines. Genetic knockout of the inflammasome adaptor protein ASC suggests that cell death associated with HIV-dependent inflammasome activation is primarily CARD8-dependent whereas cytokine release may be amplified through secondary modulation by the NLRP3 inflammasome. Additionally, I identified mutant HIV-1 proteases from a panel of protease inhibitor resistant HIV-1 strains that differentially cleave and activate CARD8 compared to wildtype HIV-1.HIV-1 arose from multiple cross-species transmissions from simian immunodeficiency virus (SIV) infecting other primates. While some non-human primates infected with SIVs exhibit inflammatory pathologies, humans present with the most severe inflammatory pathogenesis, progressing to acquired immunodeficiency syndrome (AIDS) without anti-retroviral therapy. The findings outlined in this thesis suggest a model whereby human-specific activation of the CARD8 inflammasome may contribute to chronic immune activation and may partially explain the heightened pathogenesis of HIV-1 in humans relative to SIV in other non-human primate reservoirs. 

Subject Added Entry-Topical Term  

Virology.

Subject Added Entry-Topical Term  

Immunology.

Subject Added Entry-Topical Term  

Evolution & development.

Subject Added Entry-Topical Term  

Cellular biology.

Subject Added Entry-Topical Term  

Molecular biology.

Index Term-Uncontrolled  

Cross-species transmission

Index Term-Uncontrolled  

Inflammasomes

Index Term-Uncontrolled  

Protease

Index Term-Uncontrolled  

Simian immunodeficiency virus

Added Entry-Corporate Name  

University of Washington Molecular and Cellular Biology

Host Item Entry  

Dissertations Abstracts International. 85-10B.

Electronic Location and Access  

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Control Number  

joongbu:655102