東華大學圖書館 |

語系: 繁體中文

說明(常見問題)

回圖書館首頁

手機版館藏查詢

登入

回首頁

切換: 標籤 | MARC模式 | ISBD

Mechanisms of HIV-1 Restriction by t...

Antonucci, Jenna Marie.

FindBook

Google Book

Amazon

博客來

Mechanisms of HIV-1 Restriction by the Host Protein SAMHD1.

紀錄類型:	書目-電子資源 : Monograph/item
正題名/作者:	Mechanisms of HIV-1 Restriction by the Host Protein SAMHD1./
作者:	Antonucci, Jenna Marie.
出版者:	Ann Arbor : ProQuest Dissertations & Theses, : 2018,
面頁冊數:	192 p.
附註:	Source: Dissertation Abstracts International, Volume: 80-03(E), Section: B.
Contained By:	Dissertation Abstracts International80-03B(E).
標題:	Molecular biology. -
電子資源:	http://pqdd.sinica.edu.tw/twdaoapp/servlet/advanced?query=10991832
ISBN:	9780438463240

Mechanisms of HIV-1 Restriction by the Host Protein SAMHD1.
Antonucci, Jenna Marie.

Mechanisms of HIV-1 Restriction by the Host Protein SAMHD1. - Ann Arbor : ProQuest Dissertations & Theses, 2018 - 192 p.

Source: Dissertation Abstracts International, Volume: 80-03(E), Section: B.

Thesis (Ph.D.)--The Ohio State University, 2018.

Human immunodeficiency virus type 1 (HIV-1) is a human retrovirus that replicates in cells via a well-characterized viral lifecycle. Inhibition at any step in the viral lifecycle results in downstream effects that can impair HIV-1 replication and restrict infection. For decades, researchers have been unable to determine the cause of myeloid-cell specific block in HIV-1 infection. In 2011, the discovery of the first mammalian deoxynucleoside triphosphate (dNTP) triphosphohydrolase (dNTPase) sterile alpha motif and HD domain containing protein 1 (SAMHD1) answered that question and introduced an entirely novel field of study focused on determining the mechanism and control of SAMHD1-mediated restriction of HIV-1 replication. Since then, the research on SAMHD1 has become a timely and imperative topic of virology. The following body of work includes studies furthering the field by confirming the established model and introducing a novel mechanism of SAMHD1-mediated suppression of HIV-1 replication.

ISBN: 9780438463240Subjects--Topical Terms:

517296
Molecular biology.

Mechanisms of HIV-1 Restriction by the Host Protein SAMHD1.
LDR:05820nmm a2200373 4500 001 2202477
005 20190510112843.5
008 201008s2018 ||||||||||||||||| ||eng d
020 $a 9780438463240
035 $a (MiAaPQ)AAI10991832
035 $a (MiAaPQ)OhioLINK:osu1524006072232491
035 $a AAI10991832
040 $a MiAaPQ $c MiAaPQ
100 1 $a Antonucci, Jenna Marie. $3 3429234
245 1 0 $a Mechanisms of HIV-1 Restriction by the Host Protein SAMHD1.
260 1 $a Ann Arbor : $b ProQuest Dissertations & Theses, $c 2018
300 $a 192 p.
500 $a Source: Dissertation Abstracts International, Volume: 80-03(E), Section: B.
500 $a Adviser: Li Wu.
502 $a Thesis (Ph.D.)--The Ohio State University, 2018.
520 $a Human immunodeficiency virus type 1 (HIV-1) is a human retrovirus that replicates in cells via a well-characterized viral lifecycle. Inhibition at any step in the viral lifecycle results in downstream effects that can impair HIV-1 replication and restrict infection. For decades, researchers have been unable to determine the cause of myeloid-cell specific block in HIV-1 infection. In 2011, the discovery of the first mammalian deoxynucleoside triphosphate (dNTP) triphosphohydrolase (dNTPase) sterile alpha motif and HD domain containing protein 1 (SAMHD1) answered that question and introduced an entirely novel field of study focused on determining the mechanism and control of SAMHD1-mediated restriction of HIV-1 replication. Since then, the research on SAMHD1 has become a timely and imperative topic of virology. The following body of work includes studies furthering the field by confirming the established model and introducing a novel mechanism of SAMHD1-mediated suppression of HIV-1 replication.
520 $a SAMHD1 was originally identified as a dGTP-dependent dNTPase that restricts HIV-1 infection by hydrolyzing intracellular dNTPs to a level that inhibits efficient reverse transcription of HIV-1 genomic RNA into complementary DNA (cDNA). Although this model was confirmed by several studies, work published in 2014 suggested that SAMHD1 is a nucleic-acid binding protein that restricts HIV-1 replication through its ribonuclease (RNase) activity against the viral RNA genome in non-dividing immune cells. These findings revealed a new mechanism of SAMHD1-mediated HIV-1 restriction and raised important questions as to the contribution of each enzyme activity, dNTPase and RNase, to HIV-1 restriction.
520 $a Based on previous studies, we tested our hypothesis that the RNase activity of SAMHD1 might limit HIV-1 protein production in virus producing cells, as transcribed viral RNA would be subject to cleavage by SAMHD1. Our data suggest that newly transcribed mRNAs of HIV-1, Influenza A virus (IAV), and Sendai virus (SeV) are not subjected to nucleolytic cleavage by SAMHD1's RNase activity. We further confirmed SAMHD1 expression does not affect HIV-1 protein production, viral particle release, and infectivity of newly synthesized HIV-1 when the block in reverse transcription is bypassed. While SAMHD1 had no effect on incoming viral genomic RNA levels, we confirmed that SAMHD1 reduces intracellular dNTPs and inhibits efficient production of HIV-1 late reverse transcription products in non-dividing cells. Taken together, our study confirmed a dNTPase-dependent restriction of HIV-1 infection by SAMHD1.
520 $a A critical barrier to developing a cure for HIV-1 infection is the long-lived viral reservoir that exists in resting CD4+ T-cells, the main targets of HIV-1. The viral reservoir is maintained through a variety of mechanisms, including regulation of the HIV-1 long terminal repeat (LTR) promoter. Recombinant SAMHD1 binds HIV-1 DNA or RNA fragments in vitro, but the function of this binding remains unclear. SAMHD1 restricts HIV-1 replication in non-dividing cells and is highly expressed in resting CD4+ T-cells, but its role in HIV-1 latency remains unknown. Here we report a new function of SAMHD1 in regulating HIV-1 latency. We found that SAMHD1 suppressed HIV-1 LTR promoter-driven gene expression and reactivation of viral latency in cell lines and primary CD4+ T-cells. Furthermore, SAMHD1 bound to the HIV-1 LTR in vitro and in a latently infected CD4+ T-cell line, suggesting that the binding may negatively modulate reactivation of HIV-1 latency. Our findings indicate a novel role for SAMHD1 in regulating HIV-1 latency, which enhances our understanding of the mechanisms regulating proviral gene expression in CD4+ T-cells.
520 $a To further understand the mechanism regulating the activity of SAMHD1, we solved novel crystal structures of full-length mouse SAMHD1 (mSAMHD1) to identify residues essential for the intra- and inter-subunit interaction between the SAM and HD domains. Interestingly, while the SAM domain of human SAMHD1 (hSAMHD1) is dispensable for HIV-1 restriction, we found that the SAM domain of mSAMHD1 is required for efficient HIV-1 restriction. Further, we determined that destabilization of the SAM-to-HD domain interaction abrogated the HIV-1 restriction activity of mSAMHD1. Interestingly, stabilization of the SAM-to-HD domain interaction in hSAMHD1 resulted in enhanced HIV-1 restriction. These data increase our understanding of the mechanism regulating SAMHD1-mediated HIV-1 restriction.
520 $a The following studies have been critical for defining the mechanism of SAMHD1-mediated HIV-1 restriction. Taken together, our results can help better understand HIV-1 pathogenesis and how SAMHD1 functions as a retroviral restriction factor.
590 $a School code: 0168.
650 4 $a Molecular biology. $3 517296
650 4 $a Microbiology. $3 536250
650 4 $a Virology. $3 642304
690 $a 0307
690 $a 0410
690 $a 0720
710 2 $a The Ohio State University. $b Microbiology. $3 3282852
773 0 $t Dissertation Abstracts International $g 80-03B(E).
790 $a 0168
791 $a Ph.D.
792 $a 2018
793 $a English
856 4 0 $u http://pqdd.sinica.edu.tw/twdaoapp/servlet/advanced?query=10991832