LEADER 05898nam 2200601Ia 450 001 9910739405103321 005 20200520144314.0 010 $a1-4614-7291-1 024 7 $a10.1007/978-1-4614-7291-9 035 $a(CKB)2670000000406480 035 $a(EBL)1398422 035 $a(SSID)ssj0000958049 035 $a(PQKBManifestationID)11574128 035 $a(PQKBTitleCode)TC0000958049 035 $a(PQKBWorkID)10985574 035 $a(PQKB)10878759 035 $a(DE-He213)978-1-4614-7291-9 035 $a(MiAaPQ)EBC1398422 035 $a(PPN)172419034 035 $a(EXLCZ)992670000000406480 100 $a20130805d2013 uy 0 101 0 $aeng 135 $aur|n|---||||| 181 $ctxt 182 $cc 183 $acr 200 00$aHuman immunodeficiency virus reverse transcriptase $ea bench-to-bedside success /$fStuart LeGrice, Matthias Gotte, editors 205 $a1st ed. 2013. 210 $aNew York $cSpringer$d2013 215 $a1 online resource (358 p.) 300 $aDescription based upon print version of record. 311 $a1-4899-9953-1 311 $a1-4614-7290-3 320 $aIncludes bibliographical references and index. 327 $a1.7.1 Highly Active Antiretroviral Therapy (HAART)1.8 Prevention of HIV Transmission; 1.9 Conclusions; References; Part I Structure and Function of HIV RT; Chapter 2: Proviral DNA Synthesis in HIV: Background; 2.1 Introduction; 2.2 The Viral RNA Genome and DNA Provirus; 2.3 Location of the Reverse Transcription Process; 2.4 HIV-1 Reverse Transcriptase; 2.5 Selection of the tRNA Primer for HIV-1; 2.6 Placement of tRNA3Lys onto the Viral Genome; 2.7 Initiation of Reverse Transcription; 2.8 First (Minus)-Strand DNA Transfer; 2.9 Recombination Between the Two Copies of the RNA Genome 327 $a2.10 Plus-Strand DNA Synthesis2.11 tRNA Primer Removal from the (+)PBS; 2.12 Plus (Second)-Strand DNA Transfer; 2.13 Priming and Termination of DNA Synthesis Within the cPPT Region; 2.14 Completion of the Viral DNA Genome; 2.15 Integration of the HIV-1 Genome into the Host Genome; 2.16 Unintegrated Viral DNA; 2.17 Conclusion; References; Chapter 3: The RNase H Domain: Structure, Function and Mechanism; 3.1 Overview; 3.2 Structures of RNases H1; 3.3 Substrate Binding; 3.4 Catalysis; 3.5 Catalytic Mechanism of HIV-1 RNase H; 3.6 The Role of RNase H Activity in Reverse Transcription 327 $a5.2.1 Interaction Between HIV-1 RT and Nucleoside Triphosphates5.2.2 Crystallographic Structural Studies; 5.3 Mechanisms of Drug Resistance; 5.3.1 Resistance Through Increased Discrimination Against the Active Form of the Drug; 5.3.2 Resistance Through ATP-Mediated Excision of Chain-Terminating Nucleotides; 5.3.3 Mutations in RT that Antagonize the Effect of TAMs; 5.4 Structural Dissection of Drug-Resistant RT; 5.4.1 TAMs and Excision of AZTMP; 5.4.2 The K65R Mutation: Resistance to Tenofovir Disoproxil Fumarate (TDF) and Suppression of TAMs; 5.5 Uptake and Phosphorylation of NRTIs and NtRTIs 327 $a5.6 Intracellular dNTP Concentrations 330 $aThe Reverse Transcriptase (RT) of Human Immunodeficiency Virus Type 1 (HIV-1) arguably ranks amongst one of the most extensively studied retroviral enzymes. Heterologous expression and purification of HIV-1 RT in the early eighties, approval of the first nucleoside analogue RT inhibitor (NRTI) in 1987, discovery of resistance to RT inhibitors, approval of the first non-nucleoside analogue RT inhibitor (NNRTI) in 1996 and the various crystal structures of RT with and without bound substrate(s) and/or inhibitors represent only a few of the important milestones that describe the a bench-to-bedside success in the continuing effort to combat HIV-1 infection and its consequences. Nucleoside and nonnucleoside RT inhibitors remain important components in frequently used drug regimens to treat the infection. RT inhibitors also play important roles in recently validated strategies to prevent transmission of the virus. The relevance of HIV-1 RT as a drug target has simultaneously triggered interest in basic research studies aimed at providing a more detailed understanding of interactions between proteins, nucleic acids, and small molecule ligands in general terms. In light of the ever-growing knowledge on structure and function of HIV-1 RT, this enzyme serves as a valuable ?model system? in efforts to develop novel experimental tools and to explain biochemical processes. This monograph is designed to provide an overview of important aspects in past and current HIV-1 RT research, with focus on mechanistic aspects and translation of knowledge into drug discovery and development. The first section includes chapters with emphasis placed on the coordination of the RT-associated DNA polymerase and ribonuclease H (RNase H) activities. The second covers mechanisms of action and future perspectives associated with NRTIs and NNRTIs, while the third section includes chapters focusing on novel strategies to target the RT enzyme. Chapters of the final part are intended to discuss mechanisms involved in HIV variability and the development of drug resistance. We hope that these contributions will stimulate interest, and encourage research aimed at the development of novel RT inhibitors. The lack of bona fide RNase H inhibitors with potent antiviral activity provides an example for challenges and opportunities in the field. 606 $aImmunology 606 $aHIV infections$xResearch$xMethodology 615 0$aImmunology. 615 0$aHIV infections$xResearch$xMethodology. 676 $a616.979201 701 $aLeGrice$b Stuart$01760841 701 $aGotte$b Matthias$01760842 801 0$bMiAaPQ 801 1$bMiAaPQ 801 2$bMiAaPQ 906 $aBOOK 912 $a9910739405103321 996 $aHuman immunodeficiency virus reverse transcriptase$94199979 997 $aUNINA