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UNIVERSITÉ DE STRASBOURG

UMR CNRS 7021 Laboratoire de Bioimagerie et Pathologies

THÈSE

présentée par :

Rajhans SHARMA

soutenue le : 10th Avril 2018 Discipline/ Spécialité : Sciences du vivant/Biophysique

Caractérisation et ciblage de la

de HIV-1 avec des acides nucléiques

THÈSE dirigée par :

M. MELY Yves Professeur, Université de Strasbourg

RAPPORTEURS :

Mme. MAHUTEAU-BETZER Florence Chargée de recherche, Institut Curie,Paris Mme. GATTO Barbara Associate Professor, University of Padova

AUTRES MEMBRES DU JURY :

M. LEONARD Jérémie Chargé de recherche, Universitié de Strasbourg

UNIVERSITY OF STRASBOURG

UMR CNRS 7021 Laboratory of Bioimaging and Pathologies

THESIS

presented by :

Rajhans SHARMA

Defense on : 10th April, 2018

For obtaining the degree of : Doctorate of University of Strasbourg Discipline/ Specialization : Life sciences/Biophysics

Characterization and targeting the

dynamic recognition of Trp37-G during the interaction of NCp7 protein of HIV-1 with nucleic acids

THESIS directed by :

Mr. MELY Yves Professor, University of Strasbourg

REPORTERS :

Mrs. MAHUTEAU-BETZER Florence Chargée de recherche, Institut Curie, Paris Mrs. GATTO Barbara Associate Professor, University of Padova

OTHER MEMBERS OF JURY :

Mr. LEONARD Jérémie Chargé de recherche, University of Strasbourg

Table of Contents

Acknowledgement

on papuruschoco pain

Brochon

cakes (free food)

List of Abbreviations

A C E G H I K Kd M N P Q R S s T U V Z

1. Bibliographic Review

1.1. Human Immunodeficiency Virus Type 1 (HIV-1)

1.1.1. Overview

1.1.2. Origin Timeline

1.1.3. Classification and Transmission

1.1.4. Structural Organization

1.1.5. Genomic Organization

viral genome gag, pol, env, tat, rev, vprvifvpunef. gag, pol, envtatrev vprvifvpunef

Untranslated Region (UTR)

A. The R region

TAR poly(A)

B. U5 Region

PBS

C. ȥ-site

SL1 e.g. e.g. SL2: SL3

SL4 or AUG:

D. U3 region

PPTPPTC

RRE

1.1.6. Viral Proteins

GagGag

PolGag

Env

A. Structural Proteins

Matrix Protein (MA)Į

Capsid Protein (CA)

Nucleocapsid Protein (NC)

p6:

B. Enzymatic Proteins

Protease (PR):

Reverse Transcriptase (RT):

Integrase (IN):

C. Envelope Proteins

Surface Glycoproteins (SU or gp120):

Transmembrane Protein (TM or gp41):

D. Regulatory Proteins

Trans activator of Transcription (Tat):

Regulator of Virion Expression (Rev):

E. Accessory Proteins

Viral Protein R (Vpr): Į

Viral Infectivity Factor (Vif):

Viral Protein U (Vpu):

Negative Regulatory Factor (Nef):

1.1.7. Replication Cycle of HIV-1

1.1.7.1. Early Phase

binds fusion

Fusion

Reverse transcription

Integration

1.1.7.2. Late Phase

transcription translation assembly

Budding

left

Maturation

1.1.8. Antiretroviral Therapy (ART)

a) Nucleoside/Nucleotide Reverse Transcriptase Inhibitors (NRTIs/NtRTIs) b) NonNucleoside Reverse Transcriptase Inhibitors (NNRTIs) c) Integrase Inhibitors d) Protease Inhibitors e) Entry Inhibitors

Fusion inhibitors

Small CCR5 antagonists

f) Combinational Therapy

1.2. Structure-Function Relationship of Nucleocapsid

Protein

1.2.1. Introduction

1.2.2. Nucleic Acid Chaperoning of NC

1.2.3. Role of NC During HIV-1 Reverse Transcription

A. Initiation

B. Minus strand transfer

C. Plus strand transfer

1.2.4. Role of NC Domain of Gag in Viral Assembly

1.2.4.1. NC Promoted RNA Dimerization

1.2.4.2. NC - SL3 Recognition

1.2.4.3. Gag-Gag oligomerization and trafficking to plasma membrane

1.3. Fluorescence and Nucleic Acids

1.3.1. Introduction to Fluorescence

Franck Condon

fluorescencephosphorescence (kr

Intersystem crossing (kISC)

LGå

Gå krknr #>Oëτ lßë pττττττ:τt;

Intg Intensityx

Intg Intensitystd ßëßÌç×

$NECDPJAOO

Lτs

Gå kr Gå

Hτsτr?=ß6Cà

Cáτ

OôÙ?7

gm gn (4

Lτs

E->3?

Lτs

K k

ì4>3?

k

Resonance energy transfer

kr

GÍ:N;

Lτs

l44 N p

τττττττ:τy;

R0)r D

Aì½

L44: 44:
ESIPT

1.3.2. Introduction to Nucleic Acids

1.3.2.1. Nucleic Acid Structures

anti syn endoendo anti syn synanti anti syn endo endo endo endo endoAnti endoAnti endosyn endoanti

1.3.2.2. Non-canonical structure of nucleic acids

Cruciform

Hairpin

Bubble and Bulges

Bending

Triplex

iMotifs

Guanine quadruplexes

1.3.3. Fluorescence Nucleobase Analogues

external modification

Internal modification

Chromophoric base analogues

Pteridines

Nucleosides containing expanded nucleobases

Nucleosides containing extended nucleobases

Isomorphic Nucleobases

syszvyvzAPT s y vysz sy

1.3.4. Emerging Applications of Fluorescent Nucleobase Analogues

k1k-1 in vitro in vivo in vivo in vivoquotesdbs_dbs23.pdfusesText_29

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