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Therapy of Viral Infections pp 183–222Cite as

Targeting Cellular Cofactors in HIV Therapy

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Part of the book series: Topics in Medicinal Chemistry ((TMC,volume 15))

Abstract

Besides viral proteins cellular factors play a key role in the replication of the human immunodeficiency virus HIV-1. The outcome of virus replication is determined by the balance between the activity of a number of cellular dependency factors and restriction factors. Whereas the first are essential cofactors for diverse steps in the viral replication cycle, the latter counteract virus replication by sensing particular viral components as non-self, often as mediators of the innate immune system. Cellular cofactors include receptors for HIV-1 entry, LEDGF as cofactor for the viral integrase, the RNA helicase DDX3 involved in the nuclear export of unspliced viral RNAs, and diverse cellular kinases that promote viral replication. Cellular restriction factors are often antagonized by HIV-1 accessory proteins in order to counteract their restrictive function on viral replication. Although cellular cofactors in the HIV field are understood as factors promoting viral replication, we add a subchapter on the most important restriction factors (Trim5α, APOBEC3G, SAMHD1, and tetherin/BST-2). Today highly active antiretroviral therapy (HAART) mostly targets HIV proteins like reverse transcriptase, protease, or integrase to specifically interfere with virus replication. However, the identification of cellular cofactors and the increasing knowledge on their mode of action at defined steps in the HIV-1 replication cycle have opened new avenues towards the development of HIV-1 inhibitors. Here we summarize the most important cellular factors involved in HIV-1 replication along with therapeutic approaches developed to target them, preferentially without harming their normal cellular function.

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Abbreviations

β-TrCP:

β-transducin repeat containing protein

APOBEC3G:

Apolipoprotein B mRNA editing enzyme 3G

BRD4:

BET bromodomain protein 4

BST-2:

Bone stromal protein 2

CADA:

Cyclotriazadisulfonamide

CCD:

Catalytic core domain

CCR5:

Chemokine receptor 5

CD4:

Cluster of differentiation 4

CD4bs:

CD4 binding site

CD4i:

CD4 induced

CHR:

C-heptad repeat

CRL:

Cullin ring E3 ligases

CRM1:

Chromosome region maintenance 1

CypA:

Cyclophylin A

DCAF:

Ddb1-and Cul4 associated factor

DC-SIGN:

Dendritic cell-specific intercellular adhesion molecule-3-grabbing non-integrin

DDX3:

X-linked DEAD-box polypeptide 3

DFS:

Dense fine speckles

ECL:

Extracellular loop

Env:

Envelope

HAART:

Highly active antiretroviral therapy

HDACI:

Histon deacetylase inhibitors

HDGF:

Hepatoma-derived growth factor

HCV:

Hepatitis C virus

HCK:

Hematopoietic cell kinase

HIV:

Human immunodeficiency virus

HRP:

Hepatoma-derived growth factor-related proteins

IBD:

Integrase binding domain

IFN:

Interferon

IN:

Integrase

JAK1:

Janus kinase 1

LEDGF:

Lens epithelium-derived growth factor

mAb:

Monoclonal antibody

MLL:

Mixed-lineage leukemia

MPER:

Membrane proximal external region

Nef:

Viral protein Nef (originally negative factor)

NES:

Nuclear export signal

NHR:

N-heptad repeat

NLS:

Nuclear localization signal

NV:

Norovirus

PAMP:

Pathogen-associated molecular patterns

PIC:

Preintegration complex

PKC:

Protein kinase C

P-TEFb:

Positive Transcription Elongation Factor b

PSIP1:

PC4- and SFRS-interacting protein

RIG:

RIG-like helicases

RRE:

Rev responsive element

sCD4:

Soluble CD4

SAMHD1:

Sterile alpha motif (SAM) and Histidine/aspartate (HD) residues

SDR:

Supercoiled DNA recognition domain

Talens:

Transcription activator-like effector nucleases

TLR:

Toll-like receptor

TNPO3:

Transportin 3

Trim5 α:

Tripartite motif 5α

Vif:

Viral infectivity factor

VIRIP:

Virus inhibitory peptide

Vpr:

Viral protein R

Vpx:

Viral protein X

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Authors and Affiliations

  1. Georg-Speyer-Haus, Institute for Tumor Biology and Experimental Therapy, Paul-Ehrlich-Str. 42-44, 60596, Frankfurt, Germany

    Ralf Dürr & Ursula Dietrich

  2. Institute of Medical Virology, Goethe University, Frankfurt, Germany

    Oliver Keppler

  3. Laboratory for Molecular Virology and Gene Therapy, K.U. Leuven, Leuven, Belgium

    Frauke Christ

  4. Institute of Molecular Genetics, IGM-CNR, Pavia, Italy

    Emmanuele Crespan, Anna Garbelli & Giovanni Maga

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  1. Ralf Dürr
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  1. Institut für Pharmazeutische Chemie, Philipps-Universität Marburg, Marburg, Germany

    Wibke E. Diederich

  2. -, Bayer Pharma AG, Lead Discovery Berlin - Structural Biology, Berlin, Germany

    Holger Steuber

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Dürr, R. et al. (2014). Targeting Cellular Cofactors in HIV Therapy. In: Diederich, W., Steuber, H. (eds) Therapy of Viral Infections. Topics in Medicinal Chemistry, vol 15. Springer, Berlin, Heidelberg. https://doi.org/10.1007/7355_2014_45

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