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HIV-1 Integrase Multimerization as a Therapeutic Target

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The Future of HIV-1 Therapeutics

Part of the book series: Current Topics in Microbiology and Immunology ((CT MICROBIOLOGY,volume 389))

Abstract

HIV integration. A tetramer of HIV integrase (B) assembles on viral DNA (A) ends and mediates its integration into host cell chromatin. Cellular protein LEDGF/p75 (C) binds IN tetramer in the nucleoprotein complex and navigates HIV-1 integration in active genes

Multimeric HIV-1 integrase (IN) plays an essential, multifunctional role in virus replication and serves as an important therapeutic target. Structural and biochemical studies have revealed the importance of the ordered interplay between IN molecules for its function. In the presence of viral DNA ends, individual IN subunits assemble into a tetramer and form a stable synaptic complex (SSC), which mediates integration of the reverse transcribed HIV-1 genome into chromatin. Cellular chromatin-associated protein LEDGF/p75 engages the IN tetramer in the SSC and directs HIV-1 integration into active genes. A mechanism to deregulate the productive interplay between IN subunits with small molecule inhibitors has recently received considerable attention. Most notably, allosteric IN inhibitors (ALLINIs) have been shown to bind to the IN dimer interface at the LEDGF/p75 binding pocket, stabilize interacting IN subunits, and promote aberrant, higher order IN multimerization. Consequently, these compounds impair formation of the SSC and associated LEDGF/p75-independent IN catalytic activities as well as inhibit LEDGF/p75 binding to the SSC in vitro. However, in infected cells, ALLINIs more potently impaired correct maturation of virus particles than the integration step. ALLINI treatments induced aberrant, higher order IN multimerization in virions and resulted in eccentric, non-infectious virus particles. These studies have suggested that the correctly ordered IN structure is important for virus particle morphogenesis and highlighted IN multimerization as a plausible therapeutic target for developing new inhibitors to enhance treatment options for HIV-1-infected patients.

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Abbreviations

IN:

Integrase

PIC:

Preintegration complex

SSC:

Stable synaptic complex

NTD:

N-terminal domain

CCD:

Catalytic core domain

CTD:

C-terminal domain

LEDGF:

Lens epithelium-derived growth factor

IBD:

Integrase-binding domain

ALLINI:

Allosteric integrase inhibitors

LEDGIN:

LEDGF-IN Inhibitor

NCINI:

Non-catalytic integrase inhibitor

tBPQAs:

tert-butoxy-(4-phenyl-quinolin-3yl)-acetic acids

INLAIs:

Integrase-LEDGIN allosteric inhibitors

INSTI:

Integrase strand transfer inhibitor

RAL:

Raltegravir

EVG:

Elvitegravir

DTG:

Dolutegravir

RNP:

Ribonucleoprotein complex

2-LTR:

2-long terminal repeat

HTRF:

Homogeneous time-resolved fluorescence

SAXS:

Small-angle X-ray scattering

PFV:

Prototype foamy virus

MVV:

Maedi–visna virus

BSA:

Buried surface area

FRET:

Förster resonance energy transfer

DLS:

Dynamic light scattering

HTS:

High-throughput screening

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Acknowledgments

This work was supported by NIH grants AI062520, AI110310 and GM103368 (to M.K), and AI097044 and AI110270 to J.K.

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Authors and Affiliations

  1. The Center for Retrovirus Research and College of Pharmacy, The Ohio State University, Columbus, OH, 43210, USA

    Lei Feng, Ross C. Larue, Alison Slaughter, Jacques J. Kessl & Mamuka Kvaratskhelia

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  1. Lei Feng
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  2. Ross C. Larue
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  3. Alison Slaughter
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  4. Jacques J. Kessl
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  5. Mamuka Kvaratskhelia
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Correspondence to Mamuka Kvaratskhelia .

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Editors and Affiliations

  1. Departments of Molecular and Experimental Medicine and Immunology and Microbial Science (MEM 131), The Scripps Research Institute, La Jolla, California, USA

    Bruce E. Torbett

  2. Department of Integrative Structural and Computational Biology, and RCSB Protein Data Bank, The Scripps Research Institute, La Jolla, California, USA

    David S. Goodsell

  3. Department of Pathology, University of California, San Diego, La Jolla, California, USA

    Douglas D. Richman

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Feng, L., Larue, R.C., Slaughter, A., Kessl, J.J., Kvaratskhelia, M. (2015). HIV-1 Integrase Multimerization as a Therapeutic Target. In: Torbett, B., Goodsell, D., Richman, D. (eds) The Future of HIV-1 Therapeutics. Current Topics in Microbiology and Immunology, vol 389. Springer, Cham. https://doi.org/10.1007/82_2015_439

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