HIV-1 Integrase Multimerization as a Therapeutic Target

  • Lei Feng
  • Ross C. Larue
  • Alison Slaughter
  • Jacques J. Kessl
  • Mamuka KvaratskheliaEmail author
Part of the Current Topics in Microbiology and Immunology book series (CT MICROBIOLOGY, volume 389)


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.


Dime Interface Strand Transfer Prototype Foamy Virus Catalytic Core Domain Bury Surface Area 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.





Preintegration complex


Stable synaptic complex


N-terminal domain


Catalytic core domain


C-terminal domain


Lens epithelium-derived growth factor


Integrase-binding domain


Allosteric integrase inhibitors


LEDGF-IN Inhibitor


Non-catalytic integrase inhibitor


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


Integrase-LEDGIN allosteric inhibitors


Integrase strand transfer inhibitor








Ribonucleoprotein complex


2-long terminal repeat


Homogeneous time-resolved fluorescence


Small-angle X-ray scattering


Prototype foamy virus


Maedi–visna virus


Buried surface area


Förster resonance energy transfer


Dynamic light scattering


High-throughput screening



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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Copyright information

© Springer International Publishing Switzerland 2015

Authors and Affiliations

  • Lei Feng
    • 1
  • Ross C. Larue
    • 1
  • Alison Slaughter
    • 1
  • Jacques J. Kessl
    • 1
  • Mamuka Kvaratskhelia
    • 1
    Email author
  1. 1.The Center for Retrovirus Research and College of PharmacyThe Ohio State UniversityColumbusUSA

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