HIV-1 integrase multimerization as a therapeutic target

Curr Top Microbiol Immunol. 2015;389:93-119. doi: 10.1007/82_2015_439.


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.

Publication types

  • Research Support, N.I.H., Extramural
  • Review

MeSH terms

  • Acquired Immunodeficiency Syndrome / drug therapy*
  • HIV Integrase / chemistry
  • HIV Integrase / physiology*
  • HIV Integrase Inhibitors / therapeutic use*
  • Humans
  • Protein Multimerization / drug effects*
  • Protein Subunits


  • HIV Integrase Inhibitors
  • Protein Subunits
  • HIV Integrase
  • p31 integrase protein, Human immunodeficiency virus 1