Chapter

The Future of HIV-1 Therapeutics

Volume 389 of the series Current Topics in Microbiology and Immunology pp 93-119

Date:

HIV-1 Integrase Multimerization as a Therapeutic Target

  • Lei FengAffiliated withThe Center for Retrovirus Research and College of Pharmacy, The Ohio State University
  • , Ross C. LarueAffiliated withThe Center for Retrovirus Research and College of Pharmacy, The Ohio State University
  • , Alison SlaughterAffiliated withThe Center for Retrovirus Research and College of Pharmacy, The Ohio State University
  • , Jacques J. KesslAffiliated withThe Center for Retrovirus Research and College of Pharmacy, The Ohio State University
  • , Mamuka KvaratskheliaAffiliated withThe Center for Retrovirus Research and College of Pharmacy, The Ohio State University Email author 

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Abstract

https://static-content.springer.com/image/chp%3A10.1007%2F82_2015_439/MediaObjects/183195_1_En_439_Figa_HTML.gif

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.