Retroviral Integrase Proteins and HIV-1 DNA Integration

Abstract

Retroviral integrases catalyze two reactions, 3-processing of viral DNA ends, followed by integration of the processed ends into chromosomal DNA. X-ray crystal structures of integrase-DNA complexes from prototype foamy virus, a member of the Spumavirus genus of Retroviridae, have revealed the structural basis of integration and how clinically relevant integrase strand transfer inhibitors work. Underscoring the translational potential of targeting virus-host interactions, small molecules that bind at the host factor lens epithelium-derived growth factor/ p75-binding site on HIV-1 integrase promote dimerization and inhibit integrase-viral DNA assembly and catalysis. Here, we review recent advances in our knowledge of HIV-1 DNA integration, as well as future research directions.Retroviral replication proceeds through an obligate proviral or integrated DNA recombination intermediate. Integration provides a favorable environment for efficient gene expression, ensures inheritance of the virus in both daughter cells during mitosis, and forms the basis for latent HIV-1 reservoirs that persist in the face of highly active antiretroviral therapy. The early events of retroviral replication take place within the context of nucleoprotein complexes that are derived from the core of the infecting virus particle (1, 2). Within the confines of the reverse transcription complex (RTC), 2 the reverse transcriptase enzyme copies single-stranded viral RNA into a linear double-stranded DNA molecule containing a copy of the LTR sequence at each end. The viral integrase (IN) engages the LTR ends prior to catalyzing two spatially and temporally distinct chemical reactions. Soon after their synthesis (3), IN site-specifically processes each LTR end adjacent to an invariant CA dinucleotide (4, 5), yielding CA OH 3Ј-hydroxyl groups that serve as the nucleophiles for the second reaction, DNA strand transfer. Because the viral replication intermediate at this point gains the ability to catalyze DNA strand transfer activity, 3Ј-processing operationally marks the transition of the RTC to the pre-integration complex (PIC) (Fig. 1). In the strand transfer step, IN utilizes the 3Ј-oxygen atoms to cut chromosomal DNA in a staggered fashion and simultaneously join the viral DNA ends to the 5Ј-phosphates of the target DNA (4, 6, 7). The resulting DNA recombination intermediate, with unjoined viral DNA 5Ј-ends, is repaired by host cell enzymes to yield the integrated provirus flanked by the duplication of the sequence of the staggered DNA cut (Fig. 1). The spumaviruses, which compose one of seven Retroviridae genera, are an exception to this generalized scheme, as DNA synthesis is largely complete prior to target cell infection (8). Research on the functionality of the active nucleoprotein complexes that mediate HIV-1 DNA integration has led to the development of antiviral inhibitors that target the IN and block integration. IN Domain Structure and Reaction MechanismRetroviral INs belong to a superfamily of proteins known as the retroviral IN superfam...

Anti-HIV-1 integrase compounds from Dioscorea bulbifera and molecular docking study

“…The missing residues in the loop at positions 141-144 were incorporated and the polar hydrogen atoms were added to this chain (Vajragupta et al 2005). The second Mg 2+ was placed in the same relative position according to the two metal structures of the Prototype Foamy Virus IN (PDB code 3OYA), a structural homolog of HIV-1 IN (Krishnan and Engelman 2012).…”

Anti-HIV-1 integrase activity and molecular docking of compounds fromAlbizia procerabark

“…The missing residues in the loop at positions 141-144 were incorporated and polar hydrogen atoms were added to this chain (Vajragupta et al, 2005). The second magnesium ion was placed in the same relative position according to the two metal structures of the Prototype Foamy Virus integrase (PDB code 3OYA), a high structural homolog to HIV-1 IN (Krishnan & Engelman, 2012).…”

Interaction between Reverse Transcriptase and Integrase Is Required for Reverse Transcription during HIV-1 Replication

“…Structural studies of the prototype foamy virus (PFV) intasome found the tetramer to be the active IN configuration (9,11,12). HIV-1 IN has also been proposed to function as a tetramer (10,(13)(14)(15)(16)(17).Mutations in …”