Abstract
Integrase (IN) is a clinically validated target for the treatment of human immunodeficiency virus infections and raltegravir exhibits remarkable clinical activity. The next most advanced IN inhibitor is elvitegravir. However, mutant viruses lead to treatment failure and mutations within the IN coding sequence appear to confer cross-resistance. The characterization of those mutations is critical for the development of second generation IN inhibitors to overcome resistance. This review focuses on IN resistance based on structural and biochemical data, and on the role of the IN flexible loop i.e., between residues G140-G149 in drug action and resistance.
Highlights
BackgroundDuring replication of the human immunodeficiency virus type 1 (HIV-1, Figure 1), integrase (IN)
During replication of the human immunodeficiency virus type 1 (HIV-1, Figure 1), integrase (IN)plays key roles at various steps of the replicative cycle [1]
prototype foamy virus (PFV) IN differs from HIV-1 IN by the presence of an N-terminal extension domain (NED), which is conserved among the spumaviral and gammaretroviral INs (Figure 3A) [4,33]
Summary
During replication of the human immunodeficiency virus type 1 (HIV-1, Figure 1), integrase (IN). A water molecule is used as the nucleophile to cleave the terminal dinucleotide GT This first transesterification, 3’-processing (3’-P), takes place in the cytoplasm of the infected cell and is catalyzed by at least a dimer of IN [6] within a large nucleoprotein complex, the pre-integration complex (PIC), which includes viral and cellular co-factors in addition to IN and the reversetranscribed viral DNA [7,8]. DNA ends, or concerted integration, occurs with a five base pair stagger on opposite strands of the genomic DNA (Figure 2) [4] This second transesterification, called strand transfer (ST), uses the free 3’-OH extremity of the viral DNA as the nucleophile to attack the target DNA within at least a tetramer of IN [6]. Both 3’-P and ST activities can be reproduced biochemically with recombinant IN and oligonucleotides mimicking the viral LTR [13,14,15]
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
