Analyzing the effects of sub‐optimal doses of raltegravir on HIV‐1 integration

Abstract

Integration of the DNA copy of HIV‐1 genome into the host chromosome is required for viral replication and is, for this reason, an important drug target. The HIV‐encoded enzyme integrase (IN) catalyzes two critical steps: 3′ processing of the viral DNA ends, followed by the strand transfer reaction which inserts the viral DNA into host DNA. Raltegravir is the first approved drug that blocks the integration of the viral DNA. Using the Rous Sarcoma Virus (RSV)‐derived vector system RCAS, we previously showed that mutants in which one of the viral DNA ends was not a good substrate for IN were integrated abnormally, leading to rearrangements of the host genome including duplications, inversions and, occasionally, the acquisition of sequences from other chromosomes. Based on these results, we expected that suboptimal concentrations of IN inhibitors, like Raltegravir, which could also block one end of the viral integration reaction, would cause similar aberrant integrations. In contrast to the normal proviruses recovered from untreated cells, all of which were normal, 10–15% proviruses isolated after treatment with a suboptimal dose of Raltegravir were aberrant and these integrations were accompanied by chromosomal defects similar to those seen with the RCAS system. These rearrangements of the host DNA raise concerns for HIV‐1‐infected patients who do not consistently follow their Raltegravir regimen.